WO2004096222A1 - Utilisation de 1-(5-isoquinolinesulfonyl)homopiperazine, de ses metabolites actifs, de ses isomeres et de ses sels pour traiter et prevenir l'hypopigmentation - Google Patents

Utilisation de 1-(5-isoquinolinesulfonyl)homopiperazine, de ses metabolites actifs, de ses isomeres et de ses sels pour traiter et prevenir l'hypopigmentation Download PDF

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Publication number
WO2004096222A1
WO2004096222A1 PCT/EP2004/004620 EP2004004620W WO2004096222A1 WO 2004096222 A1 WO2004096222 A1 WO 2004096222A1 EP 2004004620 W EP2004004620 W EP 2004004620W WO 2004096222 A1 WO2004096222 A1 WO 2004096222A1
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WIPO (PCT)
Prior art keywords
cyclosporin
isoquinolinesulfonyl
homopiperazine
vitiligo
hypopigmentary
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PCT/EP2004/004620
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English (en)
Inventor
Stefan Bell
Dagmar Ewald
Stephanie Fritz
Andreas Goppelt
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Switch Biotech Ag
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Publication date
Priority claimed from EP03009921A external-priority patent/EP1479386A1/fr
Priority claimed from EP03026250A external-priority patent/EP1550446A1/fr
Application filed by Switch Biotech Ag filed Critical Switch Biotech Ag
Publication of WO2004096222A1 publication Critical patent/WO2004096222A1/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • 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

Definitions

  • the invention relates to the use of a compound according to formula (I):
  • the invention relates to the use of l-(5-isoquinolinesulfonyl)homopiperazine , its active metabolites, its isomers and pharmaceutically acceptable salts
  • the invention also relates to methods of treatment and or prevention of hypopigmentary disorders.
  • melanocytes are the sole source of the pigment melanin. Melanin is synthesized within the melanocytes and later transferred to the surrounding keratinocytes. The colour of the skin is determined to a large extent by the amount and type of melanin within the epidermis. In general dysfunction of the melanocytes or the loss of the melanocytes itself leads to loss of pigmentation. The mechanisms for the destruction of melanocytes are likely to be multiple and complex, possibly a composite of several normal processes influencing melanocyte function, proliferation and/or survival. Also the pathomechanism of hyperpigmentary disorders is largely unclear. Vitiligo, for example is a pigmentation disorder afflicting up to 2% of the worldwide population.
  • vitiligo disease is characterized by milky white macules on the skin, either due to missing melanin pigment or to complete absence of melanocytes in the dermo-epidermal junction of vitiligo areas. Vitiligo tends to be progressive throughout the life of affected individuals.
  • Other disorders of hypopigmentation that are caused by a defect in melanin production or transfer include the Chediak-Higashi syndrome, Hermansky-Pudlak syndrome, the Waardenburg syndromes I-IV, the Angelman and Prader- Willi syndrome.
  • Albinism instead is characterized by genetic defects that impede the synthesis of melanin.
  • Piebaldism is characterized by the absence of melanin at birth due to a deficiency of melanocytes.
  • melanocytes fail to complete their migration from the neural crest to the epidermis.
  • melanocytes can be found in epidermis of early lesions that are only partially depigmented.
  • late lesions that were totally depigmented there is complete absence of melanocytes.
  • Autoimmune disease Specific autoantibodies to melanocyte cell surface antigens are present in the circulation of most patients with vitiligo. These antibodies are unusual in persons with nonpigmentary skin diseases. Vitiligo antibodies are shown to have the functional capacity to kill pigment cells in vitro and can do so by two different mechanisms: complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity.
  • a dysfunction of nervous function might be involved in the pathogenesis of vitiligo as shown by an altered balance of neuropeptides in vitiliginous skin.
  • Neuropeptides are able to induce melanocyte dendricity and participate in the regulation of cell substrate adhesion, cell motility and shape.
  • Neuropeptides may also regulate melanin synthesis or affect melanosomal transfer to surrounding keratinocytes.
  • systemic photochemotherapy gives satisfactory results only in some early disease states, however, treatment is time-consuming and has a high risk of developing cancer after prolonged treatment.
  • Other therapies comprise systemic steroids,e.g. prednisone, hydrocortisone or triamcinolone, which however are also not suitable for prolonged treatment.
