EP3675814A1 - Composition for topical treatment of non-microorganism-caused inflammatory skin and mucous-membrane diseases - Google Patents

Abstract

The invention relates to a composition for topical treatment of non-microorganism-caused inflammatory skin and mucous membrane diseases, such as psoriasis type I and type II, preferably psoriasis vulgaris, psoriasis guttata, psoriasis nummeralis, erythrodermal psoriasis, psoriasis pustulosa; in particular neurodermitis, atopic eczema, atopic dermatitis and pytiriasis capitis, wherein the composition contains at least one lysosomotropic antiapoptotically active substance or a substance combination of at least one lysosomotropic antiapoptotically active substance and at least one antioxidatively active substance. A series of compounds can be used as a lysosomotropic antiapoptotically active substance or a substance combination of at least one lysosomotropic antiapoptotically active substance, in particular those which have, as an essential structural element, a basic, aliphatic and protonatable side chain or ring structure, a pKa value between 6 and 8.5 and an n-octanol-water distribution coefficient log P value > 4.0. These can be, for example, benzodiazapine derivatives, phenoxazine derivatives, or annule derivatives, in particular amitriptyline.

Description

 description

Composition for topical treatment of non-microorganism caused inflammatory skin and mucous membrane diseases

The present invention relates to a composition for topical

Treatment of non-microorganism-induced inflammatory skin and

Mucosal diseases according to the preamble of claim 1. The invention further relates to a use of the composition for the topical treatment of non-microorganism-induced inflammatory skin and

Mucosa diseases according to claim 24.

Background of the invention

Topically applicable preparations are intended to provide the skin, appendages, mucous membranes and internal body surfaces with one or more active ingredients. In the cosmetic / dermatological-pharmaceutical field, suitable bases are a (O / W / W / O) cream or ointment, a gel (hydrogel or oleogel), a fluid (lotion or milk), a paste, an envelope paste or a Suspension). Especially with functionally impaired skin, the local application offers the advantage of targeted,

patient-appropriate and needs-based use of effective compounds, bypassing the systemic side effects and side effects of these compounds.

Psoriasis vulgaris is a common and almost always chronic dermatological disease, the prevalence of which is 1, 5 - 2% in the population of the western industrialized nations and about 80% of which are suffering from psoriasis vulgaris. More than 90% of patients experience a chronic course (Nevitt, GJ et al., Br J Dermatol 1996, 135: 533-7). From patient surveys, it is known that only about a quarter of patients report a high level of satisfaction, a good 50% a middle level and about one fifth a low level of satisfaction with their therapeutic success (Stern, RS et al .; J Investig Dermatol Symp Proc. 2004; 9: 136-9). There is also one high rate of adherence problems with up to 40% drug intake (Richards, HL et al., J Am Acad Dermatol 1999, 41: 581-3).

 Psoriasis is now considered a systemic disease that

Skin symptoms, possible joint involvement and characteristic

Comorbidities includes. Psoriatic arthritis (PsA) is diagnosed in about every fifth patient treated for psoriasis by the dermatologist (Reich, K. et al., Br J Dermatol., 2009; 160: 1040-7). typical

Comorbidities in psoriatic patients are other chronic inflammatory

Diseases such as rheumatoid arthritis (about four times more common), inflammatory bowel disease (about twice as common), lipid metabolism disorders and arterial hypertension (Augustin, M., et al., Acta Derm Venereol, 2010; 90: 147-51). On

common or at least overlapping disease mechanism is therefore to be assumed.

Psoriasis is a complex immunological reaction of the skin with a pronounced inflammatory component and an epidermal hyperproliferation of keratinocytes with disturbed differentiation. After activation of elements of the innate immune system (keratinocytes, dendritic cells), specific T cells are activated which preferentially migrate into the skin. This is due to homing receptors expressed on the surface of inflammatory cells, such as the cutaneous lymphocyte-associated antigen (CLA). Apparently, under the influence of messengers such as IL-12 and IL-23, there is preferential expansion of certain functional T cells. Subpopulations include the so-called Th1 and Th17 cells, which in turn prefer messengers with pro-inflammatory

Secrete properties such as TNFalpha, IL-17 and IL-22. These maintain the psoriatic inflammatory process involving local cells

(Endothelial cells, fibroblasts and keratinocytes), which in turn enhance the cutaneous immune response by expression of adhesion molecules and other mediators. As a consequence of this cascade, a significant immigration becomes more neutrophic

Granulocytes seen in the epidermis can lead to typical sterile microabscesses. An increased proliferative activity and disturbed maturation of keratinocytes is the cause of psoriasis characteristic hyperparakeratosis. In the clinical forms of pustular psoriasis is the cutaneous inflammatory response and immigration of neutrophilic granulocytes is particularly pronounced (Nestle, FO et al; N Eng J Med. 2009; 361: 496-509).

Atopic eczema (or atopic dermatitis) is a common skin disorder that occurs in children and adolescents as well as adults. Atopic dermatitis is a chronic or chronic-relapsing, non-contagious skin disease whose classic morphology and localization

varies depending on age and is usually associated with severe itching. The disease has different degrees of severity, the

Majority of patients suffer from a mild form of atopic dermatitis. However, depending on the location and extent of atopic dermatitis (up to erythroderma), it may be a serious skin disease that significantly and long term reduces the quality of life of the sufferer. More common complications of atopic dermatitis are infections, viral infections or mycoses (Biedermann, T .; Acta Derm-Venereol., 2006; 86: 99-109). In Germany, about 23% of infants and

Infants, 8% of schoolchildren and 2 to 4% of adults in medical

Treatment (Schmitt J, et al., Dermatologist 2009; 60: 320-327); in children it is

Neurodermatitis making it the most common chronic disease ever (Schmitt, J Dtsch Dermatol Ges. 2009; 7: 345-51). Atopic dermatitis manifests itself in about half of the patients in the first six months of life, in 60% of the cases in the first

And more than 70 to 85% of cases before the age of five. Early onset of disease, comorbidity with other diseases of the atopic

Formenkreises, severe disease in childhood and positive

Family history of atopy is predictive of persistence of atopic dermatitis into adulthood (Williams, HC, et al., The natural history of atopic dermatitis.) In: Williams HC: Atopic Dermatitis: The Epidemiology, Causes and Prevention of Atopic Eczema, Cambridge, UK: Cambridge University Press, 2000: 41-59), Rajka G.

Essential aspects of atopic dermatitis. In: Rajka G: Essential aspects of atopic dermatitis. Berlin: Springer publishing house Berlin Heidelberg, 1989).

A significant proportion of patients (50-80%, depending on the study) have IgE-mediated sensitization to aerosol allergens and / or food allergens (sometimes in association with allergic rhinoconjunctivitis, allergic bronchial asthma or a clinically relevant food allergy) (extrinsic) shape atopic dermatitis). This delimits a form in which the clinical picture may be identical but no corresponding sensitization

be detected (so-called intrinsic form, not IgE-associated form). (Tang, T.S., et al., J Allergy Clin Immunol., 2012; 129: 1209-U360).

The importance of activated T cells and of dendritic cells carrying IgE antibodies as well as of phase-dependent polarized cytokine patterns in the skin can be considered as reliable (Werfel, T .; J Invest Dermatol., 2009: 129: 1878-1891). Furthermore, allergen-specific immune responses play an important role. Not only aerosol and food allergens (Heratizadeh, A. et al., Current Allergy and Asthma Reports 201 1; 1 1: 284-291) but also microbial factors and allergens

(Crameri, R. et al., Allergy. 2014; 69: 176-85), and possibly also responses to endogenous proteins (Tang, TS, et al., J Allergy Clin Immunol., 2012; 129: 1209-U360), seem to be the disease and influence the course.

 The appearance of atopic dermatitis differs depending on the stage (acute or chronic) and age. In early childhood (0 - 2 years) are usually eczema in the area of the face, capillium and extensor prevailing, later often find flexion eczema, and in adults depending on skin-stressing activities also hand eczema or the so-called prurigo form with highly itchy nodules and nodules. Minimal variants of atopic dermatitis may manifest as cheilitis, perineche, earlobe ragances, mummy encephalitis, pulpitis sicca on the hands and feet (scaly redness and tears in the area of the finger and / or toe tips). The course of atopic dermatitis is variable with episodes of various duration and severity. The disease can recur frequently.

 A defective barrier function of the skin is a central element of the disease. Skin dryness is very common in atopic dermatitis and contributes to

Barrier defect of the skin in the disease. Skin dryness alone can cause

Inflammation (known, for example, in older people without atopic dermatitis as "eczema craquelee") There are a number of biochemical findings that suggest that in patients with atopic dermatitis there is an abnormal composition of skin lipids, including the inflammation in the skin, which is phase-dependent an interaction inter alia between keratinocytes, dendritic cells, cutaneous mast cells and T cells with corresponding proinflammatory cytokines underlying, leads secondary to a reduction of the barrier function (Werfel, T .; J Invest Dermatol., 2009: 129: 1878-1891).

Although the manifestations of psoriasis and atopic dermatitis are very different, at the level of the inflammatory mediators, which are the

Induce and maintain skin changes, find common ground.

Affected are the keratinocytes, which in both cases are not able to form a normal skin. In the inflammatory process, common findings on the cellular and messenger substance levels are to be found according to current findings. Atopic dermatitis begins with an acute phase initiated by excessive Th2, Th22 and Th17 cell activation. The transition to the chronic phase is marked by the onset of Th1 cell activation in addition to the Th2 and Th22 cells. Th17 T cells are now considered to be the main driver of the disease in psoriasis. The levels of interleukins IL-17A, IL-17C and IL-17F secreted by them are elevated in the psoriatic skin compared to normal skin. Interleukin-17 ligands activate IL-17 receptors on keratinocytes and

Immune cells and work in synergy with Th1 and Th22 cytokines to induce the clinical features of psoriasis (Guttman-Yassky, E. et al., Exp Dermatol. 2017; Mar. 7, doi: 10.1 1 1 1 / exd.13336 ). Thus, it is not surprising that the anti-IL-12 / IL-23 antibody ustekinumab leads to an improvement in the appearance of the skin both to improve psoriasiform and eczematous skin changes. The IL17A antibody ixekizumab is expected to have a comparable improvement effect. An innovative topical therapy for both skin diseases must therefore target the common inflammatory mediators.

State of the art

Psoriasis. The state of the art (therapeutic options) is mainly defined in the guidelines given in the S3 guideline for the treatment of psoriasis vulgaris (Nast, A. et al., AWMF online 201 1, AWMF Registry No. 013/001; 199, continued in AWMF online 2017, AWMF Register No. 013/001, l_S3, 1-156). When

Basic therapy of psoriasis vulgaris is the topical application of drug-free ointment bases as well as topical preparations of urea (3 - 10%) and

Salicylic acid (3 - 10%). The drug therapies are divided into topical and systemic therapies. Topical therapy includes calcineurin inhibitors (pimecrolism, tacrolism), dithranol, glucocorticoids (hydrocortisone, bethamethasone dipropionate, mometasone, clobetasol), coal tar, tazarotene and vitamin D3 and analogues (calcipot ol, tacalcitol). In systemic therapy

(described, inter alia, in US201,100,22918 (A1)), the antibodies find adalimumab (binding of soluble and membrane-bound TNFalpha; US201,100,22918 (A1)), etanercept (binds as a soluble receptor free but not membrane-bound TNFalpha;

US201 1 171227 (A1)), infliximab (specific binding to both soluble and transmembranous and receptor bound TNFalpha; JP2015013869 (A)).

Ustekinumab (binding of the p40 subunit of IL23 and IL12, US201,100,22918 (A1)), secukinumab, ixekizumab (binding of IL17A; TN2013000145 (A1)) and

Low molecular weight compounds such as ciclosporin, fumaric acid esters, methotrexate, retinoids (isotretionin, etretinate, acitretin) application. There are also

various topical treatment options with black seed (Nigelia sativa), olive oil, cocoa butter or vitamin A / B12 are described, for example in US2017189466 (A1)).

 Neurodermatitis. The state of the art (therapy options) is defined primarily in the guidelines for the treatment of psoriasis vulgaris (Heratizadeh, A. et al., AWMF online 2015, AWMF Reg. No. 013/027; 127)

Active ingredients and forms of therapy. The basic therapy of atopic dermatitis is the topical application of drug-free ointment bases with occlusion effect

Water loss from outer layers of the skin prevented (for example, by white paraffin), as well as improving the binding of water in the skin,

for example by urea or by addition of additional water to the dry outer layers of the skin, for example by hydrophilic creams. It uses fatty ointment bases for dry skin or hydrating oil-in-water emulsions on less dry skin. The drug therapies are divided into topical and systemic therapies. Topical therapy includes Calcineu n inhibitors (pimecrolism, tacrolism), glucocorticoids (hydrocortisone, bethamethasone valerate, fluticasone propionate, clobetasol propionate,

Triamcinolone actonide), shale oils and coal tar. In systemic therapy of atopic dermatitis, antibodies have so far been used only sporadically (sometimes in off-label use). Omalizumab (anti-IgE, (MX2007009436 (A)) tocilizumab (anti-IL-6 receptor antagonist (US2017121412 (A1)), dupilumab (IL-4 / IL-13 receptor antagonist), ustekinumab (binding of p40 Subunit of IL23 and IL12; US201 1002918 (A1)) and low molecular weight compounds such as azathioprine, cyclosporin, mycophenolate mofetil, methotrexate, retinoids (alitretinoin) application. IL25

(PH12017500403 (A1) and IL31 (US2017044253 (A1)) Although antibodies have been patented for the indication of atopic dermatitis, only nemolizumab (IL31) has made it almost to market maturity.

Document EP 2 727 473 A2 relates to a combination of effective substances which may have synergistic effects in a variety of diseases (multiple targeting). The goal is pain relief and the prevention of

Histamine receptor-mediated itching and the treatment of atopic

Called dermatitis.

As effective compounds, at least two compounds selected from a 5-hydroxytryptamine subtype 2 (5-HT2) receptor antagonist; a P2X receptor antagonist and any glycine receptor agon, a glycine transporter (GlyT) antagonist, a gamma-aminobutyric acid (GABA) receptor agon, and a GABA transporter 1 (GATI) antagonist.

Document EP 2 727 473 A2 also explicitly mentions amitriptyline in Example 1 for the suppression of neuropathic pain in the rat model. A

However, comprehensible teaching for the treatment of atopic dermatitis / psoriasis is not disclosed.

Furthermore, WO 2004/080 468 A1 discloses pharmaceutical preparations containing a multiplicity of basic active substances with improved bioavailability over or through the skin.

Document WO 2006/018 088 A1 relates to the use of PDE5 inhibitors in pigment disorders, e.g. Vitiligo. Examples of compounds which are mentioned are sildenafil and tadalafil. Chloroquine is mentioned as an accompaniment

Document WO 2007/103 687 A2 discloses compositions and a

Method of treating tar-responsive dermatological disorders, including psoriasis, eczema, atopic dermatitis, seborrheic dermatitis, tinea versicolor, vitiligo, pruritus, yeast and dermatophyte infections.

This document further describes synergistic effects for cosmetic, topical and pharmaceutical applications. For this purpose, according to document WO 2007/103 687 A2 25, a large list of active ingredients is always used in combination with tar. This list includes an alphabetical listing of all possible (approved) drugs of the pharmacopoeia, but without any traceable evidence.

In addition, WO 201 1/075 654 A1 discloses a method and

Compositions for the treatment of dermatitis, which are preferably based on viral and bacterial infections.

According to the teaching of WO 201 1/075 654 A1 is a

Composition of several active ingredient components, which may also contain, for example, amitriptyline in combination with an antioxidant, in particular linoleic acid, the quantitative composition preferably dosages of 1% to 10% (w / w) for the therapeutic agent and 0.1% to 0.5% (w / w ) for the antioxidant.

Finally, document W 02016/141 219 A1 discloses strontium-based compositions and formulations for pain, itching and inflammation, i.a. atopic dermatitis, along with a favoring one

Component selected from: amitriptyline, paroxetine, doxepin, hydroxyzine, mirtazapine, and the like. a. including chlorpromazine, polyhydroxyphenol and antihistamines. All compositions disclosed there necessarily contain strontium.

Object of the present invention

The previously known therapeutic options are usually accompanied by more or less strong adverse drug reactions, which reduce the compliancy or adherence of the patient on the one hand, and on the other hand also the risk of infection (especially in the case of antibody treatment) or, as in the case of glucocorticoids, cause skin changes and are therefore subject to an application period. A way out is here an interval therapy. Tacrolism can cause and increase skin infections with bacteria (folliculitis) or viruses (HPV-induced diseases such as Verrucae vulgares or herpes simplex infections)

Photosensitivity of the skin. Dithranol is difficult to dose. An overdose leads to skin damage (blistering, necrosis). For a treatment with

Ciclosporin and the possible lack of vaccine success or because of possible complications, vaccinations with live vaccines are not recommended. In glucocorticoids skin atrophy is at the forefront; in the Intertrigenes (armpit, last) there is also the risk of

Superinfections and in the face the triggering of rosacea and steroid acne. Leukocytopenia, lymphocytopenia and eosinophilia are frequently observed under fumaric acid ester therapy. Especially in the first weeks after

Treatment starts in up to 60% of patients with gastrointestinal complaints and flushing symptoms. In retinoids, irreversible hyperostoses, the cheilitis (occurring in nearly 100% of the treated patients) and the long-lasting ones

Teratogenicity problems; Metothrexate is problematic for hepatotoxicity. The systemic application of anti-TNFalpha antibodies in particular

Immune system. In adalimumab infections occur more frequently, reactions at the injection site (rash, urticaria, itching). The risk of serious infections including sepsis, in rare cases fatal, is increased under anti-TNFalpha therapy. With infliximab, acute infusion reactions are common. These are usually mild and associated with shivering, headache, flushing, nausea, dyspnea or infiltration at the infusion site. In patients with infliximab

specific antibodies, the likelihood of an infusion reaction is higher. But also anaphylactoid reactions independent of the presence of infliximab-specific antibodies are possible.

