WO2000037071A1

WO2000037071A1 - Topical treatment of skin disease

Info

Publication number: WO2000037071A1
Application number: PCT/DK1999/000722
Authority: WO
Inventors: Hans Christian Wulf
Original assignee: Aps Kbus 8 Nr. 4788
Priority date: 1998-12-21
Filing date: 1999-12-21
Publication date: 2000-06-29
Also published as: AU1773600A

Abstract

The invention concerns the use of lysine and/or lysine analogs in a topical treatment of skin diseases.

Description

TOPICAL TREATMENT OF SKIN DISEASE

The present invention relates to treatment of skin diseases, such as psoriasis and eczemas. In particular, the invention relates to a topical treatment of skin diseases and the use of lysine-related compounds in such a treatment. More particular, the invention concerns the use of lysine, a synthetic lysine analog, or a derivative thereof, or a salt thereof, or a combination thereof in the treatment of skin diseases.

BACKGROUND OF THE INVENTION

Skin disorders are common. In the USA nearly one-third of those aged 1-74 years have one or more significant skin disorders (Stern, 1993). The prevalence of psoriasis is around 1% to 4% in different populations and solely in- hospital treatment of psoriasis patients in the USA amounts to a cost of 100 million dollars annually (Stern, 1993). The prevalence of childhood atopic dermatitis is increasing and is now over 10% (Leung, 1993).

Skin diseases are treated with a variety of different topical and/or systemic medications. For topical treat- ment of many skin diseases such as psoriasis and eczema the most widely used therapy is the local application of glucocorticosteroids. Topical glucocorticoid therapy is potent but has a number of disadvantages. In many patients such therapy does not improve the condition. Fur- thermore, the treated patients can develop serious and irreversible systemic side effects such as growth retardation and Cushing^{^}s syndrome. Locally side effects are striae, atrophy, acne, purpura and many others (Stough- ton, 1993). Thus, evolution of new topical treatment mo- dalities are clearly needed. Also systemic therapy of skin diseases is not always successful and potentially dangerous. For example, methotrexate treatment of patients with psoriasis is widely used but can cause cirrhosis of the liver, pulmonary fibrosis and pancytopenia, again underlining the urgent need for development of new effective therapies for skin disorders which do not possess significant side effects (Shupack, 1993).

The majority of skin diseases are caused by unknown endogenous factors although the course of the disease can be modulated by the environment as has been documented for common as well as more rare skin diseases such as psoriasis, atopic dermatitis, contact dermatitis, bullous skin disorders, mb. Darier, and Hailey-Hailey^{^} s disease. For example, the first attack of psoriasis is often ini- tiated following a throat infection with streptococcal bacteria in the genetically predisposed individual. Also administration of certain drugs such as lithium can aggravate the clinical condition of a psoriatic (Christophers, 1993). Furthermore, in patients who develops an allergic contact dermatitis, e.g. caused by exposure to nickel in the environment, one often sees an unexplained endogenous determined spread of the eczematous condition although no exposure to the offending allergen can be demonstrated.

As exemplified in the following description of the evolution of psoriasis the endogenous factors contributing to the pathogenesis of the diseases are not understood (Christophers, 1993). The hallmark of the psoriasis le- sion is the hyperproliferation of the keratinocytes but which mechanisms that causes this highly increased proliferation are unknown. Methotrexate modulates the psoriatic lesion probably by decreasing the division of cells (Shupack, 1993). Others have observed an activation of the immune system in psoriatic lesions which led to cyclosporine treatment of psoriasis patients because this drug is an immunosuppressive agent. The arachidonic acid metabolic pathway has likewise been suggested to contribute to the pathogenesis of psoriasis but drugs which inhibits this pathway have not been notably clinical useful and are not standard therapy (Christophers, 1993). Also the plasminogen activator system has been implicated in the evolution of psoriasis because this potent biological pathway is expressed in the psoriatic lesions (Spiers, 1994) and plasminogen activators can induce growth of epidermal cells (Kirchheimer , 1989). However, as described in detail below it is disputed if a systemic therapy with inhibitors of plasminogen activation is of any beneficial clinical effect. It is evident from these observations that many factors and biological systems contributes to the evolution of psoriatic lesions. To further add to the complexity of the situation these systems are often interrelated as exemplified by the fact that an activation of the plasminogen activator system can cause an activation of one of the immune systems, i.e. the complement system (Munkvad, 1993). Thus, investigators have focused on the multiple aspects of the evolution of psoriasis in previous studies and have accordingly developed therapy regimens which have different modes of action. The fact that none of these therapies have had an unequivocal clinical success underlines the uncertainty regarding the pathogenesis of psoriasis and especially the necessity for development of new therapies for this disease. This conclusion does not only apply for psoriasis but can be extrapolated to cover the vast ma- jority of described skin diseases (Christophers, 1993) including among others common conditions such as atopic dermatitis (Leung, 1993) and allergic contact dermatitis (Belsito, 1993) .

The principal components of the plasminogen activator system are tissue-type plasminogen activator (t-PA) and urokinase plasminogen activator (uPA) which convert plasminogen to the active enzyme plasmin (Munkvad, 1993). In addition to psoriasis (Spiers, 1994) expression of the plasminogen activator system has been observed in le- sional skin from patients suffering from atopic dermatitis, contact dermatitis, bullous skin disorders, mb. Dar- ier and Hailey-Hailey^{^} s disease (Lotti 1989a & 1989b; Baird, 1990; Burge, 1991). The significance of this common expression of plasminogen activator activity is not known but the investigators have suggested a pathogenic importance and therefore a number of clinical investigations have evaluated treatment with different inhibitors of plasminogen activation and notably the synthetic analogs of lysine. Such inhibitors of plasminogen activation are drugs registered for use in situations when bleeding occurs due to increased generation of plasmin, i.e following thrombolytic therapy of patients with acute myo- cardial infarction (Munkvad, 1993). Synthetic lysine analogs are also used for therapy of patients with heredi- tary angioneurotic edema (Sheffer, 1972).

Synthetic analogs of the amino acid lysine comprise drugs such as tranexamic acid, also designated trans-p-amino- methyl—cyclohexanecarboxylic acid (AMCA; AMCHA) , ε- aminocaproic acid (EACA) , p-aminomethylbenzoic acid (PAMBA) and 4-aminoethylbicyclo-[2.2.2]-octane-l- carboxylic acid (AMBOCA) (Westlund, 1982; Verstraete, 1985). All of these compounds inhibit the activation of plasminogen and to a lesser extent generated plasmin (Westlund, 1982; Verstraete, 1985). However, it should be noted that in vitro these compounds differ in their ability to inhibit activation of plasminogen. According to Westlund (1982) the order of inhibitory potency is AMBOCA > AMCA > PAMBA > EACA. AMBOCA and AMCA are about equal in potency and both about 6 to 10 times more potent than EACA, whereas PAMBA is only twice as potent when compared to EACA (Westlund, 1982). Here it should be noted that such in vitro results cannot directly be extrapolated to the situation in vivo. Thus these results does not necessarily imply that identical result are obtained when the difference in clinical efficacy between lysine analogs is studied.

As described in detail below the results of previous clinical trials which have employed synthetic lysine ana- logs for treatment of skin diseases are in conflict and methodological faults are often evident. In particular, most trials have enrolled only a limited number of patients which prevents valid conclusions to be drawn.

