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WO2000037071A1 - Traitement local de dermatoses - Google Patents

Traitement local de dermatoses Download PDF

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Publication number
WO2000037071A1
WO2000037071A1 PCT/DK1999/000722 DK9900722W WO0037071A1 WO 2000037071 A1 WO2000037071 A1 WO 2000037071A1 DK 9900722 W DK9900722 W DK 9900722W WO 0037071 A1 WO0037071 A1 WO 0037071A1
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WIPO (PCT)
Prior art keywords
analog
dermatitis
acid
lysine
skin
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PCT/DK1999/000722
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English (en)
Inventor
Hans Christian Wulf
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APS KBUS 8 NR 4788
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APS KBUS 8 NR 4788
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Priority to AU17736/00A priority Critical patent/AU1773600A/en
Publication of WO2000037071A1 publication Critical patent/WO2000037071A1/fr
Anticipated expiration legal-status Critical
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth

Definitions

  • the present invention relates to treatment of skin diseases, such as psoriasis and eczemas.
  • the invention relates to a topical treatment of skin diseases and the use of lysine-related compounds in such a treatment.
  • 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.
  • 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.
  • topical treat- ment of many skin diseases such as psoriasis and eczema
  • 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.
  • 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.
  • skin diseases such as psoriasis, atopic dermatitis, contact dermatitis, bullous skin disorders, mb. Darier, and Hailey-Hailey ⁇ s disease.
  • the first attack of psoriasis is often ini- tiated following a throat infection with streptococcal bacteria in the genetically predisposed individual.
  • administration of certain drugs such as lithium can aggravate the clinical condition of a psoriatic (Christophers, 1993).
  • patients who develops an allergic contact dermatitis e.g. caused by exposure to nickel in the environment, one often sees an unexplained end
  • 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).
  • 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).
  • plasminogen activators can induce growth of epidermal cells (Kirchheimer , 1989).
  • tissue-type plasminogen activator tissue-type plasminogen activator (t-PA) and urokinase plasminogen activator (uPA) which convert plasminogen to the active enzyme plasmin (Munkvad, 1993).
  • t-PA tissue-type plasminogen activator
  • uPA urokinase plasminogen activator
  • 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) , ⁇ - 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).
  • drugs such as tranexamic acid, also designated trans-p-amino- methyl—cyclohexanecarboxylic acid (AMCA; AMCHA) , ⁇ - aminocaproic acid (EACA) , p-aminomethylbenzoic acid (PAMBA) and 4-amino
  • 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 disease 1 ', predominantly various forms of eczema.
  • 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.
  • 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.
  • 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.
  • 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), ⁇ -amino-caproic acid (EACA), p-aminomethylbenzoic acid (PAMBA) and 4-aminoethylbicyclo-[2.2.2 ]-octane-l- carboxylic acid (AMBOCA) .
  • AMCA trans-p-amino- methyl-cyclohexane-carboxylic acid
  • EACA ⁇ -amino-caproic acid
  • PAMBA p-aminomethylbenzoic acid
  • AMBOCA 4-aminoethylbicyclo-[
  • 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 .
  • 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).
  • 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
  • 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 .
  • 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,
  • 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 .
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • lysine analogs are tranexamic acid, ⁇ -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).
  • 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), ⁇ -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.
  • ⁇ -aminocaproic acid is a synthetic amino acid with a molecular weight of 131.
  • the synthesis of ⁇ -aminocaproic acid has been described in US Patent 2,453,234.
  • ⁇ -aminocaproic acid is a registered drug which is commercial available from pharmaceutical companies, e.g. Abbott, Elkins Sinn, Immunex and Luitpold.
  • PAMBA p-aminomethylbenzoic acid
  • AMBOCA 4-aminoethylbicyclo- [2.2.2] -octane-1-carboxylic acid
  • 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.
  • 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.
  • 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
  • organic acid salts such as a salt of ace
  • 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.
  • the most preferred synthetic lysine analogs for use in the present invention are tranexamic acid ( trans-p-amino- methyl-cyclohexane-carboxylic acid (AMCA) ) and ⁇ -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.