Starting from the cited prior art, it is the object of the present invention, the inflammatory events in non-microorganism caused inflammatory skin and mucosal disorders such as particular diseases that accompany dandruff, such as psoriasis, eczema and Pytiriasis capitis interrupt. Solution of the task

The solution of this object is achieved by a composition according to claim 1 and by a use according to claim 24.

According to the invention, for example, the epidermal hyperproliferation and in particular the disturbed differentiation of keratinocytes in psoriasis is to be eliminated or at least greatly alleviated. Furthermore, eczema lesions should be at least largely eliminated.

The above object is achieved by a composition for the topical treatment of non-microorganism-induced inflammatory skin and skin

Mucosal diseases according to claim 1, wherein they have at least one

Lysosomotropic, antiapoptotically active substance, a substance combination of at least one antioxidant substance and at least one

lysosomotropic, antiapoptotically active substance, a substance combination of at least one substance acting as a reactive carbonyl species catcher and at least one lysosomotropic, antiapoptotically active substance or a substance combination of at least one antioxidant substance and at least one substance acting as a reactive carbonyl licking captive and at least one lysosomotropic substance, contains anti-apoptotic substance.

The object is further achieved by a use according to claim 24.

The subclaims represent preferred embodiments of the present invention.

Ideally, the ultimate goal of therapy for pathologically altered skin is to restore normal skin function and normal

Skin appearance. The application of the composition according to the invention in the form of an active ingredient-containing pharmaceutical preparation should be topical or local, in order to apply the active substance or substances directly to the site of the inflammation. A burden of strong adverse drug reactions, such as the systemic antibodies or the fumaric acid ester treatment can be avoided. The active substance (s) must not alter the skin structure negatively compared to the corticoids. Its essential feature is the modulation of the cytokines and inteheukins involved in the disease. In contrast to the antibodies, it does not bind the already formed cytokine or interleukin, but rather its

Disruption or genesis (transcription at the gene level or maturation) prevented and thus interrupted the self-sustaining inflammatory process. Consequently, the formation of TNFalpha, IL17A, IL23, IL12 by the drug (s) should be prevented. Ideally, others will be on

Inflammation events involved actively influenced messenger substances.

The present invention relates to an injectable and topically applicable

A preparation for use in psoriasis, atopic dermatitis and other diseases of the inflammatory non-microorganism-caused form.

The preparation described is characterized in that it contains one or more compounds which are lysosomotropic and antiapoptotically active. The therapeutic effect of the preparation is enhanced by antioxidant compounds, which are in particular also V-ATPase-protective, and / or reactive carbonyl spiezies (RCS) -catching compounds. RCS scavengers protect the cells from excessive GSH depletion and the V-ATPase immediately before electrophilic attack of the RCS on the cysteines in the catalytically active ATPase unit V1. The V-ATPase-protective effect is achieved by the antioxidant ingredients of the base, by incorporated antioxidant, monounsaturated or polyunsaturated compounds or by intramolecular antioxidant functional groups. The protection against cleavage of mono- or polyunsaturated compounds or aldolases resulting reactive RCS, in particular aldehydes, is achieved by the RCS-catching ingredients of the base, by incorporated compounds containing one or more primary aliphatic amines as a functional group. The protection from developing RCS is also achieved by secondary aliphatic amines as ingredients of the base and by incorporated compounds containing one or more secondary aliphatic amines as a functional group. Overall, the combination of lysosomotropic and V-ATPase-protective properties leads to an increase in the lysosomotropic modulating effect

Compounds on the expression of the disease characterizing cytokines and chemokines and thus a more effective, faster and better restoration of a normal skin appearance.

The clinical picture of psoriasis is characterized by an epidermal hyperproliferation with disturbed differentiation of keratinocytes (basal cells). The

Cornification at the affected sites occurs both accelerated (the skin layer renews prematurely within only three to seven days) as well as increased (hyperkeratotic) and loss of the stratum granulosum. It is disturbed in its structure and function (parakeratotic). The differentiation of the cells is no longer complete. Due to the constant new formation of the basal cells in the lowest layer of the epidermis, the cells above it are continuously pushed upwards, where they slowly dry out, chalk up and form the uppermost horny layer of the skin.

The dermatitis skin shows erythematous patches that are not well defined and are often sore and associated with severe pruritus (itching). Again, differentiation of the cells is no longer complete. The dry and brittle skin in the initial stage of atopic dermatitis is an indication of this.

The regulatory element for controlling the cell population, the formation of organs and histological structures (here the skin) is apoptosis - the controlled cell death (Huppertz, B. et al., Anat. Embryol., 1999; 200: 1-18). Disruptions in the process of this highly specific tool in the keratinocytes is an explanation that a complete differentiation does not take place. The human skin mainly contains ceramides in the "cement substance" between the dead horny cells of the stratum corneum. Ceramides are firmly anchored in the bilayers of the horny layer, where they together with other skin constituents form the most important natural barrier and counteract the drying out of the skin (Lautenschläger, H, Kosmetik International 1999, 1: 124-126). ceramides,

in particular, the C16-ceramide, whose content increases strongly in apoptotic cells, play a crucial role in apoptosis (Thomas, RL et al., J. Biol. Chem. 1999; 274: 30580-30588). In contrast, longer-chain ceramides (> C20) are not apoptotically active and are therefore responsible for the formation of the barrier function. High levels of the chemotactically effective cytokines IL16, eotaxin, "macrophage-derived-chemokines" (MDC), "thymus and activation regulated chemokines" (TARC), "regulated on activation, normal T-cell expressed and secreted" CCL5) as well as the soluble CD30 in the blood detectable "(Altmeyer, P., The Online

Encyclopedia of Dermatology, Venereology, Allergology and Environmental Medicine; L20.9; retrieved in July 2017). CCL5 is a chemokine that can induce apoptosis via its CCR5 receptor (Murooka, T. et al., J. Biol. Chem. 2006; 281: 25184-25194). The modulation of apoptosis in keratinocytes is therefore a therapeutic one

Starting point to restore the natural barrier function of the skin.

 Only fully differentiated keratinocytes can fulfill their task, but not those that have not achieved the important for their function habitus and ceramide content by premature apoptosis. The same applies to the formation of a resilient cell dressing, which represents the barrier function against moisture loss. In the course of differentiation, the ceramide content increases from 3.8 ± 0.2 (stratum basale / spinosum) over 8.8 ± 0.2 (stratum granulosum) to 18.1 ± 0.4% (stratum corneum) ( Elias, PM; Curr Probl Dermatol 1989; 18: 10-21). From this, the aim of the preparation according to the invention for both diseases is derived: stabilization of normal cell vitality and prevention of premature apoptosis.

In the previous apoptosis models, the induction of ceramide deNovo synthesis, the proteolytic degradation of aSMase (acid sphingomyelinase) and aCERase (acid ceramidase) in lysosomes is the cause of the C16 ceramide

Increase within the total ceramide increase (Elojeimy, S. et al., FEBS Lett., 2006; 580: 4751-4756; Hurwitz, R. et al., Biol Chem., Hoppe-Seyler, 1994; 375: 447-450 ). The selective formation of C16-ceramide can not be explained with this model due to the lack of selectivity of the involved ceramide synthase (CerS). C16-ceramide synthesis does not take place, but mainly a synthesis of the non-apoptotic C24: 1 ceramide (Laviad E.L., et al., J Biol Chem. 2008; 283: 5677-5684).

A paradigm shift to the lysosome as the origin of the measured C16 ceramide opens up new possibilities for explaining the development of psoriasis as well as its topical treatment. The new model (See Figures 1A and 1B) in short form as follows: The cause of the C16 ceramide increase is a change in sphingolipid metabolism in the lysosome and not the induction of deNovo ceramide synthesis. In the intact lysosome

hydrolyzes the acid ceramidase ceramide to sphingosine. By a simple

Increasing the pH in the lysosome may activate the reverse ceramide synthesis activity of aCERase. Without energy / ATP consumption, long-chain fatty acids and sphingosine can be used to synthesize long-chain ceramides (C16 ceramide in the presence of palmitic acid) (Okino, N. et al., J. Biol. Chem. 2003; 278: 29948-53). Through this mechanism, selective blocking of V-ATPase by bafilomycin A1 or archazolide and the associated increase in lysosomal pH result in apoptosis (Schwarzenberg, K. et al., J. Biol. Chem. 2013; 288: 1385-96 ).

As lysosomotropic, anti-apoptotic substances can

According to the invention, those are used which are selected from the group consisting of: lysosomotropic, antiapoptotically active substances which have as their essential structural element a basic, aliphatic and protonatable side chain or ring structure, a pK _a value between 6 and 8.5, and an n-octanol -Water distribution coefficient log P value> 4.0.

The side chain is, for example, an n-aliphatic chain with 3

 Carbon atoms into consideration. Depending on the requirements of the molecular structure and longer chains, z. B. can be used with 3 to 10 carbon atoms.

In the context of the present invention, in addition to the IUPAC indication of the name of a chemical compound, the term "NB" is used in part together with a number, for example "NB 01". This is an internal name of the inventors, which merely serves to simplify the logging of the experiments carried out and facilitates the orientation in the list of the investigated chemical compounds. In case of doubt, the lUPAC name is authoritative.

Specific chemical compounds that can be used for the purposes of the present invention are those wherein the at least one

lysosomotropic antiapoptotically active substance is selected from the group consisting of: 3- (5,6-dihydrobenzo [b] [1] benzazepine-1 1 -yl) propan-1-amine, In particular, 3- (5,6-dihydrobenzo [b] [1] benzazepine-1 1 -yl) -N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-propan-1-mannin (NB 01), 3- (5,6-dihydrobenzo [b] [1] benzazepine-1 1 -yl) -N- [2- (4-methoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 02 ), Imipramine (3- (5,6-dihydrobenzo [b] [1] benzazepine-1 1 -yl) -N, N-dimethyl-propane-1-amine), desipramine (3- (5,6-dihydrobenzo) b] [1] benzazepine-1 1 -yl) -N-methyl-propan-1-amine), trimipramine (3- (5,6-dihydrobenzo [b] [1] benzazepin-1 1-yl) -N, N, 2-trimethylpropan-1-amine); 2- (5,6-dihydrobenzo [b] [1] benzazepine-1 1 -yl) ethanamines, especially N- [2- (5,6-dihydrobenzo [b] [1] benzazepin-1 1-yl) ethyl] -2- (3,4-dimethoxyphenyl) -N-methyl-ethanamine (NB 15), N- [2- (5,6-dihydrobenzo [b] [1] benzazepin-1 1 -yl) ethyl] -2- (4-methoxyphenyl) -N-methyl-ethanamine (NB 16); 3-phenothiazin-10-yl-propan-1-amines, especially 3- (2-chlorophenothiazin-10-yl) -N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-propan-1-amine ( NB 03), 2- (4-methoxyphenyl) -N-methyl-N- (2-phenothiazin-10-ylethyl) ethanamine (NB 08), N- [2- (3,4-dimethoxyphenyl) ethyl] -N- methyl 3-phenothiazin-10-yl-propan-1-amine (NB 40), N- [2- (4-methoxyphenyl) ethyl] -N-methyl-3-phenothiazin-10-yl-propan-1-amine (NB 39),

Chlorpromazine (3- (2-chlorophenothiazin-10-yl) -N, N-dimethyl-propan-1-amine),

Levomepromazine (2R) -3- (2-methoxyphenothiazin-10-yl) -N, N, 2-trimethylpropan-1-amine Promazine (N, N-dimethyl-3- (10H-phenothiazin-10-yl) propane-1 -amine), promethazine (N, N-dimethyl-1-phenothiazin-10-yl-propan-2-amine), thioridazine (10- [2- (1-methylpiperidin-2-yl) ethyl] -2-methylsulfanylphenothiazine), triflupromazine (N, N-dimethyl-3- [2- (trifluoromethyl) -phenothiazin-10-yl] -propane-1-amine); 3-phenoxazin-10-yl-propan-1-amines, in particular N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-3-phenoxazin-10-yl-propan-1-amine (NB 37), N- [2- (4-methoxyphenyl) ethyl] -N-methyl-3-phenoxazin-10-yl-propan-1-amine (NB 20), 10- [3 - [(3S, 5R) -4- 2- (4-methoxyphenyl) ethyl] -3,5-dimethylpiperazin-1-yl] propyl] phenoxazine (NB 36); 3- (5,6-dihydrodibenzo [1,2-a: 2 ', 1'-d] [7] annulen-1 1 -ylidene) -propane-1-amines, especially 3- (5,6-dihydrodibenzo [2 , 1 -b: 1 ', 2'-e] [7] annulen-1 1 -ylidene) -N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 38), 3- (5,6-dihydrodibenzo [2,1-b: 1 ', 2'-e] [7] annulene-1 1-ylidenes) -N- [2- (4-methoxyphenyl) ethyl] - N-methyl-propan-1-amine (NB 31), nortriptyline (3- (5,6-dihydrodibenzo [2,1 -b: 2 ', 1' -f] [7] annulene-1 1-ylidenes) - N-methylpropan-1-amine, amitriptyline (3- (5,6-dihydrodibenzo [2,1-b: 2 ', 1' - f] [7] annulen-1 1 -ylidene) -N, N-dimethylpropane 1 -amin); 1 - (6,1 1 -dihydro-5H-dibenzo [1,2-a: 2 ', 1'-d] [7] annulene-1 1-yl) hexahydropyrimidines, especially 1- (6 , 1 1 -dihydro-5H-dibenzo [2,1 -b: 1 ', 2'-e] [7] annulen-1 1 -yl) -3- [2- (3,4-dimethoxyphenyl) ethyl] hexahydropyrimidine (NB 47), 1 - (6.1 l -dihydro-5H-dibenzo [2.1 -b: 1 ', 2'-e] [7] annulen-1 l -yl) -3- [2- (4-methoxyphenyl) ethyl] hexahydropyrinnidine (NB 24); N '- (6,1 1 -dihydro-5H-dibenzo [1, 2-a: 2', 1'-d] [7] annulen-1 1 -yl) propane-1,3-diamines, in particular N ' - (6,1 1 -dihydro-5H-dibenzo [1,2-a: 2 ', 1'-d] [7] annulene-1 1 -yl) -N- [2- (3,4-dimethoxyphenyl) ethyl] propane-1,3-diamine (NB 41), N '- (6,1 1 -dihydro-5H-dibenzo [1,2-a: 2', 1'-d] [7] annulen-1 1 -yl) -N- [2- (4-methoxyphenyl) ethyl] propane-1,3-diamine (NB 46); 3- (1,1,1,2-dihydro-6H-benzo [c] [1] benzazocin-5-yl) propan-1-amino, especially 3- (1,1-dihydro-6H-benzo [c] [1 ] benzazocin-5-yl) - N - [2- (4-methoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 21); 2,3,3a, 4,5,6-hexahydro-1H-pyrazino [3,2,1-jk] carbazoles, especially 3- [2- (4-methoxyphenyl) -ethyl] -2,3, 3a, 4,5,6-hexahydro-1H-pyrazino [3,2,1-jk] carbazole (NB 43); 1, 2,3,3a, 4,5,6,7-octahydro- [1,4] diazepino [3,2,1-jk] carbazole, 4- [2- (4-methoxy-phenyl) -ethyl] -1, 2,3,3a, 4,5,6,7-octahydro- [1,4] diazepino [3,2,1-jk] carbazole (NB 44); (3-aminopropyl) -1, 4-benzoxazin-3-ones, especially 4- [3- [2- (4-methoxyphenyl) ethyl-methyl-anilino] -propyl] -1, 4-benzoxazin-3-one ( NB 48); N '- (1-naphthyl) ethane-1,2-diamines, in particular N- [2- (3,4-dimethoxyphenyl) ethyl] -N' - (1-naphthyl) ethane-1,2-diamine (NB 10 ); 1 -naphthylmethananninen, in particular 2- (3,4-dimethoxyphenyl) -N- (1-naphthylmethyl) ethanannine (NB 12); , 3-carbazol-9-yl-propan-1-amines, in particular 3-carbazol-9-yl-N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 05), 3-carbazol-9-yl-N - [(4-methoxyphenyl) methyl] -N-methyl-propan-1-amine (NB 30), 9- [3- [(3S, 5R) -4- [2- (3,4-dimethoxyphenyl) ethyl] -3,5-dimethyl-piperazine-1-yl] propyl] carbazole (NB 42), 3-carbazol-9-yl-N- [2- (4-methoxyphenyl) ethyl] N-methyl-propan-1-amine (NB 06), 9- [3 - [(3S, 5R) -4- [2- (4-methoxyphenyl) ethyl] -3,5-dimethyl-piperazine-1 - yl] propyl] carbazole (NB 19), 3-carbazol-9-yl-N- [2- [4- [2- [3-carbazol-9-yl-propyl (methyl) -amino] -ethyl] -2,5 -dimethoxyphenyl] ethyl] -N-methyl-propan-1-amine (NB 45); 2-carbazol-9-ylethaneamines, especially N- (2-carbazol-9-yl-ethyl) -2- (4-methoxyphenyl) -N-methyl-ethanamine (NB 25), 9 - [[4- [2- (4 - methoxyphenyl) ethyl] piperazin-1-yl] methyl] carbazole (NB 18); 7-chloroquinoline-4-amines, especially chloroquine (4-N- (7-chloroquinolin-4-yl) -1-N, 1-N-diethylpentane-1, 4-diamine); their pharmaceutically acceptable salts; and mixtures thereof.