  • transplantation of skin has given positive results.
  • total chemical depigmentation of the skin is performed to achieve a homogeneous coloring of the skin.
  • Pityriasis alba a common hypopigmented dermatitis that occurs primarily in school-aged children.
  • this disorder is left untreated as treatments with corticosteroids or retinoic acid or PUVA treatment are not very effecient.
  • Some pigmentary disorders, like vitiligo have only skin manifestations limited to the pigmentation alterations. However, these disorders nevertheless pose severe psychological problems to the patients, as the sharp borders of depigmented areas are readily apparent to other persons, especially when occurring in the face. Vitiligo can be disfiguring and stigmatising, thereby causing significant psychological problems due to reduced social acceptance. Also, vitiligo usually persists for the whole life.
  • hypopigmentary disorders preferably vitiligo.
  • active metabolites thereof or isomers thereof or pharmaceutically acceptable salts thereof, in particular l-(5-isoquinolinesulfonyl)homopiperazine and its active metabolites and its isomers and salts are useful in the treatment and prevention of hypopigmentary disorders, especially vitiligo.
  • l-(5-isoquinolinesulfonyl)homopiperazine is especially suitable for the treatment and prevention of hypopigmentary diseases which have an inflammatory and/or autoimmune component and/or in which T cell activation and proliferation plays a role, especially preferred vitiligo.
  • Such inflammatory and/or autoimmune component may form part of the hypopigmentary disease or may be in addition thereto.
  • the present invention therefore relates to the use of a compound according to formula (I):
  • the compound is selected from the group consisting of:
  • the compound is selected from l-(5- isoquinolinesulfonyl)homopiperazine, 1 -(5 -isoquinolinesulfonyl)homopiperazine hydrochloride anhydride, l-(5-isoquinolinesulfonyl)homopiperazine hydrochloride hemihydrate and l-(5-isoquinolinesulfonyl)homopiperazine hydrochloride trihydrate.
  • the compound is an active metabolite selected from a compound according to formula (II)
  • an "active metabolite” is to be understood as metabolite of 1- (5-isoquinolinesulfonyl)homopiperazine, which is formed in vivo after administration of l-(5- isoquinolinesulfonyl)homopiperazine to a human body, and which has an activity of at least 10%, preferably of at least 50%, more preferably of at least 90%, most preferably of at least 100% in a melanocyte function assay, preferably according to Example 1, or in a T cell activation assay, preferably according to Example 2.
  • the invention also relates to a method of treating and/or preventing hypopigmentary disorders, especially vitiligo, comprising administering to a mammal a compound according to formula (I):
  • the compound is selected from the group consisting of: l-(5-isoquinolinesulfonyl)homopiperazine, and pharmaceutically acceptable salts thereof, especially its hydrochloride salts.
  • the compound is selected from l-(5- isoquinolinesulfonyl)homopiperazine, l-(5-isoquinolinesulfonyl)homopiperazine hydrochloride anhydride, l-(5-isoquinolinesulfonyl)homopiperazine hydrochloride hemihydrate and l-(5-isoquinolinesulfonyl)homopiperazine hydrochloride trihydrate.
  • the compound is an active metabolite selected from a compound according to formula (II)
  • an "active metabolite” is to be understood as metabolite of 1- (5-isoquinolinesulfonyl)homopiperazine, which is formed in vivo after administration of l-(5- isoquinolinesulfonyl)homopiperazine to a human body, and which has an activity of at least 10%, preferably of at least 50%, more preferably of at least 90%, most preferably of at least 100% in a melanocyte function assay, preferably according to Example 1, or in a T cell activation assay, preferably according to Example 2.
  • a preferred active metabolite of the present invention is the compound of formula (II), referred to as hydroxyfasudil or its salts, preferably ist hydrochloride salts.
  • the hypopigmentary disorder has an inflammatory and/or an autoimmune component.
  • the hypopigmentary disorder is selected from albinism, vitiligo, postinflammatory hypopigmentation, piebaldism, Pityariasis alba, Hypomelanoses, Leukodermas, hypopigmentation occurring e.g. after externally induced peels, e.g. chemical peels, e. g.
  • hypopigmentary disorder is a disorder in which T cell activation and proliferation plays a role, and which hypopigmentary disorder is more preferably selected from post-inflammatory hypopigmentation and vitiligo.