  • 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 .
  • 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.
  • 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.
  • virus infections 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.
  • 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.
  • 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.
  • topical therapy with tranexamic acid when compared to conventional topical treatments such as topical glucocorticoid treatment.
  • the present invention has in many cases a more potent action than conventional treatment.
  • 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.
  • topical glucocorticoid treatment notes that topical tranexamic treatment does not cause the thinning of the skin which they have experienced during the glucocorticoid treatment.
  • topical tranexamic treatment does not cause the thinning of the skin which they have experienced during the glucocorticoid treatment.
  • side effects of systemic therapy with tranexamic acid or other synthetic lysine analogs are completely avoided.
  • 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.
  • 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 e.g. anthra- lin, tars, vitamin D3 analogs, tacrolimus
  • anti-psoriatic agents e.g. anthra- lin, tars, vitamin D3 analogs, tacrolimus
  • astringents insecticides and scabicides
  • keratolytic agents keratolytic agents or wart therapies (cantharidin, podophyllin resin).
  • wart therapies cantharidin, podophyllin resin.
  • the patient may be administered in sup- plement to the external treatment, a systemic administration of an active medicament against said skin disease.
  • 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.
  • 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), ⁇ -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.
  • AMCA trans-p-amino-methyl-cyclo- hexane-carboxylic acid
  • EACA ⁇ -aminocaproic acid
  • PAMBA p-aminomethylbenzoic acid
  • AMBOCA 4-aminoe
  • 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.
  • 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.
  • compositions 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a parenterally acceptable liquid e.g. pyro- gen-free water or an aqueous solution of polyvinylpyr- rolidone
  • 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.
  • 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.
  • the pharmaceutical composition comprises a synthetic lysine analog, such as trans-p-aminomethylcyclohexanecarboxylic acid (AMCA, tranexamic acid), ⁇ -aminocaproic acid (EACA), p-aminomethylbenzoic acid (PAMBA) and 4-aminoethyl-bicy- clo-[2.2.2 ]-octane-l-carboxylic acid (AMBOCA).
  • AMCA trans-p-aminomethylcyclohexanecarboxylic acid
  • EACA ⁇ -aminocaproic acid
  • PAMBA p-aminomethylbenzoic acid
  • AMBOCA 4-aminoethyl-bicy- clo-[2.2.2 ]-octane-l-
  • 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).
  • 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,
  • 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.
  • 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.
  • 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.
  • 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.
  • the condition is in satisfactory remission then taper off the conventional therapy and solely control the disease activity by topical administration of tranexamic acid.
  • 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 solids are dissolved in purified water.
  • the parabens are added in the form of 10 percent solutions in ethanol.
  • Methylcellulose 1500 2 , . 0 g Propylenglycol 10 . , 0 g Methylparahydroxybenzoate 0 . . 1 g
  • Ointments with other concentrations can be made using the same composition of the carriers.
  • tranexamic acid (I) is sieved through a sieve with a pore width of 300 ⁇ m 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.
  • 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.
  • 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.
  • 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.
  • AMCA micronized
  • AMCA is dispersed in the basis using a suitable mill.
  • Tablet formulation Amount per tablet.
  • 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.
  • 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.
  • Hailey-Hailey s disease
  • 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.
  • tranexamic acid as 1,0 g three times daily was added in order to obtain a more rapid re is- sion.
  • systemic oral 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 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 :
  • Example 32 Cream versus ointment:
  • tissue-type plasminogen ac- tivator is present in lesional epidermis from patients with psoriasis, pemphigus, or bullous pemphigoid, but is not detected in normal epidermis. J Invest Dermatol 1990; 95: 548-52.
  • Belsito DV Allergic contact dermatitis. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, eds . Dermatology in general medicine. New York: McGraw-Hill, Inc, 1993: 1531-42.
  • T-AMCHA trans-4- (Aminomethyl)cyclohexane carboxylic acid
  • Kuliev NA The treatment of psoriatic arthropathy with a combination of mefenamic and aminocaproic acids. Vestn Dermatol Venerol 1989; 5: 43-7.