Laurberg (1977) saw no clinical effect when tranexamic acid was administered orally to patients with urticaria, whereas Yamamoto (1965) and Reiss (1971) previously had observed a beneficial clinical effect in such patients of oral treatment with tranexamic acid and EACA, respec- tively. Hatano (1962 & 1963) used tranexamic acid administered intravenously to patients with dermatitis and reported a favorable result on the clinical condition and a decrease of the plasminogen activator activity of the blood. Hatano (1962 & 1963) determined the effect of tranexamic acid on plasminogen activator activity in the blood by determination of whole clot lysis and euglobulin lysis which are inaccurate methods because the results are dependent upon concentrations of components other than plasminogen activators, e.g. fibrinogen, and also influenced by the presence of inhibitors in the sample (Munkvad, 1993). Yamamoto (1965) extended the observations of Hatano (1962 & 1963) using tranexamic acid administered orally or intravenously and observed a significant clinical response mainly in patients with "mostly allergic skin disease¹', predominantly various forms of eczema. Using systemic administration of the ly- sine analog EACA several investigators observed a favorable clinical effect in patients suffering from eczema- tous conditions (Yokayama, 1959; Reiss, 1971; Miller, 1974). In notable contrast, Haustein (1969) saw no effect when the lysine analog PAMBA was administered topically and/or orally to such patients and he concluded that the plasminogen activator system did not play an important role in allergic skin diseases. Contrary to the above mentioned lack of effect of PAMBA therapy on allergic skin diseases Dobrev (1996) observed a beneficial clinical effect of oral PAMBA treatment of patients with bul- lous skin disorders. In contrast, oral tranexamic acid therapy of identical patients was not of significant value (Marsden, 1987). Also in patients with psoriasis have conflicting results been obtained when treatment with synthetic lysine analogs have been conducted ranging from a positive effect of oral administered EACA (Kuliev, 1989) to a negligible effect of such therapy (Rowe, 1985). Neither did topical application of PAMBA to pso- riasis patients result in clinical improvement (Wurbach, 1967). Furthermore, following initial promising results of oral EACA treatment of patients with scleroderma, additional experiences disclosed that this drug had no definite benefit (Hall, 1966).

US 5,720,948 discloses a non-ionic surfactant emulsion vehicle for enhancing the penetration of a drug substance, such as transexamic acid, through the skin. However, the therapeutic effect of transexamic acid is not shown.

US Patent 4,363,818 suggests a topical administration of EACA for reduction of signs and symptoms associated with skin diseases. However, a positive effect in the treat- ment of skin diseases is not substantiated in this US patent. The topical EACA treatment is only exemplified by a treatment of a cutaneous laceration, that is, an exogenous noxious stimulus applied to normal skin. Likewise, in an experimental setting (Denda, 1997), topical tranexamic acid was applied to healthy males who were subjected to various exogenous stimuli which caused disruption of the epidermis. This is again a situation where healthy individuals were exposed to a variety of unphysiological stimuli, such as lacerations and tape stripping. It should also be noted that Denda (1997) does not state or imply that topical tranexamic therapy could be a potential useful medication for skin diseases caused predominantly by endogenous factors.

Taken together, these conflicting observations reported during the last 35 years do not point towards the present invention. The few positive observation have not lead to any broader exploitation, at least not to the knowledge of the applicant. The many negative observations seem to have kept investigators from concluding that patients with skin diseases would benefit from a topical therapy with lysine, synthetic lysine analogs, or derivatives or salts thereof, or combinations thereof.

SUMMARY OF THE INVENTION

In accordance with the present invention, a novel use of lysine, synthetic lysine analogs, and derivatives and salts thereof is provided, which leads to a medication for the use in a topical treatment of skin diseases.

More specifically, the invention concerns the use of lysine, synthetic lysine analogs, or derivatives or salts thereof or combinations thereof in the manufacture of a medicament for topical treatment of skin diseases. In particular, the invention concerns the use of synthetic lysine analogs and derivatives thereof, especially lysine analogs which are selected from trans-p-amino- methyl-cyclohexane-carboxylic acid (AMCA, tranexamic acid), ε-amino-caproic acid (EACA), p-aminomethylbenzoic acid (PAMBA) and 4-aminoethylbicyclo-[2.2.2 ]-octane-l- carboxylic acid (AMBOCA) .

In a preferred embodiment, the medicament is in the form of a wet dressing, soak, bath, shampoo, lotion, solution, tincture, aerosol, powder, cream, gel, ointment, fixed dressing, paste, occlusive dressing, semiocclusive dressing, alginate, hydrocolloid, foam or a combination thereof .

In another aspect of the present invention, the medicament for topical application comprises one or more additional drugs such as glucocorticosteroids , antibacterial agents, antifungal drugs, antiviral drugs, benzoyl perox- ide, vitamin A or vitamin A derivatives, analgesics, anti-hair loss medications (e.g. minoxidil), anti-inflammatory agents, antiperspirants , anti-pruritic agents, anti-psoriatic agents (e.g. anthralin, tars, vitamin D3 analogs, tacrolimus), astringents, insecticides and scabicides, keratolytic agents or wart therapies (cantha- ridin, podophyllin resin).

Preferably, the medicament comprises from 0.01 to 100%, preferably from 0.1 to 20%, more preferably from 1 to 10%, even more preferably from 5 to 10% and most preferably 10% weight/volume lysine, synthetic lysine analog, or a derivative thereof, or a salt thereof, or a combination thereof .

In yet another aspect of the invention, the use further comprises the use of one or more additional drugs in the manufacture of a medicament for systemic administration for treatment of the said skin disease, the medicaments being for a combined topical and systemic treatment of the said skin diseases.

The medicament for systemic administration may comprise lysine, a synthetic lysine analog, or a derivative thereof, or a salt thereof, or a combination thereof, such as AMCA, EACA, PAMBA or AMBOCA, or one or more con- ventional drugs for treatment of skin diseases such as dapsone, aminoquinolines , cytotoxic agents (e.g. methotrexate, azathioprine, 5-fluorouracil, cyclophosphamide, nitrogen mustard), retinoids, antihistamines and cyc- losporine. The systemic administration is an oral ad- ministration or an intravenous administration.

The skin diseases to be treated is caused predominantly by endogenous etiologic and/or pathogenetic factors and comprises among others psoriasis, atopic dermatitis, con- tact dermatitis, bullous skin disorders, mb. Darier, Hailey-Hailey ' s disease, exfoliative dermatitis, ich- thyosiform dermatoses, pityriais rubra pilaris , Grover's disease, keratodermas , pustular eruptions, cicatricial alopecias, non-cicatricial alopecias especially alopecia areata, rosacea, acne vulgaris, cutaneous neoplasms, pityriais rosea, parapsoriasis , lichen planus, lichen ni- tidus, Sweet's syndrome, erythema elevatum diutinum, pyo- derma gangrenosum, erythema annulare, anetoderma, nummu- lar eczematous dermatitis, autosentization dermatitis, seborrhoic dermatitis, vesicular palmoplantar eczema, hand eczema, infective dermatitis, photoassociated responses such as polymorphic light eruptions, actinic pru- rigo, hydroa vacciniforme, chronic actinic dermatitis, drug-induced photosensitivities , sunburn reactions, asteatotic eczema, pityriasis alba, dermatophytides , pityrosporal folliculitis , gravitational eczema, juvenile plantar dermatosis, perioral dermatitis, lichen simplex, pruritic conditions and eruptions including prurigo nodu- laris Hyde, urticaria, discoid and subacute lupus erythe- matosus, dermatomyositis , skin sarcoidosis, diseases caused by microbial agents notably warts.

In a further aspect, the present invention concerns a pharmaceutical composition for topical application comprising an active amount of lysine, a synthetic lysine analog, or a derivative thereof, or a salt thereof, or a combination thereof. The pharmaceutical composition may comprise one or more additional drugs for the treatment of skin diseases .

In yet a further aspect, the invention concerns a method of treating a skin disease comprising administering to the cutaneous or mucosal surface of a patient suffering from said skin disease an effective amount of a pharmaceutical composition according to the invention.

In a further embodiment of the invention, the method of treatment comprises in addition to the topical treatment a systemic treatment, either oral or intravenous, with one or more additional drugs against the said skin dis- ease, or in addition a local or universal photomedicine, such as x-ray treatment, UVB or PUVA phototherapy.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on the surprising finding that lysine, synthetic lysine analogs, or derivatives or salts thereof may be used to treat skin diseases. Despite the contrasting and confusing earlier reports concerning the causes and treatment of skin diseases, the present inventor has found that lysine, synthetic lysine analogs, or derivatives or salts thereof, or combinations thereof are unexpectedly advantageous in treating skin diseases. This could not be inferred from the state of the art and is highly surprising.

The present invention concerns compounds, which inhibit plasminogen activation and components of the plasminogen activator system, with a molecular weight within the order of a single amino acid. Basic amino acids inhibit plasminogen activator activity but the amino acid lysine has the most powerful effect (Okamoto, 1968). Various forms of chemical modification of native lysine generate the synthetic lysine analogs which also can posses the inhibitory action. For example when removing the alpha amino group from lysine the product is EACA, a potent in- hibitor. Further chemical modification of a lysine analog such as tranexamic acid can yield additional compounds or derivatives with an inhibitory action on the plasminogen activator system such as described in US Patent 4,483,867.