  • the hypopigmentary disorder is vitiligo.
  • Fasudil l-(5-isoquinolinesulfonyl)homopiperazine
  • Fasudil is a compound with vasodilatory actions which is currently in clinical trials for treating cerebral vasospasms (EP 0 870 767, EP 0 187 371B1).
  • US 6,271,224 discloses the use of Fasudil for the treatment of glaucoma and ocular ischemia.
  • Fasudil has been proposed for infectious disease (JP10045598A2), mental disorder syndrome (JP06293643A2), controlling cancer invasion and the effect of controlling carcinomatous peritonitis (EP 1064944).
  • the medicament according to the present invention is prepared in form of an ointment, a gel, a plaster, an emulsion, a lotion, a foam, a cream of a mixed phase or amphiphilic emulsion system (oil/water- water/oil mixed phase), a liposome, a transfersome, a paste or a powder, or a solution or suspension.
  • an ointment a gel, a plaster, an emulsion, a lotion, a foam, a cream of a mixed phase or amphiphilic emulsion system (oil/water- water/oil mixed phase), a liposome, a transfersome, a paste or a powder, or a solution or suspension.
  • the compound is applied topically or systemically or via a combination of the two routes, preferably topically.
  • a composition comprising a compound according to formula (I)
  • composition is used as a pharmaceutical.
  • the further active ingredient is selected from the group consisting of cyclosporin A, cyclosporin G, cyclosporin B, cyclosporin C, cyclosporin D, dihydro- cyclosporin D, cyclosporin E, cyclosporin F, cyclosporin H, cyclosporin I, ASM-240, pimecrolimus, tacrolimus, 13-desmethyl-derivatives of tacrolimus (L-685487), L-683519 and/or 17-ethyl-derivatives of tacrolimus, preferably pimecrolimus, tacrolimus, or cyclosporin A, most preferably tacrolimus; steroids, in particular betamethasone, betamethasone-17- valerate, fluocinolone, triamcinolone, triamcinolone acetonide, clobetasol, clobetasol propionate, halobetasol, hydrocorstisone, cor
  • composition according to the present invention for the manufacture of a medicament for the treatment and/or prevention of hypopigmentary disorders.
  • such composition is used for the manufacture of a medicament for the treatment and/or prevention of hypopigmentary disorders.
  • Hypopigmentary disorders according to the present invention are non-malignant disorders of the skin in mammals, including humans which are characterized by a decrease in pigmentation of the skin compared to healthy individuals. Such decrease in pigmentation may occur locally, as e.g. in mild forms of vitiligo, or may affect the whole skin. Such decrease in pigmentation may result in total loss of pigmentation, as e.g. in affected skin areas of vitiligo patients, or may result in "lighter" but still pigmented skin as in Pityriasis alba.
  • the hypopigmentary disorders, according to the present invention have an inflammatory and/or an autoimmune component.
  • the term "having an inflammatory component” is meant to designate any condition which is accompanied locally or temporally with syndromes characteristic of an inflammatory reaction, such as the induction of certain cytokines, in particular soluble IL-2R (sIL-2R), IL-6 and IL-8, and increased levels of inflammatory cells, in particular T-cells and macrophages, at sites of lesions or around lesions.
  • sIL-2R soluble IL-2R
  • IL-6 and IL-8 IL-6 and IL-8
  • inflammatory cells in particular T-cells and macrophages
  • accompanied temporally may mean that the inflammatory component precedes the hypopigmentary disorder, is concomitant therewith or follows it.
  • autoimmune component in an organism is meant to designate any condition which is characterized by a reaction of the organism's own immune system against the organism itself or tissues or cells or other components thereof.
  • An example of such a reaction is the production of auto-antibodies which are antibodies that are directed at some of an organism's own tissues or cells or other body components.
  • hypopigmentary disorders are, but not limited to, albinism, vitiligo, postinflammatory hypopigmentation, piebaldism, Pityariasis alba, Hypomelanoses, Leukodermas, hypopigmentation occuring e.g. after externally induced peels, e.g. chemical peels with phenol, or laser or cryo-surgery of the skin, Chediak-Higashi syndrome, Hermansky-Pudlak syndrome, the Angelman and Prader-Willi syndrome.