Of these disclosed chemical compounds, the following are preferred because they have shown promising results in in vitro displacement assays (displacement of lysosomal-labeling fluorescent dyes from lysosomes) as a measure of the severity of lysosomotropy and in animal experiments: In particular, those substances, wherein the at least one lysosomotropic, antiapoptotically active substance is selected from the group consisting of: 3- (5,6-dihydrobenzo [b] [1] benzazepin-1 1 -yl) propan-1-amines, 3 (5,6-dihydrobenzo [b] [1] benzazepine-1 1 -yl) -N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 01); Imipramine (3- (5,6-dihydrobenzo [b] [1] benzazepine-1 1 -yl) -N, N-dimethyl-propane-1-amine), desipramine (3- (5,6-dihydrobenzo [b] [1] benzazepine-1 1 -yl) -N-methyl-propane-1-amine); N- [2- (5,6-dihydrobenzo [b] [1] benzazepine-1 1 -yl) ethyl] -2- (3,4-dimethoxyphenyl) -N-methyl-ethanamine (NB 15); 3-phenothiazin-10-yl-propan-1-amines, 3- (2-chlorophenothiazin-10-yl) -N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 03); Chlorpromazine (3- (2-chlorophenothiazin-10-yl) -N, N-dimethyl-propan-1-amine), levomepromazine (2R) -3- (2-methoxyphenothiazin-10-yl) -N, N, 2 trimethylpropane-1-amine promazine (N, N-dimethyl-3- (10H-phenothiazin-10-yl) propan-1-amine), promethazine (N, N-dimethyl-1-phenothiazin-10-yl-propan-2-amine ), Triflupromazine (N, N-dimethyl-3- [2- (trifluoromethyl) -phenothiazine-1-yl] -propane-1-amine); 3-phenoxazin-10-yl-propan-1-amine, N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-3-phenoxazin-10-yl-propan-1-amine (NB 37); 3- (5,6-dihydrodibenzo [1,2-a: 2 ', 1'-d] [7] annulen-1 1 -ylidene) propan-1-amine, 3- (5,6-dihydrodibenzo [2, 1 -b: 1 ', 2'-e] [7] annulen-1 1 -ylidene) -N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 38 ); Nortriptyline (3- (5,6-dihydrodibenzo [2,1 -b: 2 ', 1' - f] [7] annulen-1 1 -ylidene) -N-methylpropan-1-amine, amitriptyline (3- (5 6-dihydrodibenzo [2,1 -b: 2 ', 1' -f] [7] annulen-1 1 -ylidene) -N, N-dimethylpropan-1-amine);

in particular 1 - (6,1 1 -dihydro-5H-dibenzo [1,2-a: 2 ', 1' -d] [7] annulene-1 1-yl) hexahydropyrimidines, 1- (6,1 1 -dihydro -5H-dibenzo [2,1 -b: 1 ', 2'-e] [7] annulene-1 1 -yl) -3- [2- (3,4-dimethoxyphenyl) ethyl] hexahydropyrimidine (NB 47), 1 - (6,1 1 -dihydro-5H-dibenzo [2,1 -b: 1 ', 2'-e] [7] annulen-1 1 -yl) -3- [2- (4-methoxyphenyl) ethyl ] hexahydropyrimidine (NB 24); N '- (6,1 1 -dihydro-5H-dibenzo [1,2-a: 2', 1'-d] [7] annulene-1 1 -yl) propane-1,3-diamine, N'- (6,1 1 -dihydro-5H-dibenzo [1,2-a: 2 ', 1'-d] [7] annulene-1 1 -yl) -N- [2- (3,4-dimethoxyphenyl) -ethyl ] propane-1,3-diamine (NB 41); 3- (1,1-Dihydro-6H-benzo [c] [1] benzazocin-5-yl) - N - [2- (4-methoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 21); 2,3,3a, 4,5,6-hexahydro-1H-pyrazino [3,2,1-jk] carbazole, 3- [2- (4-methoxy-phenyl) -ethyl] -2,3,3a , 4,5,6-hexahydro-1H-pyrazino [3,2,1-jk] carbazole (NB 43); 1, 2,3,3a, 4,5,6,7-octahydro- [1,4] diazepino [3,2,1-jk] carbazole, 4- [2- (4-methoxy-phenyl) -ethyl] - 1, 2,3,3a, 4,5,6,7-octahydro- [1,4] diazepino [3,2,1-jk] carbazole (NB 44); in particular 4- (3-aminopropyl) -1, 4-benzoxazin-3-one, 4- [3- [2- (4-methoxyphenyl) ethylmethyl] amino] propyl] -1,4-benzoxazin-3-one (NB 48); in particular N '- (1-naphthyl) ethane-1, 2-diamine, N- [2- (3,4-dimethoxyphenyl) ethyl] -N' - (1-naphthyl) ethane-1,2-diamine (NB 10 ); 1-naphthylmethanamine, 2- (3,4-dimethoxyphenyl) -N- (1-naphthylmethyl) ethanannine (NB 12); 3-carbazol-9-yl-propan-1-amines, 3-carbazol-9-yl-N- [2- (3,4-dimethoxyphenyl) -ethyl] -N-methyl-propan-1-mannin (NB 05); 3-carbazol-9-yl-N- [2- (4-methoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 06); 2-carbazol-9-ylethaneamines, N- (2-carbazol-9-yl-ethyl) -2- (4-methoxyphenyl) -N-methyl-ethanamine (NB 25), 9 - [[4- [2- (4- methoxyphenyl) ethyl] piperazin-1-yl] ethyl] carbazole (NB 18); Chloroquine (4-N- (7-chloroquinolin-4-yl) -1-N, 1-N-diethylpentane-1, 4-diamine); their pharmaceutically acceptable salts; and mixtures thereof.

Furthermore, in the context of the present invention, preference is given to those lysosomotropic, antiapoptotically active substances which are derived from the benzazepine skeleton, ie benzazepine derivatives; in particular 3- (5,6-dihydrobenzo [b] [1] benzazepine-1 1 -yl) propan-1-amine, 3- (5,6-dihydrobenzo [b] [1] benzazepine-1 1-yl) - N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 01); Imipramine (3- (5,6-dihydrobenzo [b] [1] benzazepine-1 1 -yl) -N, N-dimethyl-propane-1-amine), desipramine (3- (5,6-dihydrobenzo [b] [1] benzazepine-1 1 -yl) -N-methyl-propane-1-amine); Trimipramine (3- (5,6-dihydrobenzo [b] [1] benzazepine-1 1-yl) - N, N, 2-trimethylpropane-1-amine); N- [2- (5,6-dihydrobenzo [b] [1] benzazepine-1 1 -yl) ethyl] -2- (3,4-dimethoxyphenyl) -N-methyl-ethanamine (NB 15); their pharmaceutical

acceptable salts; and mixtures thereof.

Furthermore, in the context of the present invention, those lysosomotropic, antiapoptotically active substances which are derived from the phenothiazine skeleton, ie phenothiazine derivatives, in particular 3-phenothiazine-10-yl-propan-1-amines, 3- (2-chlorophenothiazine-10), are also preferred -yl) -N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 03); chlorpromazine (3- (2-chlorophenothiazin-10-yl) -N, N - dimethyl-propan-1-amine), levomepromazine (2R) -3- (2-methoxyphenothiazin-10-yl) -N, N, 2-trimethyl-1-propanamine (N, N-dimethyl-3- (10H -phenothiazin-10-yl) propan-1-amine), promethazine (N, N-dimethyl-1-phenothiazin-10-yl-propan-2-amine), thioridazine (10- [2- (1-methylpiperidin-2-yl ) ethyl] -2-methylsulfanylphenothiazin)

Triflupromazine (N, N-dimethyl-3- [2- (trifluoromethyl) phenothiazin-10-yl] propan-1-amine); and mixtures thereof. In addition, in the context of the present invention, those lysosomotropic, antiapoptotically active substances which are derived from the phenoxazine skeleton, ie phenoxazine derivatives, in particular 3-phenoxazin-10-yl-propan-1-amines, N- [2- (3 , 4-dimethoxyphenyl) ethyl] -N-methyl-3-phenoxazin-10-yl-propan-1-amine (NB 37); their pharmaceutically acceptable salts; and mixtures thereof.

Furthermore, in the context of the present invention, those lysosomotropic, antiapoptotically active substances which are derived from the annulene skeleton, ie Annulen derivatives, in particular 3- (5,6-dihydrodibenzo [1,2-a: 2 ', 1'] are also preferred. - d] [7] annulen-1 1 -ylidene) propan-1-amines, 3- (5,6-dihydrodibenzo [2,1 -b: 1 ', 2'-e] [7] annulen- 1 1 - ylidene) -N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 38); Nortriptyline (3- (5,6-dihydrodibenzo [2,1 -b: 2 ', 1' - f] [7] annulen-1 1 -ylidene) -N-methylpropan-1-amine, amitriptyline (3- (5 , 6-dihydrodibenzo [2,1 -b: 2 ', 1' -f] [7] annulen-1 1-ylidenes) -N, N-dimethylpropan-1-amine); 1- (6,1 1 -dihydro 5H-dibenzo [1,2-a: 2 ', 1' - d] [7] annulen-1 1 -yl) hexahydropyrimidines, 1- (6,1 1 -dihydro-5H-dibenzo [2,1 -b : 1 ', 2'-e] [7] annulen-1 1 -yl) -3- [2- (3,4-dimethoxyphenyl) ethyl] hexahydropyrimidine (NB 47), 1 - (6,1 1 -dihydro- 5H-dibenzo [2,1 -b: 1 ', 2'-e] [7] annulen-1 1 -yl) -3- [2- (4-methoxyphenyl) ethyl] hexahydropyrimidine (NB 24); N'- (6.1 1 -dihydro-5H-dibenzo [1, 2-a: 2 ', 1'-d] [7] annulen-1 1 -yl) propane-1,3-diamine, N' - (6, 1 1 -dihydro-5H-dibenzo [1,2-a: 2 ', 1' - d] [7] annulen-1 1 -yl) -N- [2- (3,4-dimethoxyphenyl) ethyl] propane 1, 3-diamine (NB 41), their pharmaceutically acceptable salts, and mixtures thereof.

Furthermore, in the context of the present invention, those lysosomotropic, antiapoptotically active substances which are derived from the benzazocine skeleton, ie benzazozine derivatives, in particular 3- (1,1-dihydro-6H-benzo [c] [1] benzazocine, are also preferred -5-yl) -N- [2- (4-methoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 21); their pharmaceutically acceptable salts; and mixtures thereof.

Furthermore, in the context of the present invention, those lysosomotropic, antiapoptotically active substances which are derived from the benzoxazine skeleton, ie benzoxazine derivatives, in particular 4- (3-aminopropyl) -1,4-benzoxazin-3-ones, 4 are also preferred - [3- [2- (4-methoxyphenyl) ethyl-methylamino] propyl] -1, 4- benzoxazin-3-one (NB 48); their pharmaceutically acceptable salts; and mixtures thereof.

Moreover, in the context of the present invention, those lysosomotropic, antiapoptotically active substances which are derived from the carbazole skeleton, ie carbazole derivatives, in particular 2,3,3a, 4,5,6-hexahydro-1H-pyrazino [ 3,2,1-jk] carbazole, 3- [2- (4-methoxy-phenyl) -ethyl] -2,3,3a, 4,5,6-hexahydro-1H-pyrazino [3,2,1 -jk] carbazole (NB 43); 1, 2,3,3a, 4,5,6,7-octahydro- [1,4] diazepino [3,2,1-jk] carbazole, 4- [2- (4-methoxy-phenyl) -ethyl] -1, 2,3,3a, 4,5,6,7-octahydro- [1,4] diazepino [3,2,1-jk] carbazole (NB 44); 3-carbazol-9-yl-propan-1-amine, 3-carbazol-9-yl-N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 05); 3-carbazol-9-yl-N- [2- (4-methoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 06); 2-carbazol-9-ylethanamine, N- (2-carbazol-9-yl-ethyl) -2- (4-methoxyphenyl) -N-methyl-ethanamine (NB 25), 9 - [[4- [2- (4- methoxyphenyl) ethyl] piperazin-1-yl] methyl] carbazole (NB 18); 3-carbazol-9-yl-propane-1-amines; their pharmaceutically acceptable salts; and mixtures thereof.

Furthermore, in the context of the present invention, those lysosomotropic, antiapoptotically active substances which are derived from the naphthyl skeleton, in particular N- [2- (3,4-dimethoxyphenyl) ethyl] -N '- (1-naphthyl) ethane, are also preferred -1, 2-diamine (NB 10); in particular 1 -naphthylmethanamine, 2- (3,4-dimethoxyphenyl) -N- (1-naphthylmethyl) ethanamine (NB 12); their pharmaceutically acceptable salts; and mixtures thereof.

As preferred lysosomotropic, antiapoptotically active substances which are well characterized pharmaceutically and pharmacologically, the following compounds have been found to be particularly promising in human experiments, in animal experiments and in in vitro investigations: imipramine (3- (5,6-dihydrobenzo [b ] [1] benzazepine-1 1 -yl) -N, N-dimethyl-propane-1-amine); Amitriptyline (3- (5,6-dihydrodibenzo [2,1 -b: 2 ', 1' - f] [7] annulene-1 1 -ylidene) -N, N-dimethylpropan-1-amine); 3-carbazol-9-yl-N- [2- (4-methoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 06); Nortriptyline (3- (5,6-dihydrodibenzo [2,1 -b: 2 ', 1' - f] [7] annulen-1 1 -ylidene) -N-methylpropane-1-amine; 3-carbazole-9- yl-N- [2- (4-methoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 06); chloroquine (4-N- (7-chloroquinolin-4-yl) -1-N, 1 N-diethylpentane-1,4-diamine); Chloropropenes ((3Z) -3- (2-chlorothioxanthen-9-ylidenes) -N, N-dimethylpropan-1-amides, their pharmaceutically acceptable salts, and mixtures thereof.

The present invention is of particular importance if the lysosomotropic, antiapoptotically active substances used are combined with at least one antioxidant substance.

In the context of the present invention, the antioxidant active substance is selected from the group consisting of: mono- or polyunsaturated compounds, in particular mono- or polyunsaturated fatty acids, preferably linoleic acid (C 18: 2 fatty acid), gamma-linolenic acid (C 18: 3) Fatty acid), docosahexaenoic acid, eicosapentaenoic acid; mono- or polyunsaturated oils of vegetable origin, in particular almond oil, evening primrose oil, olive oil; Terpenes, especially tocopherol, retinol, aescin, beta carotene; Polyphenols, especially rutoside, quercetin; Ginkgolides and ascorbic acid; and mixtures thereof.

In the context of the present invention, the substance effective for protection against cleavage of monounsaturated or polyunsaturated compounds or aldehydes formed by aldolases (reactive carbonyl pyrogen scavengers) can be selected from the group consisting of: primary aliphatic amines as compounds containing functional groups Glycine, alanine, lysine, β-alanyl-L-histidine, β-alanyl-N-methyl-L-histidine, L-lysine-L-histidine, 6-aminohexanoic acid, 6-aminohexanoly-L-histidine, amifostine, pyridoxamine; secondary aliphatic amines as a functional group, preferably amifostine; and mixtures thereof.

Preferably, the composition of the invention is formulated as a pharmaceutical composition.

The galenic preparation of the desired drug is adjusted as usual to the pharmaceutical / pharmacological needs.

The composition of the invention may, for example, as a semi-solid preparation in the form of a cream, an ointment, a hydrogel, an oleogel, a Paste, an envelope paste, a lotion, a milk, an emulsion, a liposomal formulation of a suspension or a drug-containing patch.

If desired, the composition according to the invention can also be formulated as a liquid preparation in the form of an aqueous, hydrophilic or hydrophobic liquid which, if necessary, contains one or more solubilizers.

In a preferred embodiment of the present invention, the at least one lysosomotropic, antiapoptotically active substance or the combination of these with at least one antioxidant substance in a pharmaceutical basis contains, in particular ointment base, optionally including pharmaceutically acceptable excipients.

For the compositions according to the invention, the pharmaceutical base may be at least one antioxidant, in particular a fatty acid (C18: 2).

For the purposes of the present invention, it is possible in principle to use any pharmaceutical base which is well known to the person skilled in the art, but those bases are preferred which are selected from the group consisting of: wool waxes; Fatty alcohols, in particular wool wax alcohols, cetylstearyl alcohol, decyl oleate; Sunflower oil, peanut oil, refined and hydrogenated peanut oil, vegetable hard fat, hard paraffin, aliphatic hydrocarbons (C40-C60); stearates; viscous paraffin, white petrolatum, unsaturated fatty acids, almond oil, evening primrose oil, olive oil or other mono- or polyunsaturated compounds that are antioxidant and stabilize the redox potential in the cell; and mixtures thereof.