Accordingly, the present inventions concerns the use of lysine, a synthetic lysine analog, or a derivative or salts thereof, or combinations thereof in the formulation of a medicament for topical application for the treatment of skin diseases.

The cause of the significant effect of the compounds used in accordance with the present invention is not known with certainty. One theory which is in accordance with previous observations (Reinartz, 1993) is that the complex formation between synthetic lysine analogs and plasminogen prevents that such complexed plasminogen binds to the surface of keratinocytes . Binding of plasminogen to the surface of keratinocytes significantly enhances acti- vation of plasminogen and generation of plasmin because plasminogen activators, notably uPA, also binds to spe- cific receptors on such surfaces. Concomitant binding of a plasminogen activator and plasminogen to a surface is known to significantly increase the activation process (Munkvad, 1993). The resulting reduced generation of plasmin when synthetic lysine analogs are present is beneficial because increased plasmin activity may contribute to the evolution of skin lesions in diseases such as psoriasis, atopic dermatitis, contact dermatitis, bul- lous skin disorders, mb. Darier and Hailey-Hailey" s dis- ease (Lotti 1989a & 1989b; Baird, 1990; Burge, 1991; Spiers, 1994).

In a preferred embodiment, synthetic lysine analogs are used in the manufacture of a medicament for topical ap- plication in the treatment of skin diseases. Examples of useful analogs are described by Okamoto (1968). Others will be known in the art and/or obvious to the skilled person.

The most extensively studied synthetic lysine analogs are tranexamic acid, ε-aminocaproic acid, PAMBA and AMBOCA (Okamoto, 1968; Westlund, 1982; Verstraete, 1985). Lysine and the synthetic lysine analogs inhibit plasminogen activator activity by inhibiting the generation of plas- min and to lesser extent generated plasmin (Okamoto, 1968; Westlund, 1982; Verstraete, 1985). These amino acids bind reversibly to specialized structures on the plasminogen molecule which prevents the binding of plasminogen to surfaces such as fibrin and thus the activa- tion of plasminogen by plasminogen activators bound to fibrin (Verstraete, 1985). By this mechanism the breakdown of fibrin is prevented and thus bleeding from increased plasminogen activator activity can be eliminated or reduced (Verstraete, 1985). Preferred analogs for use in the present invention are analogs selected from the group comprising trans-p-amino- methyl-cyclohexane-carboxylic acid (AMCA, tranexamic acid), ε-amino-caproic acid (EACA), p-aminomethylbenzoic acid (PAMBA) and 4-aminoethylbicyclo- [ 2.2.2 ]-octane-l- carboxylic acid (AMBOCA) .

Tranexamic acid is a synthetic amino acid with a molecular weight of 157 (Verstraete, 1985). The synthesis of tranexamic acid has been described (US Patent 3,499,925) as has its derivatives with an inhibitory action of the plasminogen activator system (US Patent 4,483,867). Tranexamic acid is a registered drug which is commercial available from pharmaceutical companies, e.g. Pharmacia & Upjohn.

ε-aminocaproic acid (EACA) is a synthetic amino acid with a molecular weight of 131. The synthesis of ε-aminocaproic acid has been described in US Patent 2,453,234. ε-aminocaproic acid is a registered drug which is commercial available from pharmaceutical companies, e.g. Abbott, Elkins Sinn, Immunex and Luitpold.

p-aminomethylbenzoic acid (PAMBA) is a synthetic amino acid with a molecular weight of 160. The activity of p- aminomethylbenzoic acid is described by e.g. Okamoto, (1968), Westlund (1982) and Verstraete (1985).

4-aminoethylbicyclo- [2.2.2] -octane-1-carboxylic acid (AMBOCA) is a synthetic amino acid which activity is described by e.g. Westlund (1982).

Derivatives of tranexamic acid are known in the art and described for example in US Patent 4,483,867 and 5,690,914. Derivatives of other synthetic lysine analogs are similarly known in the art or obvious to the skilled person. Derivatives of other synthetic lysine analogs are similarly known in the art or obvious to the skilled person. Examples may be alkylesters and the like.

The above mentioned analogs and derivatives may be used as such because they are very soluble in water and produce pH values which are in the neutral range.

Salt formation could come into question in case salt for- mation should affect the aqueous solubility (salts of low soluble substances to increase the solubility; salts of very soluble substances to reduce solubility) or to modify pH of the aqueous solution.

Salts of the analogs and derivatives should be therapeu- tically acceptable and preferably without any significant effect on the aqueous solubility. Furthermore, the salts of the analogs should be physiologically acceptable and without effect upon the stability of the analog.

The salts of the lysine and/or lysine analogs may be in the form of inorganic acid salts such as salts of hydrochloric acid, sulfuric acid, phosphoric acid and hy- drobromic acid or a sodium salt, a potassium salt, an am- monium salt, a magnesium salt or a calcium salt, or organic acid salts such as a salt of acetic acid, lactic acid, maleic acid, fumaric acid, tarteric acid, citric acid, methanesulfonic acid and p-toluene sulfonic acid or a monoethanolamine salt, a diethanolamine salt or a triethanolamine salt, and the like.

No publication discloses topical administration of tranexamic acid to patients with skin diseases. It was not known that topical tranexamic acid treatment of various skin diseases could eradicate or alleviate the associated objective signs and symptoms. Although some investiga- tions have suggested that systemic tranexamic acid therapy is useful for some skin diseases, as described in detail above these observations does not imply that a topical formulation of tranexamic acid would possess a phar- maceutical action on skin diseases . Thus it is well known that whereas systemic methotrexate treatment of patients with psoriasis is effective topical application of methotrexate is in contrast of no value (van Scott, 1959). The finding that topical tranexamic acid treatment clearly is beneficial is furthermore surprising because topical administration of PAMBA to patients with a variety of skin diseases is previously reported to be of no beneficial value (Wiirbach, 1967; Haustein, 1969). The only well documented action of tranexamic acid and other synthetic lysine analogs is their inhibitory action on the plasminogen activator system. It is thus further unexpected that solely inhibition of this biological system can result in a substantial clinical effect because only limited attention has been paid to the significance of the plasminogen activator system for evolution of skin diseases. Topical administration of EACA for reduction of signs and symptoms associated with skin diseases was suggested in US Patent 4,363,818. However, this is not in conflict with the present invention because this topical EACA treatment is exemplified by treatment of a cutaneous laceration, i.e an exogenous noxious stimulus applied to normal skin. The present invention concerns therapy of skin diseases caused predominantly by endogenous factors. Thus, as described in detail above the most important and common skin diseases such as psoriasis and various forms of eczema arises because of largely unknown endogenous factors. Various exogenous factors can only modulate the course of the disease. In the same way, in the experimental setting by Denda (1997), topical tranexamic acid was applied to healthy males who were subjected to various exogenous stimuli which caused disruption of the epider- mis. This is again a situation totally contrasting the field of the present invention which concerns therapy of skin diseases largely due to endogenous unknown causes and not the application of tranexamic acid to healthy in- dividuals exposed to a variety of unphysiological stimuli. Thus, it is to be understood that the present invention is not intended for treatment of skin conditions which are exclusively caused by exposure to one or more exogenous factors capable of causing disease in all indi- viduals. Such factors comprises lacerations and tape stripping to mention but a few.

The most preferred synthetic lysine analogs for use in the present invention are tranexamic acid ( trans-p-amino- methyl-cyclohexane-carboxylic acid (AMCA) ) and ε-aminocaproic acid (EACA).

Skin diseases have a multitude of causes. Some diseases can be elicited in all individuals independent of the in- dividuals genetic predisposition and state of the skin. Characteristic examples of such skin diseases are radiation dermatitis induced by high doses of x-ray, lacerations or eczematous changes caused by tape stripping of the skin. The present invention is not intended for treatment of such conditions but for therapy of skin diseases which develops because of predominantly endogenous etiologic and/or pathogenic factors. This does not exclude diseases in which exogenous factors also contribute to evolution of the disease. For example, in sunburn re- actions the radiation of the sun is a clear exogenous etiologic factor but a genetic predisposition is very important as the reaction to a fixed light exposure is very different in the light-skinned, red-haired type contrasting the individual with dark brown or black skin colour. An additional example is psoriasis where about 50% of children of two psoriatics will develop the disease again underscoring the significant genetic predisposition (Christophers, 1993). However, exogenous factors are clearly important for development of psoriasis in the predisposed as illustrated by the fact that the clinical condition of a patient with psoriasis can become worse if he receives treatment with β-blocking agents or lithium (Christophers, 1993).