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Abstract

L'invention concerne l'utilisation de lysine et/ou d'analogues de la lysine dans le traitement local de dermatoses.
PCT/DK1999/000722 1998-12-21 1999-12-21 Traitement local de dermatoses Ceased WO2000037071A1 (fr)

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AU17736/00A AU1773600A (en) 1998-12-21 1999-12-21 Topical treatment of skin disease

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DKPA199801691 1998-12-21
US11375198P 1998-12-23 1998-12-23
US60/113,751 1998-12-23

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Cited By (19)

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DE10106852A1 (de) * 2001-02-14 2002-09-05 T Luger Entzündungshemmende Verbindungen
WO2004071510A1 (fr) * 2003-02-11 2004-08-26 Cipla Ltd Composition pharmaceutique comprenant des immunosuppresseurs pour le traitement de la dermatophytose
WO2004026295A3 (fr) * 2002-09-17 2004-11-11 Phenion Gmbh & Co Kg Utilisation de substances pour proteger la peau
EP1581269A1 (fr) * 2002-12-16 2005-10-05 Langer, Hans-Georg Composition hemostatique pour soigner les plaies
WO2008050173A1 (fr) * 2006-10-26 2008-05-02 Chanel Parfums Beaute Composition topique de soin de la peau contenant un ester d'acide tranexamique
WO2011069915A1 (fr) * 2009-12-11 2011-06-16 Chanel Parfums Beaute Composition à usage externe et procédé de production associé
EP2409693A3 (fr) * 2010-07-23 2012-02-22 Auriga International Isothiocyanates et dérivés pour l'utilisation dans le traitement et/ou la prévention des lucites
WO2012101102A3 (fr) * 2011-01-24 2013-05-02 Chanel Parfums Beaute Composition se présentant sous la forme d'une émulsion huile dans eau et son procédé de production
US8734421B2 (en) 2003-06-30 2014-05-27 Johnson & Johnson Consumer Companies, Inc. Methods of treating pores on the skin with electricity
US8744567B2 (en) 2009-11-13 2014-06-03 Johnson & Johnson Consumer Companies, Inc. Galvanic skin treatment device
US9044397B2 (en) 2009-03-27 2015-06-02 Ethicon, Inc. Medical devices with galvanic particulates
EP3130328A1 (fr) * 2015-08-13 2017-02-15 Colgate-Palmolive Company Composition de soins bucco-dentaires pour soulagement du saignement des gencives
WO2017050937A1 (fr) * 2015-09-22 2017-03-30 Omnio Ab Inhibiteurs du plasminogène pour traiter, réduire ou prévenir les blessures induites par rayonnement
WO2018187470A1 (fr) 2017-04-04 2018-10-11 Anti-Plasmin Technologies, Llc Procédés destinés à améliorer un traitement médical non chirurgical
WO2022074228A1 (fr) * 2020-10-09 2022-04-14 Mc2 Therapeutics Ltd Traitement d'affections dermatologiques
US11413279B2 (en) * 2017-08-27 2022-08-16 Anti-Viral Technologies, Llc Methods and compositions for the antiviral use of synthetic lysine analogs and mimetics
CN115443130A (zh) * 2020-02-03 2022-12-06 传明科技有限责任公司 用于治疗疾病的方法和组合物
US20230080241A1 (en) * 2020-02-14 2023-03-16 Tranexamic Technologies, Llc Methods and compositions for antimicrobial use of synthetic lysine analogs, derivatives, and mimetics, and prodrugs
US11666532B2 (en) 2018-01-19 2023-06-06 Hyloris Developments Sa Tranexamic acid oral solution

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Cited By (34)