In addition to the active ingredients disclosed within the scope of the present invention, the composition according to the invention may additionally contain urea and / or salicylic acid in order to accelerate and / or assist the desquamation and / or keratolysis. In the context of the present invention, the composition according to the invention is used advantageously for the topical treatment of non-microorganism-caused inflammatory skin and mucous membrane diseases.

In practical trials, it has been found that skin and mucous membrane diseases, in particular psoriasis type I and type II, preferably psoriasis vulgaris, psoriasis guttata, psoriasis nummeralis, erythrodermal psoriasis, psoriasis pustulosa; In particular eczema, atopic eczema, atopic dermatitis and pytyriasis capitis can be successfully treated with the composition according to the invention and essentially without side effects.

Within the scope of therapeutic freedom, the composition extensively tested to date has been the lysosomotropic, antiapoptotically active substance amitriptyline or a pharmaceutically acceptable salt thereof and the antioxidant C18: 2 fatty acid substance. Through these combinations, the skin symptoms in psoriasis, atopic dermatitis and pytyriasis capitis disappeared almost completely within 3 weeks of local application.

The content of the inventive preparation of the antioxidant C18: 2 fatty acid at 0.5% (m / m) is many times higher than of antioxidants, which are typically used as adjuvants for stabilizing pharmaceutical preparations. C18: 2 fatty acid is an active substance in the preparation according to the invention and is declared as such.

Further, for example, as lysosomotropic antiapoptotic effective

Compound 3-carbazol-9-yl-N- [2- (4-methoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 06) increased C16-ceramide levels below per apoptotic stimulation (e.g. B. TNFalpha in Fig. 1 B) stop. NB 06 triggers a chloroquine-like increase in the intralysosomal pH from 4.6-4.8 to 6.2-6.4 (lysosomotropic effect). The activity of aCERase shifts towards its synthase activity.

C24: 1 -Ceramide from deNovo ceramide synthesis is no longer degraded and accumulates (eg, TNFalpha in Fig. 1B). The increase of C24: 1 ceramide is therefore the consequence of an enrichment and not a synthesis induction. Accordingly, with the local application of a lysosomotropic compound according to the invention, premature apoptosis and inadequate

Differentiation of keratinocytes can be prevented and offers a new

Treatment option of psoriasis, atopic dermatitis and pytiriasis capitis.

The biological target of NB 06 in the living cell is the lysosome, the main effect is lysosomotropy. Consequently, all metabolic and

Signaling pathways can be influenced by NB 06, which run across the lysosome. NB 06 not only interferes with classical metabolic processes such as proteolysis and degradation of membrane lipids, but also alters the presentation of lipid antigens. Lysosomal lipid-binding proteins are necessary to lipid or

To present glycolipid antigens such as the four MHC-I-like glycoproteins CD1 a-d (Kolter, T. et al., FEBS Lett., 2010; 584: 1700-1712). In the hybridization experiment, the time-dependent gene expression of known genes involved in inflammatory reactions in human mono-Mac-6 cells under lipopolysaccharide (LPS), in combination with NB 06 or only under NB 06 over a period of 6 hours was considered (results in FIG. 2B and 3A). LPS (E. coli serotype 01 1 1: B4) stimulates the genes associated with inflammatory reactions in mono-Mac-6 cells. NB 06 provides insight into lysosomal gene expression. Genes of FIG. 3A influenced by NB 06 are involved in the following biological processes (selection): CXCL3, CXCL2 - neutrophil cell migration, CCL4 macrophages and NK cell migration; T cell-DC interactions, CCL20 - Th17 responses; B cells and DC homing to intestinal-associated lymphoid tissue, CXCL10 - pro-inflammatory, Th1 response; Th1, CD8, NK cell migration, apoptosis (Griffith, JW et al., Annu., Rev. Immunol., 2014; 32: 659-702), PTX3 - promotion of fibrocyte differentiation, regulation of inflammation and complement activation, essential component of the humoral innate immunity (Magrini, E. et al., Trends Mol. Med. 2016; 22: 497-510), PTGS2-inducible enzyme (constitutively expressed in brain and kidney), expression increased in a variety of cells in response to cytokines, Mitogens and Endotoxins (Kurumbail, R. Curr. Opin. Struct. Biol. 2001; 1 1: 752-760), ICAM1 - Leukocyte Adhesion and Leukocyte Transendothelial Migration (TEM) (Yang, L. et al., Blood ; 106: 584-592), IL23A - mediation of

innate and adaptive arms of the immune system (expression of the IL-23 receptor) (Memari, B. et al., J. Immunol 195 (2015) 4479-4491),. IL6 - the strongest pro inflammatory cytokine (Schaper, F. et al .; Cytokine Growth Factor Rev. 2015; 26: 475-487) and TNFalpha - a multifunctional pro-inflammatory cytokine belonging to the tumor necrosis factor superfamily. These genes play a central role in a variety of biological processes such as apoptosis, induction of genes,

Lipid metabolism, cytokine secretion, cell activation, cell death, cell adhesion,

Cell differentiation, cell stimulation and cell proliferation. NB 06 shows here its modulating properties on the gene expression of various pro

inflammatory messengers (interleukins and cytokines), which is also present without triggering inflammation. Lysosomotropic compounds such as NB 06 can therefore also be used as therapeutics for interrupting inflammatory processes and thus for their treatment.

Pharmaceutical preparations which exclusively target the lysosomotropic, anti-apoptotic effect therefore consist only of an inert base and the lysosomotropic active substance (s). As an application example is a

Preparation of amitriptyline in the base "lysosomotropic anti-apoptotic preparation" (Figure 4) has been used for the treatment of psoriasis / atopic dermatitis.

The acidic intralysosomal pH (4.6-4.8) is built up by the vacuolar H + ATPase (V-ATPase, EC 3.6.3.6) and a lysosomal redox chain that transports protons into the lumen of lysosomes maintained. When

Energy source uses the lysosomal redox chain cytoplasmic NADH (Gille, L. et al., Arch Biochem Biophys., 2000; 375: 347-54), the V-ATPase ATP as

Energy source (Pillay, CS et al., Biochem J. 2002; 363: 417-429). The V-ATPase is the essential proton pump for the formation and maintenance of the lysosomal proton gradient. The V-ATPase has two regulatory mechanisms: a reversible dissociation or reorganization of the functional units V1 and V0 depending on

Glucose concentration in the cytosol. In addition to the glucose-dependent regulation, the ATPase activity of V-ATPase is also dependent on the cytosolic glutathione (GSH) and thus on the cytosolic redox potential. The catalytically active 73 kDa subunit has a conserved region (P-LOOP) with two cysteine (Cys) residues at positions 254 and 532, which can form disulfide bridges. The thiol-disulfide equilibrium is redox-sensitive and allows the regulation of V-ATPase via the redox potential in the cytoplasm (Pillay, CS et al., Biochem J. 2002, 363: 417-429). at With excessive levels of cytosolic GSH level, Cys 254 and 532 disulfide, thus blocking the catalytic site. The formed disulfide bridge is almost irreversible. Once formed, it can no longer be completely separated by physiological GSH concentrations in the cytoplasm (Nishi, T. et al., Nat Rev Mol Cell Biol., 2002; 3: 94-103). The V-ATPase remains irreversibly partially inhibited. As a result, the pH in the lysosome begins to increase and approaches the cytosolic pH. Both aSMase and aCERase lose their hydrolysis activity step by step. In contrast to aSMase, aCERase has dependent pH values on two different enzymatic activities: a ceramide hydrolase activity (optimal pH of 4.0-5.0) and an ATP-independent reverse ceramide synthase activity ( revaCERase) (optimal pH 5.5-6.5) (He, X. et al., Anal Biochem., 2003; 314: 1 16-120). The lysosomal NADH-dependent redox chain transports two single electrons from cytosolic NADH to oxygen in the lysosomal lumen, followed by two protons (Gille, L. et al., Arch Biochem Biophys., 2000; 375: 347-54). Inhibition by a redox-potential-dependent modification, such as the formation of disulfide bridges, is unknown. When NADH is heavily depleted, this proton pump also fails. Via NADH it is also coupled to the cytosolic redox pool.

Increasing the pH of the lysosome activates the aCERase reverse aCERase activity. It has the following substrate specificity: palmitic (C16, 35%), stearic (C18, 30%) and eicosanoic acid (C20 or longer <15%) of the maximum conversion (reference is C12, dodecanoic acid) (Okino, N. et al., J Biol Chem. 2003; 278: 29948-29953). Under these conditions, the apoptosis marker C16-Cer can be generated specifically from sphingosine and palmitic acid without energy / ATP consumption. The derived model of the lysosomal, V-ATPase function-dependent control of C16-ceramide synthesis by the reverse synthase activity of aCERase and the description of the function of the lysosomal V-ATPase as a crucial trigger enzyme (switch) for the formation of C16 ceramide in the cell is an important building block for understanding C16 ceramide formation in apoptosis. The irreversible formation of the disulfide bridge between the cysteins 254 and 532 in the catalytically active ATPase unit V1 is an important milestone for C16 ceramide synthesis in the lysosome and thus for apoptosis. This oxidation process is the much-described "point of no return" in signal transduction within the cell towards apoptosis. This also defines a decisive parameter for the effect of pro and antiapoptotic compounds.

The combination of lysosomotropic, antiapoptotic and antioxidant / lysosomal protective therapies is a synergistic therapeutic approach that is capable of disrupting both the self-reinforcing inflammatory response in psoriasis and other CCR6-driven diseases, as well as the formation of protective, ceramide-rich bilayers Horn layer to promote and secure. The topical application of the combination is an approach to minimization and

Avoidance of possible negative effects associated with a broad immunosuppression by systemic application of antibodies, in a similar way

Therapeutic success.

The topically applicable preparation can be used independently of "clinically relevant active infections" (for example active tuberculosis) Increasing infections (upper respiratory tract, fungal infection of the oral mucosa, inflammation of the conjunctiva and a fungal infection on hair, nails or skin ( Tinea) have been described, for example, in systemic IL1 ZA antibody therapy, and the described psoriasis preparation for topical use is not expected to increase the risk of infection.

Pharmaceutical preparations aiming at the synergistic lysosomotropic, antiapoptotic and antioxidant / lysosomal protective approach therefore consist of one or more lysosomotropic, antiapoptotic agents, one or more antioxidant / lysosomal protective / V-ATPase protective agents and a basis. As an application example, a preparation of amitriptyline has been used in the "lysosomotropic, anti-apoptotic and antioxidant / lysosomal protective and V-ATPase-protective preparation" (FIG. 4 D-K, FIG. 5 and 6) basis for the treatment of psoriasis / atopic dermatitis ,

In a further development of the pharmaceutical preparation, the increasingly present reactive oxygen species (ROS) and in particular the reactive carbonyl species (RCS) have also been taken into account. RCS are generated produced by lipid peroxidation and include the monoaldehydes (eg hexanal), alkenals (eg acrolein), the bifunctional alkenals (eg 4-hydroxy-2-nonenal), 1, 2-dicarbonyls (e.g. Methylglyoxal), 1,3-dicarbonyls (z malondialdehyde) and 1,4-dicarbonyls (e.g., isolevuglandins and 4-oxo-2-nonenal) (Davies, SS et al .; Curr Pharmacol Rep. 2017; 3: 51-67). Sphingosine phosphate lyase enhances stress-induced ceramide formation and apoptosis through the formation of 4-hydroxy-2-nonenal from sphingosine-1-phosphate (Reiss, U. et al., J Biol Chem., 2004; 279: 1281-1290 ). In addition, they contain agents that detoxify reactive oxygen species (ROS) and particularly reactive carbonyl species (RCS) through enamine / imine formation, thus minimizing oxidative stress in keratinocytes or preventing severe depletion of GSH levels. The irreversible formation of the disulfide bridge between the cysteines 254 and 532 in the catalytically active ATPase unit V1 of the V-ATPase by oxidative stress can thus be prevented. As nucleophiles, the two cysteines of V-ATPase by enamine / imine formation before a

Reaction protected with RCS.

Pharmaceutical preparations aiming at the synergistic lysosomotropic, anti-apoptotic and strongly antioxidative, reactive carbonyl-spiking / lysosome-protective therapeutic approach therefore consist of one or more lysosomotropic, anti-apoptotic active ingredients, one or more antioxidant / lysosomal protective / V-ATPase protective agents or more reactive carbonyl species scavengers and a base.

Advantages of the invention

The topical in psoriatic therapy and partly in the

Neurodermatitis therapy used drugs (dithranol, coal tar, retinoids and vitamin D3 derivatives) usually produce ROS, increase the intracellular redox potential consume reduction equivalents and try to fight via apoptosis induction epidermal hyperproliferation with disturbed differentiation of keratinocytes The quality of treatment in Germany shows that the average severity of illness remains relatively high and that the quality of life is sometimes significantly reduced, even among psoriasis patients regularly treated by dermatologists. These findings suggest that patients are having too much time ineffective drugs / procedures. "(S3 guideline on the treatment of psoriasis vulgaris (Nast, A. et al., AWMF online 201 1, AWMF Registry No. 013/001, l_S3, 1-199) Apoptosis of keratinocytes in topical therapy misses the therapeutic goal of freedom from appearance, that is the absence of cutaneous symptoms of psoriasis, whereas in the clinical picture of atopic dermatitis premature apoptosis is the cause of lesions in the skin.

 A paradigm shift towards the prevention of apoptosis and stabilization of the keratinocytes as described above is the more promising therapeutic target. Only fully differentiated keratinocytes can fulfill their task, but not those that have not achieved the important for their function habitus and ceramide content by premature apoptosis.

 Local delivery of reduction equivalents not only prevents the formation of the disulphide bridge of lysosomal V-ATPase (protective effect), but also provides membrane lipid-protective reduction equivalents that render ROS and lipid peroxides in the cell harmless. Not to

Reduction equivalents required for cell protection purposes are available to the reducing agent pool of the cell and do not need to be regenerated. The antioxidant BHT ^* in FIG. 2A shows this effect by favoring the deNovo synthesis of C24: 1 ceramide and thus promoting the formation of the protective, ceramide-rich bilayer of the horny layer. NADPH / NAD (P) H consuming synthetic steps are the reduction of 3-ketosphinginan to sphinginan (by the 3-ketosphinginan reductase) and of dihydroceramide to ceramide (by the dihydroceramide desaturase). These two reduction steps are less competitive under these conditions for the neutralization of ROS. It is also an explanation of the efficacy of black cumin (Nigelia sativa), olive oil, cocoa butter or vitamin A / B12 described in US2017189466 (A1)). In moderate to severe forms of psoriasis and atopic dermatitis, the pure antioxidant / RCS-trapping /

Lysosome protective therapy approach is insufficient to achieve the therapeutic goal of normal skin appearance.

Composition of the preparation

The object is achieved in that topically

prepares preparations containing a combination of a) one or more lysosomotropic, antiapoptotically active agents and a base;

 b) one or more lysosomotropic, anti-apoptotic drugs and an antioxidant / lysosomal protective / V-ATPase protective base; c) one or more of a lysosomotropic, anti-apoptotic active, one or more antioxidant / lysosomal protective / V-ATPase protective agents and a base; and

 d) one or more lysosomotropic, anti-apoptotic,

antioxidant / lysosomal protective / V-ATPase-protective agents and a basis

 are. In addition, additives suitable for topical application, additional active ingredients and optionally adjuvants may be present, which bring about an improved efficiency of the active ingredients. The improved efficiency is characterized by improved penetration or a depot / retardation effect effect.

 Semi-solid preparations according to the invention are a cream, an ointment, a hydrogel, an oleogel, a paste, a syrup, an envelope paste or a

medicated plaster; Liquid preparations are a solution, a lotion, a milk, a suspension. Bases according to the invention are all basic preparations of the European Pharmacopoeia (Ph.Eur.), The German Pharmacopoeia (DAB) of the German Pharmaceuticals Code (DAC) and the New Formulation Form (NRF). For more stringent requirements due to the individual circumstances of the active ingredient to the recipe base are also commercially available special

Bases according to the invention.

 Further topical preparations according to the invention are rinsing solutions, a stick, a stick, a foam, a shampoo, a spray or a metering spray

(Preparations in pressure containers).

Included as a preparation according to the invention are all precursors to

Preparation of the preparation according to the invention, in particular active substance-containing

Concentrates and granules for the production.

The semi-solid topical lysosomotropic and antiapoptotic effective

Formulations contain the lysosomotropic, anti-apoptotic active ingredient its salts, possible derivatives or prodrugs preferably in a mass fraction of From 0.0001 to 5% (m / m, based on the pure active ingredient), more preferably from 0.005 to 1%, most preferably from 0.01 to 0.5%, and most preferably from 0.025 to 0.1%; and water, emulsifiers, ointment and gel bases, gel formers,

Additives (fragrances, preservatives and stabilizers), additives.