The invention is thus intended to be limited to treatment of skin diseases wherein the skin disease predominantly is caused by endogenous etiologic and/or pathogenic factors .

Previously, the state of the plasminogen activator system has only been investigated in conditions such as psoriasis, atopic dermatitis, contact dermatitis, bullous skin disorders, mb. Darier and Hailey-Hailey' s disease. However, it is expected that in other skin diseases the plasminogen activator system likewise is expressed in diseases skin.

Thus, the present invention is not limited to treatment of the above mentioned conditions. It should be clear that the present invention is intended for therapy of all skin diseases which are caused predominantly by endogenous pathogenic factors whether these are unknown or mediated by one or more biological effector systems such as the immune system. Also skin diseases induced by bacteria, virus, fungi or other microorganisms are potential candidates for therapy using the present invention. To take virus infections as an example individuals differs in susceptibility to infections with human papilloma virus which generates warts probably because of differences in their state of immunity (Lowy, 1993). This observation again demonstrates that endogenous factors can be the major determinant for development of overt disease even in the presence of a well recognized exogenous factor, in this case the human papilloma virus. In favor of tranexamic acid treatment of virus infections such as warts are furthermore reports which demonstrates that synthetic ly- sine analogs are effective in reducing the replication of other types of virus (Zhirnov, 1984).

The present invention accordingly concerns the treatment of all kinds of predominantly endogenously mediated skin diseases including such skin diseases which can be preceded and initiated by exogenous factors. Skin diseases which may be treated according to the present invention includes among others psoriasis, atopic dermatitis, contact dermatitis, bullous skin disorders, mb. Darier and Hailey-Hailey ' s disease, exfoliative dermatitis, ich- thyosiform dermatoses, pityriais rubra pilaris, Grover's disease, keratodermas, pustular eruptions, cicatricial alopecias, non-cicatricial alopecias especially alopecia areata, rosacea, acne vulgaris, cutaneous neoplasms, pityriais rosea, parapsoriasis, lichen planus, lichen ni- tidus, Sweet" s syndrome, erythema elevatum diutinum, pyo- derma gangrenosum, erythema annulare, anetoderma, nummu- lar eczematous dermatitis, autosentization dermatitis, seborrhoic dermatitis, vesicular palmoplantar eczema, hand eczema, infective dermatitis, , photoassociated responses such as polymorphic light eruptions, actinic pru- rigo, hydroa vacciniforme, chronic actinic dermatitis, drug-induced photosensitivities, sunburn reactions, asteatotic eczema, pityriasis alba, dermatophytides, pityrosporal folliculitis, gravitational eczema, juvenile plantar dermatosis, perioral dermatitis, lichen simplex, pruritic eruptions including prurigo nodularis Hyde, urticaria, discoid and subacute lupus erythematosus , der- matomyositis , skin sarcoidosis, skin diseases caused by microbial agents notably warts. The medicament of the present invention may take any form intended for topical application. Such application includes wet dressing, soak, bath, shampoo, lotion, solution, tincture, aerosol, powder, cream, gel, ointment, fixed dressing, paste, occlusive dressing, semiocclusive dressing, alginate, hydrocolloid, foam or any combination thereof.

The use according to the present invention comprises from 0.01 to 100%, preferably from 0.1 to 20%, more preferably from 1 to 10%, even more preferably from 5 to 10% and most preferably 10% weight/volume of lysine, a synthetic lysine analog, or a derivative thereof, or a salt thereof, or a combination thereof in the medication.

There are at least 3 advantages of topical therapy with tranexamic acid when compared to conventional topical treatments such as topical glucocorticoid treatment. Firstly, the present invention has in many cases a more potent action than conventional treatment. Thus, the inventor has almost only treated patients with severe skin diseases who were unresponsive to topical treatment even with the most potent formulations of topical glucocorti- coids and in the majority of the patients observed a fa- vorable clinical response. Second, and of equal importance, local side effects following the application of tranexamic acid are few and without significance. A few patients have reported a stinging or burning sensation lasting for minutes after the application. Furthermore, patients who has received prolonged topical glucocorticoid treatment notes that topical tranexamic treatment does not cause the thinning of the skin which they have experienced during the glucocorticoid treatment. Third, the side effects of systemic therapy with tranexamic acid or other synthetic lysine analogs are completely avoided. Thus, such systemic treatment is associated with milder side effects such as gastrointestinal upset especially diarrhea but also serious events like thrombo-embolic episodes or myopathy (Ogston, 1989). These untoward effects have not been observed in patients who have been treated with topical tranexamic acid underlining that the medication for topic administration according to the present invention is a very safe medication and indicating that systemic absorption of the applied tranexamic acid is negligible.

However, if topical treatment with lysine, a synthetic lysine analog, or a derivative thereof, or a salt thereof, or a combination thereof does not lead to a satisfactory result, the patient can be administered a me- dicament comprising lysine, a synthetic lysine analog, or a derivative thereof, or a salt thereof, or a combination thereof together with one or more additional drugs for treatment of the skin disease, such as gluco-corticoster- oids , antibacterial agents, antifungal drugs, antiviral drugs, benzoyl peroxide, vitamin A or vitamin A derivatives, analgesics, anti-hair loss medications (e.g. mi- noxidil), anti-inflammatory agents, antiperspirants , anti-pruritic agents, anti-psoriatic agents (e.g. anthra- lin, tars, vitamin D3 analogs, tacrolimus), astringents, insecticides and scabicides, keratolytic agents or wart therapies (cantharidin, podophyllin resin). The present invention also concerns such combined medicaments.

Alternatively or in addition, if topical treatment with lysine, a synthetic lysine analog, or a derivative thereof, or a salt thereof, or a combination thereof alone or together with one or more additional medications for topical application does not lead to a satisfactory result, the patient may be administered in sup- plement to the external treatment, a systemic administration of an active medicament against said skin disease. Accordingly, the present invention further concerns the combined use of topically administered lysine, a synthetic lysine analog, or a derivative thereof, or a salt thereof, or a combination thereof and one or more sys- temically administered medicaments for treatment of a skin disease. The medicament for systemic administration may comprise lysine, a synthetic lysine analog, or a derivative thereof, or a salt thereof, or a combination thereof. Preferably the analog used in the medicament for systemic administration is a synthetic lysine analog, preferably selected from trans-p-amino-methyl-cyclo- hexane-carboxylic acid (AMCA, tranexamic acid), ε-aminocaproic acid (EACA), p-aminomethylbenzoic acid (PAMBA) and 4-aminoethyl-bicyclo-[2.2.2 ]-octane-l-carboxylic acid (AMBOCA) , more preferably selected from AMCA and EACA and most preferably AMCA.

Alternatively, the medicament for systemic administration may comprise one or more drugs known in the art of systemic treatment of skin diseases such as dapsone, amino- quinolines, cytotoxic agents (e.g. methotrexate, azathio- prine, 5-fluorouracil, cyclophosphamide, nitrogen mustard), retinoids, antihistamines and cyclosporine. The systemic administration may be oral or intravenous. Such a combine topical and systemic use and treatment is also intended to be an aspect of the present invention.

Tranexamic acid and other synthetic lysine analogs are available as drugs for systemic administration as tablets, syrups or in injectable form. The present invention concerning topical administration of lysine, a synthetic lysine analog, or a derivative thereof, or a salt thereof, or a combination thereof is intended for use in all possible forms of topical administration such as wet dressings, soaks and baths, shampoo, lotions, solutions, tinctures, aerosols, powders, creams, gels, ointments, fixed dressings, pastes, occlusive and semiocclusive dressings, alginates, hydrocolloids and foams, or combinations hereof. The liquid preparations are most useful for acute exudative skin diseases and are also easiest to apply to hairy areas. Creams and ointments are more lubricating.

The ingredients employed in the preparations for topical administration include among others pharmaceutically acceptable carriers. Such carriers are meant to include any liquid, gel, solvent, liquid diluent, fluid ointment base, filler, dye, and the like which is suitable for use in contact with living animal tissue. Suitable carriers are within the knowledge of the skilled person.