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DE10106852A1 (de) * 2001-02-14 2002-09-05 T Luger Entzündungshemmende Verbindungen
WO2004026295A3 (fr) * 2002-09-17 2004-11-11 Phenion Gmbh & Co Kg Utilisation de substances pour proteger la peau
EP1581269A1 (fr) * 2002-12-16 2005-10-05 Langer, Hans-Georg Composition hemostatique pour soigner les plaies
WO2004071510A1 (fr) * 2003-02-11 2004-08-26 Cipla Ltd Composition pharmaceutique comprenant des immunosuppresseurs pour le traitement de la dermatophytose
US8734421B2 (en) 2003-06-30 2014-05-27 Johnson & Johnson Consumer Companies, Inc. Methods of treating pores on the skin with electricity
WO2008050173A1 (fr) * 2006-10-26 2008-05-02 Chanel Parfums Beaute Composition topique de soin de la peau contenant un ester d'acide tranexamique
US9044397B2 (en) 2009-03-27 2015-06-02 Ethicon, Inc. Medical devices with galvanic particulates
US8744567B2 (en) 2009-11-13 2014-06-03 Johnson & Johnson Consumer Companies, Inc. Galvanic skin treatment device
JP2011140487A (ja) * 2009-12-11 2011-07-21 Chanel Keshohin Gijutsu Kaihatsu Kenkyusho:Kk 外用組成物及びその製造方法
US8758785B2 (en) 2009-12-11 2014-06-24 Chanel Parfums Beaute Composition for external use and method for producing the same
US8647650B2 (en) 2009-12-11 2014-02-11 Chanel Parfums Beaute Composition for external use and method for producing the same
WO2011069915A1 (fr) * 2009-12-11 2011-06-16 Chanel Parfums Beaute Composition à usage externe et procédé de production associé
EP2409693A3 (fr) * 2010-07-23 2012-02-22 Auriga International Isothiocyanates et dérivés pour l'utilisation dans le traitement et/ou la prévention des lucites
CN103476390B (zh) * 2011-01-24 2016-11-09 香奈儿香水美妆品公司 水包油型乳液组合物及其生产方法
CN103476390A (zh) * 2011-01-24 2013-12-25 香奈儿香水美妆品公司 水包油型乳液组合物及其生产方法
US9345651B2 (en) 2011-01-24 2016-05-24 Chanel Parfums Beaute Oil-in-water emulsion composition and method for producing the same
WO2012101102A3 (fr) * 2011-01-24 2013-05-02 Chanel Parfums Beaute Composition se présentant sous la forme d'une émulsion huile dans eau et son procédé de production
EP3130328A1 (fr) * 2015-08-13 2017-02-15 Colgate-Palmolive Company Composition de soins bucco-dentaires pour soulagement du saignement des gencives
CN106420379A (zh) * 2015-08-13 2017-02-22 高露洁-棕榄公司 具有减轻牙龈出血功效的洁齿剂组合物
WO2017050937A1 (fr) * 2015-09-22 2017-03-30 Omnio Ab Inhibiteurs du plasminogène pour traiter, réduire ou prévenir les blessures induites par rayonnement
EP3606499A4 (fr) * 2017-04-04 2021-03-24 Anti-Plasmin Technologies, LLC Procédés destinés à améliorer un traitement médical non chirurgical
JP2020513011A (ja) * 2017-04-04 2020-04-30 アンタイ−プラスミン テクノロジーズ， エルエルシー 非外科的治療を向上させる方法
US12251363B2 (en) 2017-04-04 2025-03-18 Anti-Plasmin Technologies, Llc Compositions to enhance a non-surgical medical treatment
US11241405B2 (en) 2017-04-04 2022-02-08 Anti-Plasmin Technologies, Llc Methods to enhance a non-surgical medical treatment
WO2018187470A1 (fr) 2017-04-04 2018-10-11 Anti-Plasmin Technologies, Llc Procédés destinés à améliorer un traitement médical non chirurgical
JP7675501B2 (ja) 2017-04-04 2025-05-13 アンタイ－プラスミン テクノロジーズ， エルエルシー 非外科的治療を向上させる方法
AU2018248422B2 (en) * 2017-04-04 2024-02-15 Anti-Plasmin Technologies, Llc Methods to enhance a non-surgical medical treatment
US11413279B2 (en) * 2017-08-27 2022-08-16 Anti-Viral Technologies, Llc Methods and compositions for the antiviral use of synthetic lysine analogs and mimetics
US11666532B2 (en) 2018-01-19 2023-06-06 Hyloris Developments Sa Tranexamic acid oral solution
CN115443130A (zh) * 2020-02-03 2022-12-06 传明科技有限责任公司 用于治疗疾病的方法和组合物
US20230080241A1 (en) * 2020-02-14 2023-03-16 Tranexamic Technologies, Llc Methods and compositions for antimicrobial use of synthetic lysine analogs, derivatives, and mimetics, and prodrugs
EP4103167A4 (fr) * 2020-02-14 2024-03-13 Tranexamic Technologies, LLC Méthodes et compositions destinées à l'utilisation antimicrobienne d'analogues, de dérivés, de mimétiques et de promédicaments synthétiques de la lysine
WO2022074228A1 (fr) * 2020-10-09 2022-04-14 Mc2 Therapeutics Ltd Traitement d'affections dermatologiques
JP2023545753A (ja) * 2020-10-09 2023-10-31 エムシー２・セラピューティクス・リミテッド 皮膚状態の処置

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