The semisolid topical lysosomotropic and antiapoptotic and antioxidative / lysosomal protective / V-ATPase protective active preparations contain the lysosomotropic, antiapoptotically active agent its salts, possible derivatives or prodrugs preferably in a mass fraction of 0.0001 to 5% (m / m, based on the pure active ingredient), more preferably from 0.005 to 1%, most preferably from 0.01 to 0.5%, and most preferably from 0.025 to 0.1%; the antioxidant / lysosomal protective / V-ATPase-protective active ingredients preferably in a mass fraction of 0.0001 to 50%, particularly preferably 0.1 to 30%, very particularly preferably; 0.20 to 25% and especially 0.25 to 20%; and water, emulsifiers, ointment and gel bases, gelling agents, additives (fragrances,

Preservatives and stabilizers), additives.

The semisolid preparations according to the invention may be, for example: O / W, W / O emulsions, hydrogels and oleogels, preferably from hydrocarbons, natural or synthetic fats, oils, waxes, fatty alcohols, fatty acid esters, fatty acid partial esters, glycerides (such as mono-, di , Triglycerides), lecithins,

Phospholipids, sphingolipids, gangliosides, cerebrosides, phosphatidycholine,

Ceramides, lipo- or amphiphilic plant substances, natural hydrocolloids (such as

Casseinates, gelatin, pectins), synthetic or partially synthetic colloids or mixtures thereof, in particular acrylate polymers (carbomers) or

Cellulosic polymers, water, alcohols; especially preferably from 4.0 g

Glycerol Monostearate 60, 6.0 g Cetyl Alcohol, 7.5 g Medium Chain Triglycerides (Neutral Oil), 25.5 g White Vaseline, 7.0 g Macrogol 20-glycerol monostearate, 10.0 g Propylene Glycol, 40.0 g Purified Water (O. / W emulsion), more preferably from 2 (4-tert-butylbenzyl) propionaldehyde, decyl oleate, glycerol monostearate, macrogolstearyl ether, methyl 4-hydroxybenzoate, sodium ethyl 4-hydroxybenzoate, stearic acid, trometamol, bleached wax, water (O / W emulsion). Lysosomotropic, antiapoptotically effective active substances according to the invention are also the salts, possible derivatives, precursors or prodrugs of the described active compounds which have a lysosomotropic effect.

Antioxidative / lysosomal protective / V-ATPase protective agents according to the invention are monounsaturated or polyunsaturated compounds, contained or incorporated in the base, which have antioxidant activity and stabilize the redox potential in the cell; in particular mono- or polyunsaturated fatty acids, more preferably linoleic acid (C18: 2 fatty acid), gamma-linolenic acid (C18: 3 fatty acid), docosahexaenoic acid, eicosapentaenoic acid; in particular mono- or polyunsaturated oils, particularly preferably almond oil, evening primrose oil, olive oil; in particular terpenes, more preferably tocopherol, preferably tocopherol acetate, retinol, aescin, beta-carotene; in particular polyphenols, particularly preferably rutoside, quercetin, in particular ginkgolides, ascorbic acid.

Antioxidative / lysosomal protective / V-ATPase-protecting agents according to the invention are also primary and secondary aliphatic amines, contained or incorporated in the base, which are prepared by cleavage of one or more times

protect unsaturated compounds or aldehydes (reactive Carbonylspiezies, RCs) formed by aldolases (enamine / imine formation); in particular amino acids, di- and tripeptides, their biogenic amines and derivatives, particularly preferably glycine, alanine, lysine, β-alanyl-L-histidine, β-alanyl-N-methyl-L-histidine, L-lysine-L-histidine, 6-aminohexanoic acid, 6-aminohexanoly-L-histidine, especially amifostine, pyridoxamine

If appropriate, useful additional active ingredients may be selected for the therapeutic target. Particularly preferred are preparations in which 0.01 to 30% (m / m), preferably 5 to 20%, especially 3 -10% urea; wherein 0.1 to 30%, preferably 1 to 10%, especially 2 to 10% polidocanol are included.

Further advantages and features arise due to the consequences

described experimental data and with reference to the drawing.

It shows: Figure 1A is a model of C16 ceramide generation in the lysosome by the reverse activity of aCERase;

FIG. 1B shows the schematically illustrated ceramide metabolism in the cell; FIG.

Figure 2A shows the quantification of selected ceramides in human blood mononuclear cells (PBMC);

Figures 2B and 3 show the results of expression of selected differentially expressed genes in human Mono Mac-6 cells;

4A to 4C show a course of therapy of an atopic eczema on the upper side of a wrist with a lysosomotropic, antiapoptotically active substance according to the composition according to the invention in a first embodiment;

4D to 4K a long-term therapy course of atopic eczema at the

 Top of a wrist with a combination of a lysosomotropic, antiapoptotic substance and an antioxidant substance according to the composition of the invention in a second embodiment;

5A to 5D the treatment progress in an atopic dermatitis of

 left crook of the arm;

6A and 6B show a course of therapy of a psoriasis on the auricle;

 and

6C and 6D show a course of therapy of a psoriasis on the scalp of a patient;

embodiments

example 1 In vitro investigations

As an in vitro study, the displacement of the lysosome-labeled fluorescent dye LysoTracker Red DND-99 from lysosomes was measured. The displacement (intensity of fluorescence) is dependent on the lysosomal pH and the IC50 measurements obtained can be used to determine the lysosomotropy of basic amphiphilic compounds (Lemieux, B. et al., Anal. Biochem., 2004; 327: 247-251 249). Low IC50 readings characterize a highly lysosomotropic substance. Fluorescence detection at 577 ± 3 nm (excitation) and 590 ± 4 cm (emission). The activity of the substances was determined in triplicates and is given as median ± SE.

Table 1: IC50 measurements of the displacement of the lysosome-labeled fluorescent dye LysoTracker Red DND-99 from lysosomes

ICso Red DND-99

Lead substance Examined substances

 Repression [μΜ]

3- (5,6-dihydrobenzo [b] - imipramine 5 ± 2 [1] benzazepine-1 1 -yl) propane-1-amine

 3- (5,6-Dihydrobenzo [b] [1] benzazepine 16 ± 1 1 1 -yl) -N- [2- (4-methoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 02 )

3-phenothiazine-10-yl-propane-chlorpromazine 1 1 ± 3

 1-amine

 Levomepromazine 14 ± 2

3- (2-chlorophenothiazin-10-yl) -N- [2-12 ± 3 (3,4-dimethoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 03)

 2- (4-methoxyphenyl) -N-methyl-N- (2-15 ± 5-phenothiazin-10-yl-ethyl) -ethanamine (NB

 08)

 N- [2- (4-methoxyphenyl) ethyl] -N-methyl-9 ± 1,3-phenothiazin-10-yl-propan-1-amine

 (NB 39)

 3-phenoxazin-10-yl-propane-N- [2- (3,4-dimethoxyphenyl) ethyl] -N-13 ± 3

 1-methyl-3-phenoxazin-10-yl-propan-1-amine (NB 37)

3- (5,6-dihydrodibenzo [1,2-amitriptyline 12 ± 2 a: 2 ', 1'-d] [7] annulene-1 1-ylidenes) propane-1-amine ICso Red

 DND-99

Lead substance Examined substances

 Repression [μΜ]

3- (5,6-dihydrodibenzo [2,1 -b: 1 ', 2'-10 ± 4e] [7] annulen-11-ylidenes) -N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-propan-1-annine (NB 38)

 1- (6,11-dihydro-5H-1 - (6,11-dihydro-5H-dibenzo [2,1-b: 1 ', 2'-11 ± 4 dibenzo [1,2-a: 2', 1'-e] [7] annulen-11-yl) -3- [2- (4-d] [7] annulene-11-methoxyphenyl) ethyl] hexahydropyrinnidine

 yl) hexahydropyrinnidine n (NB 24)

 N '- (6,11-dihydro-5H-N' - (6,11-dihydro-5H-dibenzo [1,2-a: 2 ', 1' - 17 ± 2 dibenzo [1,2-a: 2 ', 1'-d] [7] annulen-11-yl) -N- [2- (4-d] [7] annulen-11-yl) propane methoxyphenyl) ethyl] propane-1,3-diamine

 1,3-diamine (NB 46)

 3- (11,12-dihydro-6H-3- (11,12-dihydro-6H-17 + 2 benzo [c] [1] benzazocine-5-benzo [c] [1] benzazocin-5-yl) - N- [2- (4-yl) propan-1-amine methoxyphenyl) ethyl] -N-methylpropane-1-amine (NB 21)

 , 3,3a, 4,5,6-hexahydro-1 H-3- [2- (4-methoxy-phenyl) -ethyl] -99 ± 2-pyrazino [3,2,1-jk] -carbazole 2,3, 3a, 4,5,6-hexahydro-1H-pyrazino [3,2,1-jk] carbazole (NB 43)

 , 2,3,3a, 4,5,6,7-octahydro-4- [2- (4-methoxy-phenyl) -ethyl] -15 ± 3

 [1,4] diazepino [3,2,1-1,3,3,3a, 4,5,6,7-octahydro- jk] carbazole [1,4] diazepino [3,2,1-jk] carbazole (NB 44)

4- (3-aminopropyl) -1, 4-4- [3- [2- (4-methoxyphenyl) ethylmethyl-38 ± 4-benzoxazin-3-one amino] propyl] -1,4-benzoxazine-3 on (NB

 48)

 N '- (1-naphthyl) ethane-1,2-N- [2- (3,4-dimethoxyphenyl) ethyl] -N' - (1 -12 ± 6-diaminaphthyl) ethane-1,2-diamine (NB 10)

 1 -naphthylmethanamine 2- (3,4-dimethoxyphenyl) -N- (1-96 ± 6-naphthylmethyl) ethanannine

(NB 12) ICso Red

 DND-99

Lead substance Examined substances

 Repression [μΜ]

3-carbazol-9-yl-propane-1 - 3-carbazol-9-yl-N- [2- (4-19 ± 5-aminomethoxyphenyl) ethyl] -N-methyl-propane-1-amine (NB 06)

 9- [3 - [(3S, 5R) -4- [2- (4-9 ± 1-methoxyphenyl) ethyl] -3,5-dimethyl-piperazin-1-yl] propyl] carbazole (NB 19)

 3-carbazol-9-yl-N- [2- [4- [2- [3-carbazol-10 ± 3, 9-yl-propyl (methyl) -amino] -ethyl] -2,5-dimethoxyphenyl] -ethyl] -N -methyl-propane-1-amine (NB 45)

9 - [[4- [2- (4-33 ± 3-methoxyphenyl) ethyl] piperazin-1-yl] methyl] carbazole (NB 18)

 7-chloroquinolin-4-amine Chloroquine 5 ± 2

Example 2

 manufacturing

The preparations according to the invention are prepared by incorporating the active substance (s) into a base, for example in Aponorm spin chicks with a semi-automatic TopiTec stirring system, 1000 rpm, stirring for 3 min

Room temperature. Alternatively, other manufacturing methods and devices are too

Use can be made, ensure the same quality of the preparation of the invention. Example 3

 application

The preparation according to the invention is suitable for topical and

dermatological / therapeutic use on the skin, hair, nails, mucous membrane (depending on the chosen basis) in mammals especially humans. The preparation according to the invention is used several times a day and distributed the single dose on the diseased skin, in particular by rubbing.

 By choosing the appropriate application form and pharmaceutical grade is the application of the drug combination according to the invention on each

Body surface, including the gastrointestinal tract, the body cavities (oral cavity, nose, vagina) and the external auditory canal possible, in particular the aural, buccal, intra-articular, intrauterine, intranasal, percutaneous, sublingual, vaginal, transdermal application or as a rinse solution. Are special

Requirements (for example, sterility, osmolarity, viscosity) to the

Application form in the European or German Pharmacopoeia or another pharmacopoeia, this is ensured during manufacture.

Example 4

 therapeutic trial

Topical application of the preparation according to the invention consisting of

Amitriptyline 0.03% in a lysosomotropic and antiapoptotic preparation, and a combined lysosomotropic, antiapoptotic and antioxidant / lysosomal protective and V-ATPase-protective preparation for the treatment of psoriasis.

Amitriptyline was selected as a lysosomal and anti-apoptotic reference drug because it was topically applied in a 2% cream application with the indication "neuropathic pain" for 6 and 12 months without significant systemic absorption and only minimal

Side effects were noted (Lynch, M.E., et al., J Pain. 2005; 10: 644-649). The amitriptyline mass fraction of the preparation according to the invention is 0.03% far below and is therefore unproblematic with regard to severe unwanted

Classify effects. Basis "Lysosomotropic anti-apoptotic preparation" (O / W Crenne,

Base cream DAC)

 per 100g consisting of:

 Glycerol monostearate 60 4.0 g

 Cetyl alcohol 6.0 g

 Medium chain triglycerides (neutral oil, Miglyol 812) 7.5 g

 White Vaseline 25.5 g

 Macrogol 20-glycerol monostearate 7.0 g

 Propylene glycol 10.0 g

 Purified water 40.0 g

Lysosomotropic anti-apoptotic preparation (O / W Crenne) 0.03%

 Amitriptyline 0.030 g

 Basis "Lysosomotropic anti-apoptotic

 Preparation "ad 100.0 g

Basis "Lysosomotropic, anti-apoptotic and antioxidative / lysosomal protective and V-ATPase-protective preparation" (O / W cream)

 0.5% / 0.5 g of unsaturated fatty acids (C18: 2), per 100 g of cream, as antioxidant / lysosomal protective and V-ATPase-protective active ingredient in 2 (4-tert-butylbenzyl) propionaldehyde, decyl oleate, odorant; glycerol,

Macrogolstearyl ether, methyl 4-hydroxybenzoate, sodium ethyl 4-hydroxybenzoate, stearic acid, trometamol, bleached wax, purified water (trade name: Linola®, Dr. Wolff, Bielefeld, Germany)

Combined lysosomotropic, anti-apoptotic and antioxidant / lysosomal protective and V-ATPase protective preparation (O / WCreme) 0.03%

 Amitriptyline 0.030 g

 Basis "Lysosomotropic, anti-apoptotic and

 antioxidant / lysosomal protective and V-ATPase

protective preparation "ad 100.0 g Both creams are prepared by adding 1.2 ml of an amitriptyline solution (25 mg / ml) and incorporating into the base (Semi-automatic TopiTec stirring system, 1000 rpm, stirring for 3 min at room temperature in Aponorm spin chives).

Therapy attempt in the context of an individual healing trial:

 Anamnesis: The patient (6 years) has had skin problems (itchy eczema on the flexor surfaces of the arms, wrists, and neck) for three years prior to the initiation of the individual therapy, and a marked lichenified skin on the elbows and wrists. Diagnosis by dermatologists: currently: mild atopic eczema, year-earlier: chronic atopic eczema, with spontaneous eczema

Deterioration.

 Therapy history: The patient was on therapy for three years

various dermatologists and dermatologists. The following therapeutic trials were undertaken within this period:

 Topical: I) Individual recipe: Urea 5% in Excipial Lipolotion; II) Alfasone Repair; III) allergic base ointment (white vaseline, thick paraffin); IV)

Individual formulation: Triclosan 4.0 g, Glycerol 85% 20.0 g, Excipial U Lipolotio ad 200.0 g; V) Locacorten Vioform (flumetasone pivalate, clioquinol, combination of medium-potent glucocorticoid and a bacteriostatic antiseptic); VI) Chlorhexidine gluconate hydrophilic cream 0.5% / 1% (NRF 1 1 .1 16); Hydrous Hydrophilic Ointment (DAB 2008); VII) Individual formulation: Lipophilic polidocanol cream 5% / 10% (NRF 1 1 .1 19.); VIII) Individual formulation: chlorhexidine digluconate solution (aqueous, 20%) 20.0 g, base cream DAC ad 100 g; IX) Individual formulation: triclosan 1, 0 g, thesit 2.5 g, base cream DAC ad 50.0 g; X) Advantan 0.1% cream.

 Systemic: Zyrtec / cetirizine juice and Fenistil drops symptomatic of the itching).

The previous therapeutic approaches have not restored the integrity of the patient's skin. The skin is reddened since the outbreak of psoriasis on the flexor sides of the arms and wrists, cracked, partially open or covered with scabs. The patient complains of severe to very intense itching at the affected areas and scratches, resulting in bloody and partially oozing wounds. Fig. 4A shows the initial situation of the right wrist, the strongest

shows attacked skin; in Fig. 5A left arm bend can be seen. Solution with the "lysosomotropic antiapoptotic preparation (O / W cream) 0.03%. 30 mg amitriptyline are based on 100 g "lysosomotropic

antiapoptotic preparation (O / W cream) "/ base cream DAC (Bombastus, Freital, Germany) are incorporated twice daily and applied thinly to the affected skin (right wrist here) (Complexion, redness, open areas).

 Review of the treatment success: After 5 days of treatment, the skin appearance is visibly improved (FIG. 4B). The open and scabby areas are significantly reduced. The itching on the wrists and the crook of the arm has gone down. The patient scarcely scratches. On day 7, the appearance of the skin deteriorates (Figure 4C). Blistering above the treated sites, severe itching, permanent scratching of the patient at the untreated sites. Patient is restless, in a bad mood.