Pharmaceutical preparations for topical use may take any suitable form and may be prepared by any method known in the art. Such preparations may be any of the following types: cutaneous solutions, cutaneous spray (powder or solution), impregnated dressings, solution for iontophoresis (could come into question in the case where the lysine analog and/or derivative is a zwitterion), ointments (hydrophobic or hydrophilic ) , creams (oil in water), gels (hydrophobic or hydrophilic), cutaneous foams, shampoos, cutaneous powder and the like. The cutaneous solutions may consist of simple aqueous solutions, eventually with the addition of an anti-microbial preservative.

Solutions can be applied directly on the skin (i.e. like a lotion), by the aid of an impregnated dressing, or applied by a spray. In any case, the formulation may be a simple aqueous solution or a complex aqueous solution. The solution is optionally added an anti-microbial pre- servative (parabens) and, possibly, a humectant such as glycerol, sorbitol or even propylenglycol which is known to enhance penetration of some substances.

Ointments are formulated as suspensions in order to main- tain a constant rate of delivery, i.e. the drug substance is dispersed in the hydrophobic carrier in a particle size adjusted to the experienced rate of delivery. Ointments are single-phase systems which can be hydrophobic like for example a simple hydrocarbon carrier, or they can by the addition of a surfactant become more hydrophilic in the sense that they can absorb minor amounts of water (i.e. humidity from the skin).

Creams are emulsions of oil-in-water , formerly the term was also used for water-in-oil emulsions. In a cream the oil droplets of natural or semisynthetic glycerides, petroleum products, waxes, sterols, volatile oils, sili- cones, and the like, represent the discontinuous phase and are dispersed in water or a polar liquid as the con- tinuous phase. Such formulations require emulsifying agents and may contain preservatives.

Gels are semi-solid preparations manufactured by solva- tion of polymers or other macromolecules . They can be hy- drophilic or hydrophobic.

Lysine, synthetic lysine analogs, derivatives thereof, salts thereof, and combinations hereof, are available, or can be produced for use, in medications suitable for sys- temic administration such as tablets, syrups or in in- jectable form.

Oral formulations of AMCA and other lysine analogs may be designed as release formulations, for example immediate release tablets, i.e. formulations in which the active substance is released to the gastro-intestinal liquids as soon as the tablet disintegrates. The load of drug substance preferably is as high as possible, for example 500 mg per tablet, because relatively high doses preferably are to be administered.

To produce pharmaceutical preparations in the form of dosage units for oral application containing lysine and/or lysine analogs in the form of the free base, or a pharmaceutically acceptable salt thereof, the active in- gredient may be mixed with a solid, pulverised carrier, for example, lactose, saccharose, sorbitol, mannitol, a starch such as potato starch, corn starch, maize starch or amylopectin, a cellulose derivative or gelatin, and also may include lubricants such as magnesium or calcium stearate or a carbowax or other polyethylene glycol waxes and compressed to form tablets or centers for dragees. If dragees are required, the centers may be coated, for example, with concentrated sugar solutions which may contain gum arabic, talc and/or titanium dioxide, or alter- natively with a lacquer dissolved in easily volatile organic solvents or mixtures of organic solvents. Dyestuffs can be added to these coatings. For the preparation of soft gelatin capsules (pearl-shaped closed capsules) consisting of gelatin and, for example, glycerol, or similar closed capsules, the active substance may be admixed with a carbowax. Hard gelatin capsules may contain granulates of the active substance with solid, pulverized carriers such as lactose, saccharose, sorbitol, mannitol, starches (for example potato starch, corn starch, or amylopectin), cellulose derivatives or gelatin, and may also include magnesium stearate or stearic acid.

Liquid preparations for oral application may be in the form of syrups, suspensions or emulsions, for example containing from about 0.1% to 20% by weight of active substance and also, if desired, such adjuvants as stabi- lizing agents, suspending agents, dispersing agents, flavouring agents and/or sweetening agents.

For parenteral application by injection the carrier may be a sterile, parenterally acceptable liquid, e.g. pyro- gen-free water or an aqueous solution of polyvinylpyr- rolidone, or a parenterally acceptable oil, e.g., arachis oil and optionally stabilising agents and/or buffer substances. Dosage units of the solution may advantageously be enclosed in ampoules, each dosage unit preferably containing from 0.1 to 10 mg of active ingredient.

As other pharmaceutical formulations according to the invention may be mentioned drops, eyedrops, nasal spray, etc.

In another aspect the present invention concerns pharmaceutical compositions for topical application comprising a pharmaceutically active amount of lysine, a synthetic lysine analog, or a derivative thereof, or a salt thereof, or a combination thereof. Preferably, the pharmaceutical composition comprises a synthetic lysine analog, such as trans-p-aminomethylcyclohexanecarboxylic acid (AMCA, tranexamic acid), ε-aminocaproic acid (EACA), p-aminomethylbenzoic acid (PAMBA) and 4-aminoethyl-bicy- clo-[2.2.2 ]-octane-l-carboxylic acid (AMBOCA).

The pharmaceutical composition may further comprise one or more additional drugs, such as glucocortico-steroid, antibacterial agents, antifungal drugs, antiviral drugs, benzoyl peroxide, vitamin A or vitamin A derivatives, analgesics, anti-hair loss medications (e.g. minoxidil), anti-inflammatory agents, antiperspirants , anti-pruritic agents, anti-psoriatic agents (e.g. anthralin, tars, vi- tamin D3 analogs, tacrolimus), astringents, insecticides and scabicides, keratolytic agents, wart therapies (can- tharidin, podophyllin resin).

The pharmaceutical composition according to the invention may comprise from 0.01 to 100%, preferably from 0.1 to 20%, more preferably from 1 to 10%, even more preferably from 5 to 10% and most preferably 10% weight/volume of lysine, synthetic lysine analog, or derivative thereof, or a salt thereof, or a combination thereof. The pharma- ceutical composition may be in the form of a wet dressing, shampoo, lotion, solution, tincture, aerosol, powder, cream, gel, ointment, fixed dressing, paste, occlu- sive dressing, semiocclusive dressing, alginate, hydro- colloid or foam.

The vehicle of the formulation for topical therapy must be chosen according to the type of skin lesion present because the correct formulation of the medicament has a substantial influence on the treatment outcome. For exam- pie, in several patients presenting with chronic, non-exudative lesions of atopic dermatitis, treatment with a cream containing 10% tranexamic acid caused a drying and irritation of the diseased skin. This was, however, also the case when the corresponding cream without tranexamic acid was applied. An ointment comprising tranexamic acid worked out much better. It is recognized in the art that an ointment is much more suited for dry skin lesions when compared to a cream, the latter being most useful for more exudative lesions. Thus, it is well known to the physician that different skin diseases are to be treated with different topical formulations.

The present invention can without restrictions in dosage or number of daily treatments be applied to the various skin diseases. The application of the topical formulations may be more times a day, daily, more times a week, weekly, etc. Often the formulations may be administered by the patient following symptoms of the disease, but preferably the topical formulations are applied one time daily to the area of skin disease. In cases of severe skin disease it may be beneficial initially to administer a conventional treatment regimen, as described above, alone or in combination with the present invention. Then, when the condition is in satisfactory remission then taper off the conventional therapy and solely control the disease activity by topical administration of tranexamic acid. However, if the patient does not obtain a satisfactory remission solely by administration of the present invention it can safely be combined with any standard dermatologic treatment.

A further aspect of the invention concerns a method of treatment of skin diseases wherein the treatment comprises administering to the cutaneous or mucosal surface of a patient suffering from said skin disease an effec- tive amount of a pharmaceutical composition according to the invention. The method may additional comprise in combination herewith a systemic administration of an effective amount of one or more additional drugs against the said skin disease, or a local or universal photomedi- cine, such as x-ray treatment, UVB or PUVA phototherapy.

The invention is further illustrated in the following examples. Unless otherwise stated, all the examples concerning treatment of patients have been performed with the use of tranexamic acid. This is done firstly to illustrate the invention and secondly because tranexamic acid is allowed for use and sold in Denmark. It is expected that other lysine analogs may work in the same way, the concentration of the analog being adjusted in the treatment according to the relative strength of the analogs. The invention is not intended to be limited by the examples but extends to the scope of the claims as read in the context of the present description.