  • An especially preferred hypopigmentary disorder of the present invention is vitiligo.
  • hypopigmentary disorders in which T cell activation and proliferation plays a role are postinflammatory hypopigmentation and vitiligo, preferably vitiligo.
  • Treatment according to the present invention relates to the complete or partial healing of the hypopigmentary disorder in mammals, including humans as well as to the stop or slowing- down of the progression of a hypopigmentary disorder.
  • the compounds of the present invention are suitable for the prevention of a hypopigmentary disorder in mammals, including humans.
  • Treatment of vitiligo according to the present invention relates to the complete or partial healing of the disorder vitiligo; i.e. complete or partial repigmentation of existing white macules on vitiligo patients, as well as to the stop or slowing-down of the extension of the white macule areas on vitiligo patients.
  • Prevention of vitiligo relates to the prevention of occurrence of vitiligo phenotype in to date unaffected persons.
  • unaffected persons are persons with higher risk of vitiligo; i.e. persons with a family history of vitiligo.
  • Examples of pharmaceutically acceptable addition salts include, without limitation, the non- toxic inorganic and organic acid addition salts such as the acetate derived from acetic acid, the aconate derived from aconitic acid, the ascorbate derived from ascorbic acid, the benzenesulfonate derived from benzensulfonic acid, the benzoate derived from benzoic acid, the cinnamate derived from cinnamic acid, the citrate derived from citric acid, the embonate derived from embonic acid, the enantate derived from enanthic acid, the formate derived from formic acid, the fumarate derived from fumaric acid, the glutamate derived from glutamic acid, the glycolate derived from glycolic acid, the hydrochloride derived from hydrochloric acid, the hydrobromide derived from hydrobromic acid, the lactate derived from lactic acid, the maleate derived from maleic acid, the malonate derived from mal
  • acids such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a chemical compound of the invention and its pharmaceutically acceptable acid addition salt.
  • An especially preferred salt according to the present invention is the hydrochloride, especially the dihydrochloride.
  • the l-(5-isoquinolinesulfonyl)homopiperazine is used in its free base form according to the present invention.
  • Metal salts of a chemical compound of the invention includes alkali metal salts, such as the sodium salt of a chemical compound of the invention containing a carboxy group.
  • the chemical compounds of the invention may be provided in unsolvated or solvated forms together with a pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • Solvated forms may also include hydrated forms such as the monohydrate, the dihydrate, the hemihydrate, the trihydrate, the tetrahydrate, and the like.
  • solvated forms are considered equivalent to unsolvated forms for the purposes of this invention.
  • some hydrates have proven to be specifically suitable for tablettation, namely the hemihydrate and trihydrate (EP 0870767B1).
  • Such hydrates are preferred hydrates of l-(5- isoquinolinesulfonyl)homopiperazine hydrochloride and dihydrochloride useable according to the present invention.
  • l-(5-isoquinolinesulfonyl)homopiperazine useable according to the invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, especially preferred in form of its hydrochloride salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.
  • Such salts of l-(5-isoquinolinesulfonyl)homopiperazine may be anhydrous or solvated, in case of the preferred hydrochloride salt, the salt preferably may be anhydrous, or solvated, especially in form of its hemidrate or trihydrate.
  • the invention provides medicaments comprising a compound useable according to the invention, or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers therefor, and, optionally, other therapeutic and/or prophylactic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.
  • a medicament of the invention may be those suitable for oral, rectal, bronchial, nasal, topical, buccal, sub-lingual, transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or those in a form suitable for administration by inhalation or insufflation, including powders and liquid aerosol administration, or by sustained release systems.
  • sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compound of the invention, which matrices may be in form of shaped articles, e.g. films or microcapsules.
  • the compounds useable according to the invention may thus be placed into the form of medicament and unit dosages thereof.
  • Such forms include solids, and in particular tablets, filled capsules, powder and pellet forms, and liquids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled with the same, all for oral use, suppositories for rectal administration, and sterile injectable solutions for parenteral use.
  • Such Medicament and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the compound useable according to the invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compounds useable according to the invention or a pharmaceutically acceptable salt of a compounds useable according to the invention.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation” is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glyceride or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
  • Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Liquid preparations include solutions, suspensions, and emulsions, for example, water or water- propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
  • the chemical compound according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the medicament is applied topically or systemically or via a combination of the two routes.