Expanded solution with the "Combined lysosomotropic, anti-apoptotic and antioxidative / lysosomal protective and V-ATPase-protective preparation (O / W cream) 0.03%." Following the recent onset of atopic dermatitis, the treatment of skin areas with the "Combined lysosomotropic, antiapoptotic and antioxidant / lysosomal protective and V-ATPase protective preparation (O / W cream) 0.03% ". 30 mg amitriptyline are incorporated into the "combined lysosomotropic, anti-apoptotic and antioxidant / lysosomal protective and V-ATPase protective preparation (O / W cream)" (Linola®, Dr. Wolff, Bielefeld, Germany) and are applied twice a day to the affected skin (right wrist)

applied. 0.5% fatty acids (C18: 2), unsaturated are the lysosomes protective and V-ATPase protective active ingredient in the base. Were observed in the

Course of therapy, the intensity of the itching and the condition of the skin (complexion, redness, open spots).

 Review of the therapeutic success: The skin on the right wrist of the patient regenerates visibly (FIGS. 4D to 4G) and forms a normal skin appearance. The itching on the wrist has disappeared. The normal skin function is

restored. After 45 days of treatment, only the "lysosomes protective and V-ATPase-protective" basis is applied to the affected patients for stabilization and prevention Applied skin areas. The skin is free of eczema, only mild sclerotic changes are still present as a result of psoriatic plaques. The patient is free from itching and pain. After 13 days of conservative therapy with the "lysosomes protective and V-ATPase protective" basis, more reddening and slight dandruff appear again

Therapy success and further regeneration of the skin, was another

three-week treatment interval with the "Combined lysosomotropic,

anti-apoptotic and antioxidant / lysosomal protective and V-ATPase protective preparation (O / W cream) 0.03% "carried out

Wrist stable and the skin is no longer of the normal skin

differ.

 The left crook of the arm was treated in the first 22 days after the right wrist approach. After 15 days, the skin condition had already been so stable that the maintenance treatment could be started with "Lysosomes protective and V-ATPase protective basis." The itching disappeared at this time, after 44 days with "Lysosome protective and V-ATPase protective basis "the skin is free of eczema and redness.

Proof of the superiority of the preparation according to the invention:

Synergistic therapeutic approach with the combined lysosomotropic, antiapoptotic and antioxidant / lysosomal protective and V-ATPase protective preparation (O / W cream) 0.03% "is capable of interrupting inflammatory events on the patient's wrist and the skin / keratinocytes to be able to fully regenerate, relapse to the well-known "lysosomal protective and V-ATPase-protective" preparation

Inflammation events flare up again. Nor is the "lysosomotropic and anti-apoptotic" formulation capable of controlling the inflammatory process

suppress, although already here in comparison to cortisone a significant improvement in the appearance of the skin is observed. Example 5

 Clinical results

Figure 1A shows a model of lysosomal C16 ceramide generation by the reverse activity of aCERase. Control by the pH in the lysosome due to the irreversible switch function of the lysosomal V-ATPase. Fig. 1B shows the

Ceramide metabolism in the cell: Crosslinking of ceramide (deNovo) syntheses with the model of C16 ceramide generation in the lysosome by the reverse activity of aCERase.

Fig. 1A particularly shows the mechanism of action of the present invention

Invention (without being bound thereto): amitriptyline as an exemplary active ingredient in a combined lysosomotropic, anti-apoptotic and antioxidant / lysosomal protective and V-ATPase-protective preparation (O / W cream) 0.03% and lysosomotropic, anti-apoptotic preparation (O / S) W cream) 0.03% prevents the hydrolyses of sphingomyelin and ceramide, sphingosine and

Palmitic acid is no longer sufficiently available for the reversible aCERase for C16-ceramide synthesis.

FIG. 1B shows the ceramide metabolism in the cell: cross-linking of ceramide (deNovo) syntheses with the model of C16-ceramide generation in the lysosome by the reverse activity of aCERase. Amitriptyline as an active ingredient in the combined lysosomotropic, antiapoptotic and antioxidant / lysosomal protective and V-ATPase protective preparation (O / W cream) according to the invention 0.03% and

Lysosomotropic, anti-apoptotic preparation (O / W cream) 0.03% prevents the hydrolyses of sphingomyelin and ceramide. C24: 1 Ceramide from the deNovo synthesis is no longer hydrolyzed in the lysosome and accumulates.

 In keratinocytes, the effect has a positive effect. Differentiated keratinocytes have high ceramide contents.

The active lysosome provides sphingosine for the second ceramide pathway via the ceramide synthases, which preferentially synthesize ceramides> C20. The antioxidant in the antioxidative / lysosomal protective and V-ATPase protective preparation (O / W cream) stabilizes the lysosomal function. In the combined Lysosomotropic, anti-apoptotic and antioxidative / lysosomal protective and V-ATPase-protective preparation (O / W cream) 0.03%, on the other hand, focus on the supply of reduction equivalents for ceramide deNovo synthesis.

Fig. 2A shows the quantification of selected ceramides in human PBMC by application of the indicated compounds / stimuli after 4 h incubation time. Alteration of C16 and C24: 1 ceramides by TNFalpha +/- NB 06, BHT ^* (2,6-di-tert-butyl-4-methoxy-phenol) and NB06. The ceramide contents are given as mean values ± SE, n = 3. One-way ANOVA in combination with a post-hoc t-test and

Bonferroni's correction for multiple testing, P <0.0001 (1-way ANOVA); Significant with P <0.05: ^*** against control, ^* TNFalpha against TNFalpha + NB 06.

Figure 2B shows the influence of NB 06 on LPS-induced, in differentiated

expressed genes in the totaIRNA of Mono-Mac-6 cells: time dependence of CSF3 and CCL18. Two other genes significantly altered by NB 06 in the hybridization experiment under LPS stimulation, which in the inflammatory process of the

rheumatoid arthritis are involved. Significance is assumed when the numerical value of differential gene expression is> 1 .5. ^* Significance of LPS + NB 06 vs LPS.

Figure 3A shows the expression of selected differentially expressed genes in mono Mac-6 cells. Human Mono Mac 6 cells were treated with 1 ng / ml LPS (E. coli serotype 01 1 1: B4) +/- 5 μM NB 06 (preincubation for 30 min) or only with 5 μM NB 06 (1 , 2, 4 or 6 h). Figure 3A shows the influence of NB 06 on LPS-induced differentially expressed genes in the totaIRNA of mono Mac-6 cells: time dependence of CXCL3, CCL4, CCL20, PTX3, CXCL10, CXCL2, PTGS2 and ICAM1-Eight significantly in the hybridization experiment genes altered by NB 06 under LPS stimulation. Figure 3B depicts the results for CXCL2, IL6, IL23A and TNFalpha, four genes significantly altered by NB 06 in real-time PCR under LPS stimulation. Significance is assumed when the numerical value of the differential

Gene expression is> 1 .5. ^* Significance of LPS + NB 06 vs LPS.

FIGS. 4A to 4K show the progress of the therapy of the right wrist by application of the preparation according to the invention for topical application "Lysosomotropic anti-apoptotic preparation (O / W cream) 0.03%" until day 7 post-application and the "Combined lysosomotropic, anti-apoptotic and antioxidant / lysosomal protective and V-ATPase protective preparation (O / W cream) 0.03%" Day 7 to day 45), then 13 days stabilization with the

"Lysosome-protective and V-ATPase-protective preparation (O / W cream)", from day 58 for protection and complete regeneration Further treatment with "Combined lysosomotropic, anti-apoptotic and antioxidative / lysosomal protective and V-ATPase-protective preparation (O / W cream) 0 , 03% "(until day 84). (K) Left

Wrist after 15 days of treatment with the combined lysosomotropic, antiapoptotic and antioxidant / lysosomal protective and V-ATPase

Protective preparation (O / W cream) 0.03% ", then 71 days with the" antioxidant / lysosomal protective and V-ATPase-protective preparation (O / W cream) ".

Fig. 4A shows eczema foci on the top of the wrist (right hand) at the beginning of the treatment.

Fig. 4B shows the same flock 4 days after starting treatment with the

"Lysosomotropic anti-apoptotic preparation (O / W cream) 0.03%." Significantly reduced itching, hardly scratching by the patient.

Fig. 4C shows treatment with the lysosomotropes 7 days after onset

anti-apoptotic preparation (O / W cream) 0.03% ". Neurodermatitis outbreak,

Blistering accompanied by strong restlessness and intense itching in the affected areas, again increased scratching. Change to the "Combined lysosomotropic, anti-apoptotic and antioxidant / lysosomal protective and V-ATPase protective preparation" (O / W cream) 0.03% ".

Figure 4D shows the affected skin areas 6 days after initiation of treatment with the "Combined Lysosomotropic, Antiapoptotic and Anti-oxidative / Lysosome Protective and V-ATPase Protective Preparation" (O / W Cream) 0.03% ". Reduced eczema, no itching, no more blisters. FIG. 4E shows the further course of therapy 15 days after treatment of the "Combined lysosomotropic, antiapoptotic and antioxidative / lysosomal protective and V-ATPase-protective preparation" (O / W cream) 0.03% ".

Fig. 4F shows the situation 22 days after treatment of the "Combined

lysosomotropic, antiapoptotic and antioxidant / lysosomal protective and V-ATPase protective preparation "(O / W cream) 0.03%". Open areas are barely recognizable, greatly improved skin appearance.

Fig. 4G shows the affected skin areas 40 days after treatment with the "Combined lysosomotropic, antiapoptotic and antioxidant / lysosomal protective and V-ATPase protective preparation (O / W cream) 0.03%." Open spots or redness are barely discernible , almost normal complexion.

Fig. 4H shows the situation 45 days after treatment with the "Combined lysosomotropic, antiapoptotic and antioxidant / lysosomal protective and V-ATPase protective preparation (O / W cream) 0.03%" and 13 days with the

"Anti-oxidative / lysosomal protective and V-ATPase-protective preparation (O / W cream)" for stabilization, mild itching reappears Renewed treatment with the "Combined lysosomotropic, antiapoptotic and antioxidant / lysosomal protective and V-ATPase protective preparation" (O. / W cream) 0.03% ".

Fig. 41 shows the affected skin sites 16 days after re-treatment with the "Combined lysosomotropic, antiapoptotic and antioxidant / lysosomal protective and V-ATPase protective preparation (O / W cream) 0.03%." Furrow formation continues to decline and regression progresses, cuticle formation comparable to sunburn. (Irritation by chlorinated pool water / heliotherapy) possible.

Fig. 4J: Condition 26 days after re-treatment with the

"Combined lysosomotropic, antiapoptotic and antioxidant / lysosomal protective and V-ATPase protective preparation (O / W cream) 0.03%." Almost normal skin appearance achieved., Minimal skin formation still present. Fig. 4K shows the top of the only slightly affected wrist of the left hand for comparison. 15 days "Combined lysosomotropic, antiapoptotic and antioxidant / lysosomal protective and V-ATPase protective preparation (O / W cream) 0.03%", then 71 days with the "antioxidant / lysosomal protective and V-ATPase protective preparation (O / W Cream) "for stabilization. After 15 days of therapy, there are no signs of eczema.

5 shows the treatment progress of a neurodermitic eczema of the left arm flexion by applying the "Combined lysosomotropic, antiapoptotic and antioxidative / lysosomal protective and V-ATPase protective preparation (O / W cream) 0.03%" to day 7 after the start of administration and the " combined

lysosomotropic, antiapoptotic and antioxidant / lysosomal protective and V-ATPase protective preparation (O / W cream) 0.03% "from day 7 to day 15.

Stabilization starting on day 16 with the "antioxidant / lysosomal protective and V-ATPase-protective preparation (O / W cream)" for stabilization.

Fig. 5A shows the eczema foci in the left crook of the arm at the beginning of the treatment.

Fig. 5B shows the condition 4 days after the start of the treatment with a lysosomotropic anti-apoptotic preparation (O / W cream) 0.03%. "Significantly reduced eczema herd, only slight redness No itching.

Figure 5C shows the situation 15 days after initiation of treatment with the "Combined lysosomotropic, antiapoptotic and antioxidant / lysosomal protective and V-ATPase protective preparation (O / W cream) 0.03%." Change to "antioxidant / lysosomal protective and V-ATPase protective preparation (O / W cream) "for stabilization). Open areas are barely visible, almost normal skin.

Fig. 5D shows the affected skin areas 15 days after treatment with the "Combined Lysosomotropic, Antiapoptotic and Antioxidant / Lysosome Protective and V-ATPase Protective Preparation (O / W Cream) 0.03%" and 44 days with the "antioxidant / lysosomal protective and V-ATPase-protective preparation (O / W cream) "for stabilization, no itching, skin is stable, too, normal skin appearance and symptom-free.

Fig. 6 shows the therapeutic progress of a psoriasis on the pinna and on the scalp of a patient by applying the "Combined lysosomotropic, antiapoptotic and antioxidant / lysosomal protective and V-ATPase protective preparation (O / W cream) 0.03%".

Figures 6A and C show the psoriasis at the beginning of the treatment. Significant lichenification or raised scab formation.

Fig. 6B shows the auricle on day 12 after the start of the application of

"Combined lysosomotropic, antiapoptotic and antioxidant / lysosomal protective and V-ATPase protective preparation (O / W cream) 0.03%"

Lichenification of the auricle has almost completely disappeared. Only slight skin formation in the context of skin regeneration to crave. Complete healing after 15 days of application.

Fig. 6D shows the hairy scalp 5 day application start with the

"Combined lysosomotropic, antiapoptotic and antioxidative / lysosomal protective and V-ATPase protective preparation (O / W cream) 0.03%." There is no more scabbing, the scalp is only slightly red in the treated area.

Further application examples with different lysosomotropic agents

In the examples, the content of lysosomotropic drug in the

Pharmaceutical preparation is given as m / m [%] and is adjusted from the lysosomes of Table 1 using the IC50 measurements of the displacement of the lysosomal-labeling fluorescent dye LysoTracker Red DND-99.

Unless otherwise specified in the examples below, the antioxidant / lysosomal protective / V-ATPase protective agent is linoleic acid, Linolenic acid, tocopherol acetate, black cumin oil or olive oil or a mixture thereof.

Assessment of the therapeutic effect of the applied test specimens, defined as the Total Sign Score (PsS) for psoriasis, the Eczema Area and Severity Index (EASI) for atopic dermatitis) in the treated area. Treatment duration up to 6 weeks.

 The endpoint is the reduction of the disease-typical score for atopic patients

Dermatitis / psoriasis at or below 75 (very good response) and at or below 95% of baseline (75% or 95% reduction in the area involved) (PASI 75 / EASI 74, PASI 95 / EASI 95). For red spots, an individual score (J-score) is used: "0" no itching, no irritation recognizable to "10" itching, strong urge to scratch, scaly skin, severe erythema.

Application Example 6

 Benzazepine derivatives (imipramine, desipramine, trimipramine, NB 02) with imipramine as lead compound

 Topical application of the preparation according to the invention consisting of

Imipramine 0.03% in a lysosomotropic and antiapoptotic preparation, and a combined lysosomotropic, antiapoptotic and antioxidant / lysosomal protective and V-ATPase protective preparation:

 a) for the treatment of psoriasis. Similar to Example 4 (therapeutic trial), two patients (23 years, female, 34 years, female) are treated twice a day on the reddened and thickened areas of the skin. After 5 or 7 days the thickened areas of the skin have decreased significantly (PASI 75), after 14 days the skin has largely normalized (PASI 95).

 b) for the treatment of atopic dermatitis. Analogously to Example 4

(Therapeutic trial) three patients (18 years, male, 54 years female, 43 years, male) are treated twice daily on the reddened skin areas and skin lesions. Between the 7th and 12th day, the redness has almost disappeared, the lesions significantly reduced (EASI 75), after 26 days the skin has changed

Normalized as far as possible and symptom-free (EASI 95). At the same time treated itchy areas of the skin are symptom-free after only 2 days (J score = 0). Application example 7

 Phenothiazine derivatives (chlorpromazine, levomepromazine, promazine, promethazine, triflupromazine, NB 03, NB 08, NB 39) with chlorpromazine as the lead compound

 Topical application of the preparation according to the invention consisting of

Chlorpromazine 0.04% in a lysosomotropic and antiapoptotic preparation, as well as a combined lysosomotropic, antiapoptotic and antioxidant / lysosomal protective and V-ATPase protective preparation:

 a) for the treatment of psoriasis. Similar to Example 4 (therapeutic trial) three patients (35 years, female, 49 years, female, 18 years, male) are treated twice a day on the reddened and thickened areas of the skin. Between 7 and 9 days, the thickened areas of the skin have decreased significantly (PASI 75), after 16 days the skin has largely normalized PASI 95).

 b) for the treatment of atopic dermatitis. Analogously to Example 4

(Therapy attempt) three patients (29 years, male, 37 years female, 49 years, male) are treated twice a day on the reddened skin areas and skin lesions. Between the 8th and 1 1 day, the redness has almost disappeared (EASI 75), the lesions significantly reduced, after 22 days, the skin has become

Normalized as far as possible and symptom-free (PASI 95). At the same time treated itchy areas of the skin are symptom-free after only 3 days (J score = 0).