EXAMPLES

Solutions .

Example 1

Solution for direct application, application by a mechanical spray or iontophoresis:

AMCA 10.0 g Methylparahydroxybenzoate 80 mg

Propylparahydroxybenzoate 20 mg

Purified water 89.9 q

100.0 g

The solids are dissolved in purified water. The parabens are added in the form of 10 percent solutions in ethanol.

Example 2

Solution for direct application or for an impregnated dressing:

AMCA 10.0 g

Propylenglycol 10.0 g

Methylparahydroxybenzoate 0.1 g Purified water 79.9 g

100.0 g

The solids are dissolved in purified water. The parabens are added in the form of 10 percent solutions in ethanol. Example 3

Viscous solution for direct application (i.e. a "lotion ' ) :

AMCA 10 . . 0 g

Methylcellulose 1500 2 , . 0 g Propylenglycol 10 . , 0 g Methylparahydroxybenzoate 0 . . 1 g Purified water 77 . , 9 q 100.0 g

2 g methylcellulose is dissolved in 60 g hot water by vi- goreous stirring. After cooling the remaining ingredients are added to a total mass of 100 g.

Ointments .

Example 4 Hydrophobic ointment

AMCA 10.0 g

Polyethylene 9.0 g

Liquid paraffin 81.0 q

100.0 g

Polyethylene (molecular weight approximately 21000) is dissolved in liquid paraffin by heating to 110 C. The solution is allowed to cool to 90 C whereafter the cooling continues with a rate of 2 C per minute with stir- ring. At room temperature AMCA (micronized) is dispersed in the basis using a suitable mill. Example 5 Water-absorbing ointment

AMCA 10.0 g

Cetostearyl alcohol 28.5 g

Polysorbate 80 1.5 g

Petrolatum 50.0 g

Liquid paraffin _,10.0 q

100.0 g

Ointments with other concentrations can be made using the same composition of the carriers.

Creams .

Example 6

I. AMCA 10.0 g

II. Polysorbate 80 0.45 g

Cetyl alcohol 4.5 g

Liquid paraffin 4.5 g

Glycerol monostearate 40-50 5.4 g

III.Glycerol 85% 3.6 g

Sorbitol 6.3 g

Purified water 65.15 g

Methylparahydroxybenzoate 0.1 g

II is mixed and melted together at approximately 70°C. Ill is heated until its boiling point and thereafter cooled until 65-70°C, and is then mixed with II during frequent stirring. Ten grams of tranexamic acid (I) is sieved through a sieve with a pore width of 300 μm into 90 grams of the cream and mixed. If the cream does not contain a preservative, it should be kept at about 5°C. If the concentration of tranexamic acid in the cream is increased to about 20% the cream often contains crystals probably caused by supersaturation of tranexamic acid. This problem can be overcome using proper pharmaceutical actions. It is believed that with the aid of a hydrophilic polymer, for example PVP, crystallization can be avoided.

Gels .

Example 7

Water-miscible gel or hydrophilic gel

AMCA 10.0 g

Carboxymethylcellulose sodium 2.0 g

Propylene glycol 24.0 g

Methylparahydroxybenzoate 0.1 g

Purified water 63.9 g 100.0 g

Methylparahydroxybenzoate is dissolved in propylene glycol. Carboxymethylcellulose sodium is added to the solution by stirring. Water is heated to boiling. The pro- polyne glycol mixture is added slowly with constant stirring until the gel is cool. AMCA is dispersed in the cooled basis by a suitable mill.

Example 8 Water-free gel - water miscible

AMCA 10.0 g

Macrogol 3000 39.0 g

Macrogol 400 51.0 g 100.0 g Macrogol 300 is melted by gently heating to about 65 C. Macrogol 400 is added and the mixture is allowed to cool to room temperature. AMCA (micronized) is dispersed in the basis using a suitable mill.

Example 9

Hydrophobic gels - water imiscible

AMCA 10.0 g White soft paraffin 78.0 g

Liquid paraffin 12.0 g

100.0 g

The soft paraffin is dissolved in liquid paraffin by heating the mixture. The solution is allowed to cool with a rate of 2 C per minute with stirring. At room temperature AMCA (micronized) is dispersed in the basis using a suitable mill.

Oral preparations .

Tablets intended for rapid disintegration and dissolution of the drug substance.

Example 10

Tablet formulation. Amount per tablet.

AMCA 500 mg

Microcrystalline cellulose 100 mg Povidone 20 mg

Magnesium stearate 3 mg

Talc 27 mg Example 11

Tablet formulation. Amount per tablet

AMCA 500 mg Calcium monohydrogen phosphate 82 mg

Croscaramellose sodium 25 mg

Povidone 20 mg

Magnesium stearate 3 mg

Talc 27 mg

Example 12

The formulations according to Examples 1-10 are repeated using EACA, PAMBA or AMBOCA in place of AMCA.

Case stories .

To illustrate the significant beneficial effect of the present invention selected cases of skin diseases are presented. Unless otherwise stated the topical 10% tran- examic acid is formulated in a cream prepared as in example 6.

The inventor experience that a topical formulation chosen to contain 10% (weight/volume) of tranexamic acid in a cream used at least once daily is effective in reducing or eliminating the treated individuals symptoms and objective signs of disease in the majority of the patients studied who has suffered from Hailey-Hailey" s disease, prurigo nodularis Hyde, various (e.g. toxic or allergic) forms of eczema, atopic dermatitis, alopecia areata, psoriasis, mb. Darier, and the like.

Example 13

Porphyria cutanea tarda: A 40-year old woman with year-round disease activity could not tolerate antimalarial drugs which induced se- vere headaches. Phlebotomies caused symptomatic anaemia and did not significantly influence the activity of disease. Following 2 days of 10% tranexamic acid therapy in a cream she experienced rapid healing of lesions and the associated itching was significantly reduced.

Example 14

Hailey-Hailey^" s disease:

A woman aged 75 years had suffered from Hailey-Hailey" s disease from the age of about 20 years. She had previously been treated with various formulations of topical glucocorticosteroids , tar preparations and lubricating creams all without any significant clinical effect. Three weeks following twice daily application of a cream con- taining 10% tranexamic acid as single therapy she noticed clearing of almost all lesions and a significant better treatment response than ever obtained before. The patient has now for over 6 months used intermittent topical tranexamic acid treatment to induce remissions either as sole treatment or combined with conventional treatments such as antibiotics, antifungal drugs, or topical glucocorticosteroids. Her daughter, similarly severely affected by this inherited disorder, has obtained an even better clinical benefit with complete clearance of all lesions.

Example 15 Mb. Darier:

A male aged 17 years had for at least 10 years experienced the skin lesions of Darier^' s disease. Systemic ret- inoid therapy was of value but did not lead to a completely satisfactory result. Additional topical tranexamic acid therapy using a cream containing 10% had a marked clinical effect. Almost disappearance of all lesions occurred when this treatment was further combined with oral administration of 1,5 g tranexamic acid three times daily. Example 16

Pruriqo nodularis Hyde:

A female aged 28 years had previously been treated with no significant clinical effect using topical remedies such as glucocorticosteroids , tars and occlusive dressings. Neither were photochemotherapy in the form of UVB treatment, and systemic therapy with thalidomide which also induced severe side effects, of any clinical bene- fit. She experienced a pronounced reduction in the size and number of visible skin lesions and of the associated pruritus within only one week of twice daily application of the cream containing 10% tranexamic acid. This very favourable treatment response has continued for over 6 months with immediate relapses when the tranexamic acid treatment is discontinued.

Example 17

Prurico nodularis Hyde: A 53-year old male with disabling prurigo nodularis Hyde had previous been administered a variety of topical treatments and systemic drugs including chemotherapy without much effect. The only treatment which gave him some temporary relief was in-hospital topical tar therapy which had to be continued for months in order to be effective. He experienced within weeks following twice daily application of 10% tranexamic acid in a cream almost complete relief of itching and clearing of lesions.

Example 18 Eczema:

A 64-year old woman with life-long atopic dermatitis at present most severe on her hands experienced that twice daily application of 10% tranexamic acid cream resulted in substantial improvement with an effect similar or bet- ter when compared to the most potent formulations of glu- cocorticosteroids .