  • the medicament is applied topically. This reduces possible side effects and limits the necessary treatment to those areas affected.
  • Example 5 shows that l-(5-isoquinolinesulfonyl)homopiperazine is especially suitable for topical administration as it enters the skin well, and considerable accumulation of the compound in the skin is achieved.
  • topical administration the use of l-(5- isoquinolinesulfonyl)homopiperazine, and its hydrochloride form are preferred, although also other salts, active metabolites and isomers may be used.
  • the medicament is prepared in form of an ointment, a gel, a plaster, an emulsion, a lotion, a foam, a cream of a mixed phase or amphiphilic emulsion system (oil/water- water/oil mixed phase), a liposome, a transfersome, a paste oder a powder.
  • an ointment a gel, a plaster, an emulsion, a lotion, a foam, a cream of a mixed phase or amphiphilic emulsion system (oil/water- water/oil mixed phase), a liposome, a transfersome, a paste oder a powder.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
  • the compounds of the present invention may be administered in a formulation containing 0,01% to 10% per weight of the compound, preferably between 0,1 % to 10% per weight of the compound, even more preferred between 0,1 % and 5% per weight of the compound.
  • topical formulations of compounds of the invention especially of 1- (5-isoquinolinesulfonyl)homopiperazine) or its hydrochloride salts, in an O/W emulsion (oil- in-water emulsion).
  • the invention thus also relates to a composition suitable for topical use, comprising a compound of the invention formulated in an O/W emulsion.
  • Such formulation has proven to be of excellent delivery for topical delivery of the compound into the skin (see Example 5).
  • the compound is a l-(5- isoquinolinesulfonyl)homopiperazine) or a hydrochloride salt thereof.
  • the compound is hydroxyfasudil or a salt thereof.
  • compositions suitable for topical administration in the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
  • the compositions may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomising spray pump.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by provision of a metered valve.
  • the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • the powder carrier will form a gel in the nasal cavity
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • the compound In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
  • compositions adapted to give sustained release of the active ingredient may be employed.
  • the pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.
  • the present invention relates to a composition
  • a composition comprising a compound according to formula (I):
  • Especially preferred active ingredients which can be used in combination with the compounds of the invention are Calcineurin inhibitors, for example Cyclosporin A, Cyclosporin G, Cyclosporin B, Cyclosporin C, Cyclosporin D, Dihydro-cyclosporin D, Cyclosporin E, Cyclosporin F, Cyclosporin H, Cyclosporin I, ASM-240, Pimecrolimus, Tacrolimus, 13-Desmethyl- derivatives of Tacrolimus (L-685487), L-683519 and/or 17-Ethyl-derivatives of Tacrolimus, preferably Pimecrolimus, Tacrolimus, or Cyclosporin A, especially preferably Tacrolimus, steroid, for example Betamethasone, Betamethasone-17-val
  • l-(5-isoquinolinesulfonyl)homopiperazine, or its salts or hydroxyfasudil or its salts are combined with a compound selected from the group of Pimecrolimus, Tacrolimus, and Cyclosporin A.
  • the invention relates to the use of one of-the above-mentioned compositions for the manufacture of a medicament for the treatment and/or prevention of hypopigmentary disorders, especially vitiligo.
  • compositions for the manufacture of a medicament for the treatment and/or prevention of hypopigmentary disorders, especially vitiligo.
  • the same administration forms as discussed above for l-(5-isoquinolinesulfonyl)homopiperazine, its active metabolites, its isomers and its salts alone, are suitable for the compositions, especially the topical application on lesions for treatment or on unaffected skin for prevention.
  • the active ingredients are administered together or spatially and/or temporally separated.
  • the present invention relates to treatments for hypopigmentary disorders, especially vitiligo comprising administration of a medicament containing l-(5- isoquinolinesulfonyl)homopiperazine, its active metabolites, its isomers and its salts alone or a pharmaceutically active salt thereof and administration of one or more further treatment forms which are known to be suitable for the treatment and/or prevention of vitiligo.