Application Example 8

 (Repetition of Example 4)

Annulen derivatives (amitriptyline, nortriptyline, NB 38) with amitriptyline as

lead compound

 Topical application of the preparation according to the invention consisting of

Amitriptyline 0.03% in a lysosomotropic and antiapoptotic preparation, and a combined lysosomotropic, antiapoptotic and antioxidant / lysosomal protective and V-ATPase protective preparation:

 a) for the treatment of psoriasis. Similar to Example 4 (therapeutic trial), two patients (45 years, 49 years, male) will be reddened and thickened

Treated skin areas twice daily. Between the 6 and 8 days, the thickened areas of the skin have decreased significantly (PASI 75), after 14 days the skin has largely normalized (PASI 95). b) for the treatment of atopic dermatitis. Analogously to Example 4

(Therapy attempt) two patients (41 years, male, 30 years female) are treated twice a day on the reddened skin areas and skin lesions. Between the 9th and 15th day, the redness has almost disappeared, the lesions significantly reduced (EASI 75), after 25 days the skin has largely normalized and is symptom-free (EASI 95). At the same time treated itchy areas of the skin are symptom-free after only 2 days (J score = 0).

Application Example 9

 Topical application of the preparation according to the invention consisting of 0.03% amitriptyline in a lysosomotropic and antiapoptotic preparation, as well as a combined lysosomotropic, antiapoptotic and antioxidant / lysosomal protective and V-ATPase protective preparation when applied to Liehen planus mueosa in the oral cavity (atopic dermatitis in the oral cavity).

 The lysosomotropic, anti-apoptotic and antioxidant / lysosomal protective and V-ATPase-protective adhesive paste 0.03% of the formulation substance (100 g) consists of amitriptyline 0.03 g, linoleic acid 0.5 g, thick paraffin 1, 0 g, hypromellose adhesive paste 40 % (manufactured in accordance with Deutscher Arzneimittel-Codex, New Formulation Form NRF p. 42). After 5 days, the yellowish-white mucous membrane lesion significantly reduced (<75% of the initial area), after 9 days the

Mouth mucosa completely restored.

 For testing selected not yet approved as a drug

Lysosomotropic compounds of Table 1 in the atopic dermatitis indication are treated by approximately 6 months old male NC / Nga mice that spontaneously develop itchy skin lesions under normal housing conditions (Martel, BC; Yale J Biol Med. 2017; 90: 389-402) Service. After occurrence of the spontaneous skin lesions and reach a size of 5 mm in diameter, the affected skin areas - as in Example 4 - treated twice daily and observed the development of the lesion with respect to redness and dilation. Based on the results of the previous one

 Observational studies (Application Example 2-4) have refrained from investigating the compounds in psoriatic mice, as the tested compounds have been shown to be effective in both indications, and a

overlapping inflammatory processes at the molecular level is assumed (Guttman-Yassky E, Exp Dermatol 2018, 27: 409-417). It can be assumed that the compounds are also effective in the psoriatic animal model.

Application Example 10

 Carbazole derivatives (NB 06, NB 18, NB 19, NB 45) with NB 06 as lead compound Topical application of the preparation according to the invention consisting of NB 06 0.04% in a lysosomotropic and antiapoptotic preparation, as well as a combined lysosomotropic, anti-apoptotic and antioxidative Lysosomal protective and V-ATPase protective preparation:

 Four mice (5 months, 7 months male, 5 months, 6 months female) are treated twice a day on the reddened areas of the skin and the skin lesions, analogously to Example 4 (therapeutic trial). Between the 12th and 15th day are the

Redness almost disappeared, the lesions significantly reduced (EASI 75), after 20 days the skin has largely normalized and is symptom-free (EASI 95).

Application Example 1 1

 Phenoxazine derivatives (NB 37) with NB 37 as lead compound

 Topical application of the preparation according to the invention consisting of NB 37 0.045% in a lysosomotropic and antiapoptotic preparation, and a combined lysosomotropic, antiapoptotic and antioxidant / lysosomal protective and V-ATPase-protective preparation:

 Four mice (4 months, 5 months male, 5 months, 4 months female) on the reddened areas of the skin and the skin lesions are treated twice a day as in Example 4 (therapeutic trial). Between the 14th and 17th day are the

Redness almost disappeared, the lesions significantly reduced (EASI 75), after 25 days the skin has largely normalized and is symptom-free (EASI 95).

Example 12

 Variants of the preparation of the active ingredient combination according to the invention

The combination of a lysosomotropic, antiapoptotic and antioxidant / lysosomal protective therapy approach is a synergistic therapeutic approach that is capable of not only the self-reinforcing inflammatory response in atopic patients Dermatitis and psoriasis, but also the inflammatory processes of other diseases in which the NB 06 modulated interleukins and cytokines are involved, in particular rheumatoid arthritis or Crohn's disease / ulcerative colitis. By modification of the preparation are also internal surfaces,

especially the intestinal epithelium, the gingiva or the vagina accessible.

In a further embodiment of the invention for the application of

The combination of active ingredients in the oral cavity according to the invention are all orally, im

Gastrointestinal tract are all orally or rectally administrable dosage forms preparations according to the invention, in particular drug forms with modified / sustained release drug release. They include suspensions, liposomal

Preparations, emulsions, compressed, enteric-coated tablets,

enteric-coated capsules, tablets, capsules or push-pull systems,

active ingredient chewing gum, suppository, sublingual tablets, adhesive pastes, granules or their retarded forms. The vaginal mucosa is according to the invention with (vaginal) ovules and tampons containing active ingredients, accessible.

In a further embodiment of the invention for the application of

The combination of active substances according to the invention in joints, intramuscularly or subcutaneously are all formulations which can be administered parenterally, preparations according to the invention, in particular dosage forms with or without modified / retarded

Drug release. They include solutions, suspensions, crystal suspensions, liposomal preparations or emulsions. The application of liposomes, in particular multilamellar, multilayer, concentric bilayers, offers the advantage that the active ingredient combination according to the invention, in particular the antioxidant / lysosomal protective active ingredient, in particular tocopherol, is usually very lipophilic and thus homogeneous, hydrophilic, with the lysosomotropic, antiapoptotic active ingredient Water-miscible solution can be applied. The content of the antioxidant, in particular of tocopherol as active ingredient, is around

Many times higher than when used as a stabilizer for the pharmaceutical

Preparation. Accordingly, tocopherol is declared in the preparation as an active ingredient and not as an adjuvant. Further preparation possibilities in the context of the present invention are the following (according to the place of application):

 Skin: carbomer gel pH 5 / pH 6.5 (NRF p. 43.)

 Emulsifier: propylene glycol, butylhydroxytoluene, 2-propanol, propylene glycol,

Cocoyl caprylic caprate, carbomer, diethylamine

 Mouth: Hypromellose adhesive paste 40% (NRF p. 42.)

 Vagina: vaginal gel pH 5 (NRF 25.3.)

 Vaginal suppositories: analogous to (NRF 25.1.)

 Vaginal capsules: Preferred embodiments are soft gelatin capsules with in particular unsaturated fatty acids, olive oil, almond oil or

 Evening primrose seed oil as an antioxidant and dissolved or dispersed lysosomotropic agent or a mixture of active ingredients.

The following are suitable for the preparation of O / W and W / O emulsions: Suitable lipophilic / amphiphilic components are hydrocarbons, natural and synthetic fats, fatty acids, oils, waxes fatty alcohols, fatty acid esters, glycerol, urea, glycerides (mono-di) , Lecithin,

Solid formulations may be, for example, tablets into which pharmaceutical preparations targeting the synergistic lysosomotropic, anti-apoptotic and antioxidant / lysosomal protective effect consist of the active ingredient incorporated in a base with antioxidant active ingredients.

A semi-solid preparation is, for example, a preparation of amitriptyline in a base consisting of fatty acids (C18: 2), unsaturated; 2 (4-tert-butylbenzyl) propionaldehyde; oleate; Odorant.

Claims

claims

1 . Composition for the topical treatment of non-microorganism causing inflammatory skin and mucous membrane diseases, characterized in that it comprises at least one lysosomotropic, antiapoptotically active substance or a substance combination of at least one lysosomotropic antiapoptotically active substance and at least one antioxidant substance and / or a reactive Carbonylspiezies intercepting substance contains.

2. Composition according to claim 1, characterized in that the non-microorganism-caused inflammatory skin and mucous membrane diseases, in particular psoriasis type I and type II, preferably psoriasis vulgaris, psoriasis guttata, psoriasis nummeralis, erythrodermal psoriasis, psoriasis pustulosa; especially eczema, atopic dermatitis, atopic dermatitis, lichen planus (oral dermatitis) and pytyriasis capitis.

3. Composition according to claim 1 or 2, characterized in that at least one lysosomotropic antiapoptotically active substance is selected from the group consisting of: lysosomotropic, antiapoptotically active substances containing as essential structural element a basic, aliphatic and protonatable side chain or ring structure, a pK _a Value between 6 and 8.5, and an n-octanol-water partition coefficient log P value> 4.0 have.

4. The composition according to claim 3, characterized in that the at least one lysosomotropic antiapoptotically active substance is selected from the group consisting of: 3- (5,6-dihydrobenzo [b] [1] benzazepin-1 1 - yl) propane-1 -amines, in particular, 3- (5,6-dihydrobenzo [b] [1] benzazepin-1 1 -yl) - N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 01), 3- (5,6-dihydrobenzo [b] [1] benzazepin-1 1-yl) -N- [2- (4-methoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 02), imipramine (3- (5,6-dihydrobenzo [b] [1] benzazepine-1 1-yl ) - N, N-dimethyl-propan-1-mannin), desipramine (3- (5,6-dihydrobenzo [b] [1] benzazepine-1 1-yl) -N-methyl-propane-1-mannin), Trimipramine (3- (5,6-dihydrobenzo [b] [1] benzazepine-1 1 -yl) -N, N, 2-trimethylpropan-1-amine); 2- (5,6-dihydrobenzo [b] [1] benzazepine-1 1 -yl) ethanamines, especially N- [2- (5,6-dihydrobenzo [b] [1] benzazepine-1 1-yl) ethyl] -2- (3,4-dimethoxyphenyl) -N-methyl-ethanamine (NB 15), N- [2- (5,6-dihydrobenzo [b] [1] benzazepin-1 1 -yl) ethyl] -2- (4-methoxyphenyl) -N-methyl-ethanannine (NB 16); 3-phenothiazin-10-yl-propan-1-amines, especially 3- (2-chlorophenothiazin-10-yl) -N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-propan-1-mannin ( NB 03), 2- (4-methoxyphenyl) -N-methyl-N- (2-phenothiazin-10-yl-ethyl) -ethanamine (NB 08), N- [2- (3,4-dimethoxyphenyl) ethyl] -N- methyl 3-phenothiazin-10-yl-propan-1-amine (NB 40), N- [2- (4-methoxyphenyl) ethyl] -N-methyl-3-phenothiazin-10-yl-propan-1-amine (NB 39), chlorpromazine (3- (2-chlorophenothiazin-10-yl) -N, N-dimethyl-propan-1-amine), levomepromazine (2R) -3- (2-methoxyphenothiazin-10-yl) -N , N, 2-thmethylpropan-1-amine Promazine (N, N-Dimethyl-3- (10H-phenothiazine-10-yl) propan-1-amine), promethazine (N, N-dimethyl-1-phenothiazine-10 ylpropan-2-amine), thioridazine (10- [2- (1-methylpiperidin-2-yl) ethyl] -2-methylsulfanylphenothiazine), triflupromazine (N, N-dimethyl-3- [2-

(trifluoromethyl) phenothiazine-l 0-yl] propan-1-amine); 3-phenoxazin-10-yl-propan-1-amines, in particular N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-3-phenoxazin-10-yl-propan-1-amine (NB 37), N- [2- (4-methoxyphenyl) ethyl] -N-methyl-3-phenoxazin-10-yl-propan-1-amine (NB 20), 10- [3 - [(3S, 5R) -4- 2- (4-methoxyphenyl) ethyl] -3,5-dimethylpiperazin-1-yl] propyl] phenoxazine (NB 36); 3- (5,6-dihydrodibenzo [1,2-a: 2 ', 1'-d] [7] annulen-1 1 -ylidene) -propane-1-amines, especially 3- (5,6-dihydrodibenzo [2 , 1 -b: 1 ', 2'-e] [7] annulen-1 1 -ylidene) -N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 38), 3- (5,6-dihydrodibenzo [2,1 -b: 1 ', 2'-e] [7] annulene-1 1 -ylidene) -N- [2- (4-methoxyphenyl) ethyl] - N-methyl-propan-1-amine (NB 31), nortriptyline (3- (5,6-dihydro-dibenzo [2,1 -b: 2 ', 1' -f] [7] annulen-1 1-ylidenes) - N-methylpropane-1-amine,

Amitriptyline (3- (5,6-dihydrodibenzo [2,1 -b: 2 ', 1' - f | [7] annulen-1 1 -ylidene) -N, N- dimethylpropane-1-amine); 1 - (6,1 1 -dihydro-5H-dibenzo [1,2-a: 2 ', 1'-d] [7] annulene-1 1-yl) hexahydropyrinnidines, especially 1- (6,1 1 -dihydro 5H-dibenzo [2,1 -b: 1 ', 2'-e] [7] annulene-1 1 -yl) -3- [2- (3,4-dimethoxyphenyl) ethyl] hexahydropyrimidine (NB 47), 1 - (6,1 1 -dihydro-5H-dibenzo [2,1 -b: 1 ', 2'-e] [7] annulene-1 1 -yl) -3- [2- (4-methoxyphenyl) -ethyl ] hexahydropyhmidine (NB 24); N '- (6,1 1 -dihydro-5H-dibenzo [1,2-a: 2', 1'-d] [7] annulen-1 1 -yl) propane-1,3-diamine, especially N ' - (6,1 1 -dihydro-5H-dibenzo [1,2-a: 2 ', 1'-d] [7] annulen-1 1 -yl) -N- [2- (3,4-dimethoxyphenyl) ethyl] propane-1,3-diannine (NB 41), N '- (6,1 1 -dihydro-5H-dibenzo [1,2-a: 2', 1'-d] [7] annulen-1 1 -yl) -N- [2- (4-methoxyphenyl) ethyl] propane-1,3-diamine (NB 46); 3- (1,1,1,2-dihydro-6H-benzo [c] [1] benzazocin-5-yl) propan-1-amine, especially 3- (1,1-dihydro-6H-benzo [c] [1 ] benzazocin-5-yl) - N - [2- (4-methoxyphenyl) ethyl] -N-methyl-propan-1-mannin (NB 21); 2,3,3a, 4,5,6-hexahydro-1H-pyrazino [3,2,1-jk] carbazoles, in particular 3- [2- (4-methoxy-phenyl) -ethyl] -2,3, 3a, 4,5,6-hexahydro-1H-pyrazino [3,2,1-jk] carbazole (NB 43); 1, 2,3,3a, 4,5,6,7-octahydro- [1,4] diazepino [3,2,1-jk] carbazole, 4- [2- (4-methoxy-phenyl) -ethyl] - 1, 2,3,3a, 4,5,6,7-octahydro- [1,4] diazepino [3,2,1-jk] carbazole (NB 44); - (3-aminopropyl) -1, 4-benzoxazin-3-ones, in particular 4- [3- [2- (4-methoxyphenyl) ethyl-methyl-amino] -propyl] -1, 4-benzoxazin-3-one ( NB 48); N '- (1-naphthyl) ethane-1,2-diamines, in particular N- [2- (3,4-dimethoxyphenyl) ethyl] -N'- (1-naphthyl) ethane-1,2-diamine (NB 10 ); 1 -naphthylmethananninen, in particular 2- (3,4-dimethoxyphenyl) -N- (1 -naphthylmethyl) ethanamine (NB 12); , 3-carbazol-9-yl-propan-1-amines, in particular 3-carbazol-9-yl-N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-propan-1-mannin (NB 05), 3-carbazol-9-yl-N - [(4-methoxyphenyl) methyl] -N-methyl-propan-1-amine (NB 30), 9- [3 - [(3S, 5R) -4- [2- (3,4-dimethoxyphenyl) ethyl] -3,5-dimethyl-piperazine-1-yl] propyl] carbazole (NB 42), 3-carbazol-9-yl-N- [2- (4-methoxyphenyl) ethyl] N-methyl-propan-1-amine (NB 06), 9- [3 - [(3S, 5R) -4- [2- (4-methoxyphenyl) ethyl] -3,5-dimethyl-piperazine-1 - yl] propyl] carbazole (NB 19), 3-carbazol-9-yl-N- [2- [4- [2- [3-carbazol-9-yl-propyl (methyl) -amino] -ethyl] -2,5 -dimethoxyphenyl] ethyl] -N-methyl-propan-1-amine (NB 45); 2-carbazol-9-ylethaneamines, especially N- (2-carbazol-9-yl-ethyl) -2- (4-methoxyphenyl) -N-methyl-ethanamine (NB 25), 9 - [[4- [2- (4 - methoxyphenyl) ethyl] piperazin-1-yl] methyl] carbazole (NB 18); 7-chloroquinolin-4-amines, in particular chloroquine (4-N- (7-chloroquinolin-4-yl) -1 -N, 1 -N- diethylpentane-1, 4-diamine); and mixtures thereof.