Example 19 Eczema:

A male aged 39 years with allergic contact dermatitis caused by hypersensitivity towards nickel, chrome and various preservatives experienced rapid relief of itching and clearing of eczematous patches by twice daily appli- cation of 10% tranexamic acid cream.

Example 20

Eczema:

A 61-year old male with allergic contact dermatitis caused by multiple allergies had within 3 weeks of topical 10% tranexamic acid cream treatment substantial clearing of excematous patches on his hands. He stated that this treatment effect was clearly superior even to treatments with the most potent glucocorticosteroids .

Example 21

Eczema:

A woman aged 51 years had for over 30 years suffered from recurrent eczema of the hands and feet with an almost continuous disease activity within the last months prior to tranexamic acid treatment. She had a type 4 allergic reaction to nickel but did not deliberately expose herself to this metal. She had previously been treated with systemic and topical glucocorticosteroids, photo- chemotherapy, grenz ray treatment, topical tar remedies, all without significant clinical benefit. Few days following initiation of two times daily topical tranexamic acid she experienced that the associated pruritus disappeared, the signs of eczema was less pronounced, and in the following weeks nearly all signs and symptoms of the disease disappeared. The eczemateous condition flared when the patient exposed herself to known provoking factors such as gardening and wet work. During one such occasion systemic oral tranexamic acid as 1,0 g three times daily was added in order to obtain a more rapid re is- sion. However, the systemic administration of tranexamic acid had severe side effects in the form of diarrhea and a resultant weight loss of more than 2 kilos within 2 weeks underlining that the present invention does not possess the side effects of the systemic treatment.

Example 22

Eczema:

A woman aged 71 years had recurrent eczema for 35 years caused by contact dermatitis, both irritative and aller- gic caused nickel, chromium, cobalt, formaldehyde and perfumes, widely distributed on her skin but especially on her feet. Previous treatments were topical glucocorticosteroids and photomedicine in the form of UVB. She treated her left foot with a 10% tranexamic acid cream twice daily and her right foot twice daily with an identical cream without any tranexamic acid. Within one month there were a marked side difference with almost disappearance of the eczema on her left foot and without improvement of the condition on her right foot. In the pa- tients experience the treatment response on her left foot was similar in effect to the most potent topical gluco- corticoids.

Example 23 Eczema:

A woman aged 53 years had for over 1 year suffered from lichen simplex chronicus on both legs. Previous therapy were daily application of the most potent glucocorticosteroids, grenz ray treatment, occlusive dressings, all without any effect. Within 2 weeks of topical therapy with the 10% tranexamic acid cream, the associated pruri- tus disappeared and the eczematous condition likewise improved. Following two months of treatment the lesions was completely cleared and the patient has presently been in remission for over 6 months.

Example 24 Eczema:

A woman aged 33 years suffering from disabling hand eczema caused by multiple type 4 allergies towards several chemicals used in the printing industry had likewise a remarkable positive treatment response of twice daily application of a cream containing 10% tranexamic acid within weeks .

Example 25 Eczema:

A 50-year old woman had for many years had allergic contact dermatitis, especially on her hands, from allergy towards rubber, nickel, perfumes and certain flowers. She experienced within weeks of treatment with topical 10% tranexamic acid in a cream a significant improvement.

Example 26 Psoriasis: A 68-year male received methotrexate therapy but it did not lead to a satisfactory clinical response. One month of treatment with the 10% tranexamic acid cream twice daily lead to a significant positive response with less scaling and infiltration, and the patient in addition no- ticed that the such treated skin was more stretchable and soft than the skin treated identically but with the cream without added tranexamic acid. Example 27 Psoriasis :

A woman aged 74 years suffering from pustulosis palmo- plantaris, a variant of psoriasis, had objective signs of improvement within months following twice daily topical 10% tranexamic acid treatment. She also received methotrexate therapy but this had not lead to a satisfactory clinical effect.

Example 28 Psoriasis :

A 56 year old woman with psoriasis lesions predominantly located on both legs noticed a similar positive effect within 1 month of topical application of 10% tranexamic acid when compared to the response obtained from a potent topical gluocorticosteroid, i.e. mometason, both applied 2 times daily.

Example 29 Psoriasis :

A 73-year old woman with psoriasis and pustulosis palmo- plantaris treated the lesions with a cream containing 10% tranexamic acid twice daily. Within weeks she noticed clearing of the psoriasis lesions and significant less pustulation than before initiation of this treatment. She stated that the treatment response was similar to that obtained following therapy with the strongest topical formulations of glucocorticosteroids such as clobetasol- proprionate.

Example 30

Hair diseases:

A male of 23 years had alopecia areata previously treated with the most potent glucocorticosteroids and grenz rays but with no effect whatsoever. Following three weeks of twice daily application of 10% tranexamic acid the pa- tient experienced a significant growth of new hair. When he discontinued the treatment the hairs developed in the treated areas did not fall out but new spots of alopecia areata kept developing.

Example 31 Uremic pruritus:

A 67-year old male with chronic renal insufficiency received UVB phototherapy due to severe itching. This treatment was only partly effective. Supplementation with topical 10% tranexamic acid cream twice daily significantly improved the condition and relieved the itching.

Example 32 Cream versus ointment:

Three patients were administered 10% tranexamic acid formulated in an ointment prepared as described in example 5. The lesions treated with this ointment healed more rapidly when compared to response obtained on other le- sions treated with 10% tranexamic acid in a cream manufactured as in example 6. This shows that in the individual patient the formulation of the topical treatment is very important for the outcome of the therapy.

Example 33

EACA versus AMCA

Using the manufacturing method described in example 6 one cream containing 10% EACA and one containing 10% tranexamic acid (AMCA) was prepared. Two patients were adminis- tered these creams and both experienced that the treatment response was significantly poorer with the cream containing EACA when compared to the one with AMCHA. This difference might reflect the 10-fold difference in inhibitory potency observed in vitro (Westlund, 1982). Thus it is necessary to use higher doses of EACA than AMCHA in the topical formulation if an identical treatment response is to be obtained.

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Claims

1. Use of lysine, a synthetic lysine analog, or a derivative thereof, or a salt thereof, or a combination thereof in the manufacture of a medicament for topical application for the treatment of skin diseases.

2. Use according to claim 1 wherein the analog is a synthetic lysine analog or a derivative thereof, or a salt thereof.

3. Use according to claim 2 wherein the analog is selected from trans-p-amino-methyl-cyclohexane-carboxylic acid (AMCA, tranexamic acid), ε-amino-caproic acid (EACA), p-aminomethylbenzoic acid (PAMBA) and 4-amino- ethylbicyclo-[2.2.2]-octane-l-carboxylic acid (AMBOCA).

4. Use according to claim 3 wherein the analog is AMCA or EACA.

5. Use according to claim 4 wherein the analog is AMCA.

6. Use according to any of claims 1-5 wherein the medicament is in the form of a wet dressing, soak, bath, sha - poo, lotion, solution, tincture, aerosol, powder, cream, gel, ointment, fixed dressing, paste, occlusive dressing, semiocclusive dressing, alginate, hydrocolloid, foam or a combination thereof.

7. Use according to any of claims 1-6 where the medicament further comprises one or more additional drugs such as glucocorticosteroids, antibacterial agents, antifungal drugs, antiviral drugs, benzoyl peroxide, vitamin A or vitamin A derivatives, analgesics, anti-hair loss medica- tions (e.g. minoxidil), anti-inflammatory agents, anti- perspirants, anti-pruritic agents, anti-psoriatic agents (e.g. anthralin, tars, vitamin D3 analogs, tacrolimus), astringents, insecticides and scabicides, keratolytic agents or wart therapies (cantharidin, podophyllin resin) .

8. Use according to any of claims 1-7 wherein the medicament further comprises pharmaceutically acceptable additives and/or carriers.

9. Use according to claims 1-8 wherein the medicament comprises from 0.01 to 100%, preferably from 0.1 to 20%, more preferably from 1 to 10%, even more preferably from 5 to 10% and most preferably 10% weight/volume lysine, synthetic lysine analog, or a derivative thereof, or a salt thereof, or a combination thereof.

10. Use according to any of claims 1-9 further comprising the use of one or more drugs in the manufacture of a medicament for systemic administration for treatment of the said skin disease, the medicaments being for a combined topical and systemic treatment of the said skin diseases.

11. Use according to claim 10 wherein the medicament for systemic administration comprises lysine, a synthetic ly- sine analog, or a derivative thereof, or a salt thereof, or a combination thereof.

12. Use according to claim 11 wherein the analog used in the manufacture of the medicament for systemic admini- stration, independently of the lysine, synthetic lysine analog, or derivative thereof, or a salt thereof, or combination thereof used in the manufacture of the medicament for topic application, is a synthetic lysine analog, preferably selected from trans-p-amino-methyl-cyclo- hexane-carboxylic acid (AMCA, tranexamic acid), ε-aminocaproic acid (EACA), p-aminomethylbenzoic acid (PAMBA) and 4-aminoethyl-bicyclo-[2.2.2 ]-octane-l-carboxylic acid (AMBOCA) , more preferably selected from AMCA and EACA and most preferably AMCA.

13. Use according to claim 10 wherein the medicament for systemic administration comprises one or more drugs such as dapsone, aminoquinolines, cytotoxic agents (e.g. methotrexate, azathioprine, 5-fluorouracil, cyclophosphamide, nitrogen mustard), retinoids, antihistamines and cyc- losporine.

14. Use according to any of claims 10-13 wherein the systemic administration is an oral administration or an intravenous administration.

15. Use according to any of the claims 1-14 wherein the skin disease is caused by endogenous etiologic and/or pathogenetic factors.

16. Use according to claim 15 wherein the disease is selected from psoriasis, atopic dermatitis, contact dermatitis, bullous skin disorders, mb. Darier, Hailey- Hailey's disease, exfoliative dermatitis, ichthyosiform dermatoses, pityriais rubra pilaris, Grover's disease, keratodermas, pustular eruptions, cicatricial alopecias, non-cicatricial alopecias especially alopecia areata, ro- sacea, acne vulgaris, cutaneous neoplasms, pityriais rosea, parapsoriasis, lichen planus, lichen nitidus, Sweet^'s syndrome, erythema elevatum diutinum, pyoderma gangrenosu , erythema annulare, anetoderma, nummular ec- zematous dermatitis, autosentization dermatitis, sebor- rhoic dermatitis, vesicular palmoplantar eczema, hand eczema, infective dermatitis, , photoassociated responses such as polymorphic light eruptions, actinic prurigo, hy- droa vacciniforme, chronic actinic dermatitis, drug-induced photosensitivities , sunburn reactions, asteatotic eczema, pityriasis alba, dermatophytides , pityrosporal folliculitis, gravitational eczema, juvenile plantar der- matosis, perioral dermatitis, lichen simplex, pruritic conditions and eruptions including prurigo nodularis Hyde, urticaria, discoid and subacute lupus erythemato- sus, dermatomyositis, skin sarcoidosis, skin diseases caused by microbial agents notably warts, and the like.

17. Pharmaceutical composition for topical application comprising a pharmaceutically active amount of lysine, a synthetic lysine analog, or a derivative thereof, or a salt thereof, or a combination thereof.

18. Pharmaceutical composition according to claim 17 wherein the analog is a synthetic lysine analog or a derivative thereof, or a salt thereof.

19. Pharmaceutical composition according to claim 18 wherein the analog is selected from trans-p-amino-methyl- cyclohexanecarboxylic acid (AMCA, tranexamic acid), ε- aminocaproic acid (EACA), p-aminomethyl- benzoic acid (PAMBA) and 4-aminoethylbicyclo- [2.2.2 ]-octane-l-carbox- ylic acid (AMBOCA) .

20. Pharmaceutical composition according to claim 19 wherein the analog is AMCA or EACA.

21. Pharmaceutical composition according to claim 20 wherein the analog is AMCA.

22. Pharmaceutical composition according to claims 17-21 wherein the composition further comprises one or more additional drugs, such as glucocorticosteroid, antibacterial agents, antifungal drugs, antiviral drugs, benzoyl peroxide, vitamin A or vitamin A derivatives, analgesics, anti-hair loss medications (e.g. minoxidil), anti-inflam- matory agents, antiperspirants , anti-pruritic agents, anti-psoriatic agents (e.g. anthralin, tars, vitamin D3 analogs, tacrolimus), astringents, insecticides and scabicides, keratolytic agents, wart therapies (cantha- ridin, podophyllin resin).

23. Pharmaceutical composition according to any of claims 17-22 wherein the composition further comprises pharmaceutically acceptable additives and/or carriers.

24. Pharmaceutical composition according to claims 17-23 wherein the composition comprises from 0.01 to 100%, preferably from 0.1 to 20%, more preferably from 1 to 10%, even more preferably from 5 to 10% and most prefera- bly 10% weight/volume lysine, synthetic lysine analog, or derivative thereof, or a salt thereof, or a combination thereof.

25. Pharmaceutical composition according to any of claims 17-24 wherein the composition is in the form of a wet dressing, shampoo, lotion, solution, tincture, aerosol, powder, cream, gel, ointment, fixed dressing, paste, oc- clusive dressing, semiocclusive dressing, alginate, hy- drocolloid or foam.

26. A method of treating a skin disease comprising administering to the cutaneous or mucosal surface of a patient suffering from said skin disease an effective amount of a composition according to any of the claims 17-25.

27. A method of treating a skin disease comprising administering to the cutaneous or mucosal surface of a patient suffering from said skin disease an effective amount of a composition according to any of the claims 17-25 and in combination herewith a systemic administration of a medicament comprising an effective amount of one or more drugs against the said skin disease, or a local or universal photomedicine .

28. A method according to claim 27 wherein the additional medicament for systemic administration comprises lysine, a synthetic lysine analog, or a derivative thereof, or a salt thereof, or a combination thereof.

29. A method according to claim 28 wherein the analog comprised in the medicament for systemic administration, independently of the lysine, synthetic lysine analog, or derivative thereof, or a salt thereof, or combination thereof used in the medicament for topic application, is a synthetic lysine analog, preferably selected from trans-p-amino-methyl-cyclohexane-carboxylic acid (AMCA, tranexamic acid), ε-amino-caproic acid (EACA), p-aminomethylbenzoic acid (PAMBA) and 4-aminoethyl-bicyclo- [ 2 . 2 .2 ] -octane-1-carboxylic acid (AMBOCA), more preferably selected from AMCA and EACA and most preferably AMCA.

30. A method according to claim 27 wherein the medicament for systemic administration comprises one or more drugs selected from dapsone, aminoquinolines , cytotoxic agents (e.g. methotrexate, azathioprine, 5-fluorouracil, cyclo- phosphamide, nitrogen mustard), retinoids, antihista- mines, cyclosporine.

31. A method according to any of claims 26-30 wherein the systemic administration is an oral administration or an intravenous administration.

32. A method according to claim 27 wherein the photomedicine is x-ray treatment, UVB or PUVA phototherapy.

33. A method according to any of claims 26-32 wherein the skin disease is caused by endogenous etiologic and/or pathogenetic factors.

34. A method according to claim 33 wherein the skin disease is selected from psoriasis, atopic dermatitis, contact dermatitis, bullous skin disorders, mb. Darier, Hailey-Hailey ' s disease, exfoliative dermatitis, ichthyosiform dermatoses, pityriais rubra pilaris, Grover's disease, keratodermas, pustular eruptions, cicatricial alopecias, non-cicatricial alopecias especially alopecia areata, rosacea, acne vulgaris, cutaneous neoplasms, pityriais rosea, parapsoriasis, lichen planus, lichen ni- tidus, Sweet's syndrome, erythema elevatum diutinum, pyo- derma gangrenosum, erythema annulare, anetoderma, nu mu- lar eczematous dermatitis, autosentization dermatitis, seborrhoic dermatitis, vesicular palmoplantar eczema, hand eczema, infective dermatitis, photoassociated responses such as polymorphic light eruptions, actinic pru- rigo, hydroa vacciniforme, chronic actinic dermatitis, drug-induced photosensitivities , sunburn reactions, asteatotic eczema, pityriasis alba, dermatophytides, pityrosporal folliculitis, gravitational eczema, juvenile plantar dermatosis, perioral dermatitis, lichen simplex, pruritic eruptions including prurigo nodularis Hyde, urticaria, discoid and subacute lupus erythematosus, der- matomyositis , skin sarcoidosis, skin diseases caused by microbial agents notably warts, and the like.