5. Composition according to one of the preceding claims, characterized in that the at least one lysosomotropic, antiapoptotically active substance is preferably selected from the group consisting of: 3- (5,6-dihydrobenzo [b] [1] benzazepin-1 1 -yl ) propan-1-amines, especially 3- (5,6-dihydrobenzo [b] [1] benzazepine-1 1 -yl) -N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-propane -1-amine (NB 01); Imipramine (3- (5,6-dihydrobenzo [b] [1] benzazepine-1 1 -yl) -N, N-dimethyl-propan-1-amine), desipramine (3- (5,6-dihydrobenzo [b] [1] benzazepine-1 1 -yl) -N-methyl-propane-1-amine), trimipramine (3- (5,6-dihydrobenzo [b] [1] benzazepin-1 1 -yl) -N, N, 2-trimethylpropane-1-amine); N- [2- (5,6-dihydrobenzo [b] [1] benzazepine-1 1 -yl) ethyl] -2- (3,4-dimethoxyphenyl) -N-methyl-ethanamine (NB 15); 3-phenothiazin-10-yl-propan-1-amines, especially 3- (2-chlorophenothiazin-10-yl) -N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-propan-1-amine ( NB 03); Chlorpromazine (3- (2-chlorophenothiazin-10-yl) -N, N-dimethyl-propan-1-amine), levomepromazine (2R) -3- (2-methoxyphenothiazin-10-yl) -N, N, 2 trimethylpropane-1-amine promazine (N, N-dimethyl-3- (1-OH-phenothiazine-10-yl) -propane-1-amine), promethazine (N, N-dimethyl-1-phenothiazin-10-yl-propan-2-yl) amine), thioridazine (10- [2- (1-methylpiperidin-2-yl) ethyl] -2-methylsulfanylphenothiazine), triflupromazine (N, N-dimethyl-3- [2-

(trifluoromethyl) phenothiazine-l 0-yl] propan-1-amine); 3-phenoxazin-10-yl-propan-1-aminee, especially N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-3-phenoxazin-10-yl-propan-1-amine (NB 37); 3- (5,6-dihydrodibenzo [1,2-a: 2 ', 1' -d] [7] annulen-1 1-ylidenes) propan-1-amines, especially 3- (5,6-dihydrodibenzo [2 , 1 -b: 1 ', 2'-e] [7] annulen-1 1 -ylidene) -N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 38); Nortriptyline (3- (5,6-dihydrodibenzo [2,1 -b: 2 ', 1' - f] [7] annulene-1 1-ylidenes) -N-methylpropan-1-amine, amitriptyline (3- (5 , 6-dihydrodibenzo [2,1 -b: 2 ', 1' - f] [7] annulen-1 1 -ylidene) -N, N-dimethylpropan-1-amine); 1 - (6,1 1 -dihydro -5H-dibenzo [1,2-a: 2 ', 1'-d] [7] annulene-1 1-yl) hexahydropyrimidines, in particular 1 - (6,1 1 -dihydro-5H-dibenzo [2,1 - b: 1 ', 2'-e] [7] annulene-1 1 -yl) -3- [2- (3,4-dimethoxyphenyl) ethyl] hexahydropyrimidine (NB 47), 1- (6,1 1 -dihydro -5H-dibenzo [2,1 -b: 1 ', 2'-e] [7] annulene-1 1 -yl) -3- [2- (4-methoxyphenyl) ethyl] hexahydropyrimidine (NB 24); N' - (6.1 1 -dihydro-5H- dibenzo [1,2-a: 2 ', 1'-d] [7] annulen-1 1 -yl) propane-1,3-diamine, especially N' - (6,1 1 -dihydro-5H-dibenzo [ 1, 2-a: 2 ', 1'-d] [7] annulene-1 1 -yl) -N- [2- (3,4-dimethoxyphenyl) ethyl] propane-1,3-diaminine (NB 41) ; 3- (1,1-Dihydro-6H-benzo [c] [1] benzazocin-5-yl) - N - [2- (4-methoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 21); 2,3,3a, 4,5,6-hexahydro-1H-pyrazino [3,2,1 -jk] carbazoles, especially 3- [2- (4-methoxy-phenyl) -ethyl] -2,3, 3a, 4,5,6-hexahydro-1H-pyrazino [3,2,1-jk] carbazole (NB 43); 1, 2,3,3a, 4,5,6,7-octahydro- [1,4] diazepino [3,2,1 -jk] carbazoles, especially 4- [2- (4-methoxyphenyl) -ethyl ] - 1, 2,3,3a, 4,5,6,7-octahydro- [1,4] diazepino [3,2,1-jk] carbazole (NB 44); 4- (3-aminopropyl) -1, 4-benzoxazin-3-ones, especially 4- [3- [2- (4-methoxyphenyl) ethyl-methylamino] propyl] -1,4-benzoxazin-3-one (NB 48); N '- (1-naphthyl) ethane-1,2-diamine, in particular N- [2- (3,4-dimethoxyphenyl) ethyl] -N'- (1-naphthyl) ethane-1,2-diamine (NB 10 ); 1 -naphthylmethanannines, especially 2- (3,4-dimethoxyphenyl) -N- (1-naphthylmethyl) ethanamine (NB 12); 3-carbazol-9-yl-propan-1-amines, especially 3-carbazol-9-yl-N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-propan-1-tannins (NB 05); 3-carbazol-9-yl-N- [2- (4-methoxyphenyl) ethyl] -N-methyl-propan-1-mannin (NB 06); 2-carbazol-9-ylethaneamines, N- (2-carbazol-9-yl-ethyl) -2- (4-methoxyphenyl) -N-methyl-ethanamine (NB 25), 9 - [[4- [2- (4- methoxyphenyl) ethyl] piperazin-1-yl] methyl] carbazole (NB 18); Chloroquine (4-N- (7-chloroquinolin-4-yl) -1-N, 1-N-diethylpentane-1, 4-diamine); and mixtures thereof.

6. The composition according to claim 5, characterized in that the at least one lysosomotropic, antiapoptotically active substance is preferably selected from the group consisting of: benzazepine derivatives, in particular 3- (5,6-dihydrobenzo [b] [1] benzazepine -1 1 -yl) propan-1-amine, 3- (5,6-dihydrobenzo [b] [1] benzazepine-1 1 -yl) -N- [2- (3,4-dimethoxyphenyl) ethyl] -N -methyl-propan-1-amine (NB 01); Imipramine (3- (5,6-dihydrobenzo [b] [1] benzazepine-1 1 -yl) -N, N-dimethyl-propan-1-amine), desipramine (3- (5,6-dihydrobenzo [b] [1] benzazepine-1 1 -yl) -N-methyl-propane-1-amine), trimipramine (3- (5,6-dihydrobenzo [b] [1] benzazepin-1 1 -yl) -N, N, 2-trimethylpropane-1-amine); N- [2- (5,6-dihydrobenzo [b] [1] benzazepine-1 1 -yl) ethyl] -2- (3,4-dimethoxyphenyl) -N-methyl-ethanamine (NB 15); and mixtures thereof.

7. The composition according to claim 5, characterized in that the at least one lysosomotropic, antiapoptotically active substance is preferably selected from the group consisting of phenothiazine derivatives, in particular 3-phenothiazin-10-ylpropan-1-amines, 3- (2 -chlorophenothiazine-10-yl) -N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 03); Chlorpromazine (3- (2-chlorophenothiazin-10-yl) -N, N-dimethyl-propan-1-amine), levomepromazine (2R) -3- (2-methoxyphenothiazin-10-yl) -N, N, 2 trimethylpropane-1-amine promazine (N, N-dimethyl-3- (10H-phenothiazin-10-yl) -propane-1-amine), promethazine (N, N-dimethyl-1-phenothiazin-10-yl-propan-2-amine ), Thioridazine (10- [2- (1-methylpiperidin-2-yl) ethyl] -2-methylsulfanylphenothiazine)

 Triflupromazine (N, N-dimethyl-3- [2- (trifluoromethyl) phenothiazin-10-yl] propan-1-amine); and mixtures thereof.

8. The composition according to claim 5, characterized in that the at least one lysosomotropic, antiapoptotically active substance is preferably selected from the group consisting of phenoxazine derivatives, in particular 3-phenoxazin-10-ylpropan-1-amines, N- [2 - (3,4-dimethoxyphenyl) ethyl] -N-methyl-3-phenoxazin-10-yl-propan-1-amine (NB 37); and mixtures thereof.

9. The composition according to claim 5, characterized in that the at least one lysosomotropic, antiapoptotically active substance is preferably selected from the group consisting of annulenes derivatives, in particular 3- (5,6-dihydrodibenzo [1, 2-a: 2 ', 1'-d] [7] annulen-1 1 -ylidene) propan-1-amines, 3- (5,6-dihydrodibenzo [2,1 -b: 1', 2'-e] [7] annulene -1 1 -ylidene) -N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 38); Nortriptyline (3- (5,6-dihydrodibenzo [2,1 -b: 2 ', 1' - f] [7] annulen-1 1 -ylidene) -N-methylpropan-1-amine,

Amitriptyline (3- (5,6-dihydrodibenzo [2,1 -b: 2 ', 1'-f | [7] annulene-1 1 -ylidene) -N, N-dimethylpropan-1-amine); 1 - (6,1 1 -dihydro-5H-dibenzo [1,2-a: 2 ', 1' -d] [7] annulen-1 1-yl) hexahydropyrimidines, 1- (6,1 1 -dihydro- 5H-dibenzo [2,1 -b: 1 ', 2'-e] [7] annulene-1 1-yl) -3- [2- (3,4-dimethoxyphenyl) ethyl] hexahydropyrimidine (NB 47), 1 - (6,1 1 -dihydro-5H-dibenzo [2,1 -b: 1 ', 2'-e] [7] annulene-1 1 -yl) -3- [2- (4- methoxyphenyl) ethyl] hexahydropyrinnicline (NB 24); N '- (6,1 1 -dihydro-5H-dibenzo [1,2-a: 2', 1'-d] [7] annulen-1 1 -yl) -propane-1,3-diamine, N'- (6,1 1 -dihydro-5H-dibenzo [1,2-a: 2 \ 1'-d] [7] annulen-1 1 -yl) -N- [2- (3,4-dimethoxyphenyl) ethyl] propane-1,3-diamine (NB 41); and mixtures thereof.

10. The composition according to claim 5, characterized in that the at least one lysosomotropic, antiapoptotically active substance is preferably selected from the group consisting of benzazozin derivatives in particular 3- (1 1, 12-dihydro-6H-benzo [c] [ 1] benzazocin-5-yl) -N- [2- (4-methoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 21); and mixtures thereof.

1 1. A composition according to claim 5, characterized in that the at least one lysosomotropic, antiapoptotically active substance is preferably selected from the group consisting of benzoxazine derivatives, in particular 4- (3-aminopropyl) -1, 4-benzoxazin-3-ones, 4- [3- [2- (4-methoxyphenyl) ethyl-methyl-amino] -propyl] -1,4-benzoxazin-3-one (NB 48); and mixtures thereof.

12. The composition according to claim 5, characterized in that the at least one lysosomotropic, antiapoptotically active substance is preferably selected from the group consisting of carbazole derivatives, in particular 2,3,3a, 4,5,6-hexahydro-1 H-pyrazino [3,2,1-jk] carbazole, 3- [2- (4-methoxy-phenyl) -ethyl] -2,3,3a, 4,5,6-hexahydro-1H-pyrazino [3,2, 1 -jk] carbazole (NB 43); 1, 2,3,3a, 4,5,6,7-octahydro- [1,4] diazepino [3,2,1-jk] carbazole, 4- [2- (4-methoxyphenyl) -ethyl] -1, 2,3,3a, 4,5,6,7-octahydro- [1,4] diazepino [3,2,1-jk] carbazole (NB 44); 3-carbazol-9-yl-propan-1-amines, 3-carbazol-9-yl-N- [2- (3,4-dimethoxyphenyl) -ethyl] -N-methyl-propan-1-amine (NB 05); 3-carbazol-9-yl-N- [2- (4-methoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 06); 2-carbazol-9-ylethaneamines, N- (2-carbazol-9-yl-ethyl) -2- (4-methoxyphenyl) -N-methyl-ethanamine (NB 25), 9 - [[4- [2- (4- methoxyphenyl) ethyl] piperazin-1-yl] methyl] carbazole (NB 18); and mixtures thereof.

13. The composition according to claim 5, characterized in that the at least one lysosomotropic, antiapoptotically active substance is preferably selected from the group consisting of amine derivatives, in particular N- [2- (3,4-dimethoxyphenyl) ethyl] -N'- (1-naphthyl) ethane-1,2-diamine (NB 10); in particular 1 -naphthylmethanamine, 2- (3,4-dimethoxyphenyl) -N- (1-naphthylmethyl) ethanamine (NB 12); 3-carbazol-9-yl-propane-1-amines; and mixtures thereof.

A composition according to claim 5, characterized in that the at least one lysosomotropic, antiapoptotically active substance is preferably selected from the group consisting of: imipramine (3- (5,6-dihydrobenzo [b] [1] benzazepine-1) -yl) -N, N-dimethyl-propane-1-amine); Amitriptyline (3- (5,6-dihydrodibenzo [2,1 -b: 2 ', 1' -f] [7] annulen-1 1 -ylidene) -N, N-dimethylpropan-1-amine); 3-carbazol-9-yl-N- [2- (4-methoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 06); Nortriptyline (3- (5,6-dihydrodibenzo [2,1-b: 2 ', 1' - f] [7] annulen-1 1-ylidenes) - N-methylpropan-1-amine; 3-carbazole-9- yl-N- [2- (4-methoxyphenyl) ethyl] -N-methyl-propan-1-amine (NB 06); chloroquine (4-N- (7-chloroquinolin-4-yl) -1-N, 1 -N-diethylpentane-1,4-diamine), chloropropenes ((3Z) -3- (2-chlorothioxanthen-9-ylidenes) -N, N-dimethylpropan-1-amine) and mixtures thereof.

15. Composition according to claim 14, characterized in that the lysosomotropic, antiapoptotically active substance amitriptyline (3- (5,6-dihydrodibenzo [2,1 -b: 2 ', 1'-f] [7] annulen-1 1 - ylidene) -N, N-dimethylpropane-1-amine).

16. The composition according to any one of the preceding claims, characterized in that the at least one antioxidant active substance is selected from the group consisting of: mono- or polyunsaturated compounds, especially mono- or polyunsaturated fatty acids, preferably linoleic acid (Ci8: 2 fatty acid ), Gamma-linolenic acid (Ci8: 3 fatty acid), docosahexaenoic acid, eicosapentaenoic acid; mono- or polyunsaturated oils of vegetable origin, in particular almond oil, evening primrose oil, olive oil; Terpenes, especially tocopherol, retinol, aescin, beta carotene; Polyphenols, especially rutoside, quercetin; Ginkgolides and ascorbic acid; and mixtures thereof.

17. composition according to any one of the preceding claims, characterized in that it is formulated as a pharmaceutical composition.

Composition according to Claim 17, characterized in that it is in the form of a semi-solid preparation in the form of a cream, an ointment, a hydrogel, an oleogel, a paste, an envelope paste, a lotion, a milk, an emulsion, a liposomal formulation, a suspension or an active ingredient-containing patch is present.

19. A composition according to claim 17, characterized in that it is present as a liquid preparation in the form of an aqueous, hydrophilic or hydrophobic liquid containing one or more solubilizers as needed.

20. The composition according to any one of the preceding claims, characterized in that it contains at least one lysosomotropic, antiapoptotically active substance or a substance combinations of at least one lysosomotropic antiapoptotically active substance and at least one antioxidant substance in a pharmaceutical basis., In particular ointment base, optionally pharmaceutically acceptable Including adjuvants is present.

21. Composition according to Claim 20, characterized in that the pharmaceutical base is at least one antioxidant, in particular a fatty acid (C18: 2).

Composition according to any one of the preceding claims, characterized in that the said pharmaceutical base is selected from the group consisting of: wool waxes; Fatty alcohols, in particular Wool wax alcohols, cetylstearyl alcohol, decyl oleate; Sunflower oil, peanut oil, refined and hydrogenated peanut oil, vegetable hard fat, hard paraffin, aliphatic hydrocarbons (C40-C60); stearates; viscous paraffin, white vaseline, unsaturated fatty acids, almond oil, evening primrose oil, olive oil or other mono- or polyunsaturated compounds that are antioxidant and stabilize the RedOx potential in the cell; and mixtures thereof.

23. The composition according to any one of the preceding claims, characterized in that they additionally urea and / or salicylic acid and / or primary and / or secondary aliphatic amines functional group-containing compounds as protection against cleavage of mono- or polyunsaturated compounds or aldolases aldehyde-containing active substance (reactive carbonyl-spike catcher), preferably selected from the group consisting of: glycine, alanine, lysine, β-alanyl-L-histidine, β-alanyl-N-methyl-L-histidine, L-lysine L-histidine, 6-aminohexanoic acid, 6-aminohexanoly-L-histidine; Amifostine, pyridoxamine; and mixtures thereof.

Composition according to at least one of the preceding claims for use in the topical treatment of non-microorganism causing inflammatory skin and mucous membrane diseases.

25. The composition according to claim 24, characterized in that the non-microorganism-caused inflammatory skin and mucous membrane diseases, in particular psoriasis type I and type II, preferably psoriasis vulgaris, psoriasis guttata, psoriasis nummeralis, erythrodermic psoriasis, psoriasis pustulosa; especially eczema, atopic eczema, atopic dermatitis and pytiriasis capitis.

26. The composition according to any one of claims 24 or 25, characterized in that are used as the lysosomotropic, antiapoptotic substance amitriptyline and C18: 2 fatty acids as antioxidant active substance.

Use of a composition according to any one of the preceding claims for the topical treatment of non-microorganism-induced inflammatory skin and mucous membrane diseases.