  • Preferred treatment forms which can be combined with the treatment with a medicament containing 1- (5-isoquinolinesulfonyl)homopiperazine, its active metabolites, its isomers and its salts alone, and optionally other active substances, are PUVA treatment, KUVA treatment, heliotherapy, climatotherapy, especially at dead sea, Laser therapy, for example low energy laser therapy, ultrapulse carbondioxide laser therapy, short pulse carbondioxide laser therapy or Ruby laser therapy, surgical therapies like minigraft, suction epidermal grafting, dermo-epidermal grafts, epidermal suspensions, in vivo cultured epidermis and melanocyte suspensions, or UVB treatment. Assays for testing subject compounds
  • keratinocytes and melanocytes may be used.
  • the commercially available MelanoDerm Skin Model uses NHEK (normal human derived keratinocytes)-NHEM (normal human derived melanocytes) cocultures (MelanoDerm Skin model) to model the human epidermis taking into account that melanocytes are dependent on keratinocyte signalling.
  • NHEKs are cultivated in culture inserts placed on the NHEM monolayers according to the instructions of the manufacturer (MatTek Corporation, Ashland, Massachusetts).
  • NHEMs undergo spontaneously melanogenesis up to 3 weeks of culturing.
  • the tissues darken faster than untreated controls.
  • in vitro assays for determining the effect of a subject compound on hypopigmentary disorders are in vitro assays based on melanin content analysis.
  • treated and control melanocytes are harvested by trypsinization. Ten percent of the melanocytes are removed and counted on a Coulter counter. The remaining melanocytes are centrifuged and the resulting cell pellet is washed in phosphate-buffered saline pH 7.4 and recentrifuged. The cell pellet is then dissolved in 1ml of 1 M sodium hydroxide. The optical density of this solution is measured spectrophotometrically at 405 nm and is compared to synthetic melanin to determine melanin content per cell. A higher melanin content reflects enhanced pigmentation.
  • the assay can be performed as follows: treated and control melanocytes are harvested by trypsinization, washed with phosphate-buffered saline (PBS), suspended in 500 ⁇ l PBS, and counted. The cells are then solubilized by adding 500 ⁇ l of ION NaOH and incubating for 30 min at room temperature. Absorbance at 475 nm is measured and compared with a standard curve for synthetic melanin.
  • the 14 C-tyrosine melanin-formation assay can be used, which measures the radioactive melanin formed when 14 C-tyrosine is converted to the acid-insoluble melanin biopolymer.
  • cell extracts from treated and control cells are incubated with 14 C- tyrosine for 1 hour and absorbed on filter paper.
  • the filter paper is dried then washed in 0.1 mol/L hydrochloric acid three times and placed in a scintillation vial with 5 ml scintillator solution. The radioactivity is counted in triplicate using the same scintillator counter.
  • the effect of a compound on a hypopigmentary disorder can be determined by measuring tyrosinase activity, which are well described in the prior art.
  • tyrosinase activity of cell culture can be determined: treated and control melanocytes are incubated with 1.0 ⁇ Ci [ Hjtyrosine per ml. 700 ⁇ l of 10% trichloroacetic acid containing 20% charcoal (charcoal solution) is added to the medium (700 ⁇ l), and the mixture is mixed in a vortex for 30 s and then centrifuged at 10,000 rpm for 10 min. Seven hundred microliters of the supernatant is transferred into a new tube and treated twice with the charcoal solution. The radioactivity of the final supernatant is determined in a liquid scintillation counter.
  • tyrosinase activity can be determined in cell extracts. For example, treated and control melanocytes are collected and washed twice with PBS, and then lyzed in 0.1 M sodium phosphate buffer (pH 6.8) containing 1% Triton X-100. After determining the protein content in the cell extract, 10 ⁇ g of each extract is incubated in 100 ⁇ l of 100 mM sodium phosphate buffer (pH 6.8) containing 1.0 ⁇ Ci [ 3 H]tyrosine per ml, 5 ⁇ g L- dihydroxyphenylalanine, and 1% Triton X-100 for 15 min at 37°C.
  • Vitiligo eds. S. Harm and J. J.Nordlund, Blackwell Science, Chapter 33: Animal models by L. Lamoreux and R. E. Boissy
  • Smyth chicken exhibiting a genetically inherited form of vitiligo-like depigmentation resulting from the loss of melanocytes in feathers is discussed as vitiligo model.
  • the pigmentation phenotype of this animal model appears to involve an immune response.
  • the so-called vitiligo mouse is described. In this model no immune component is involved and the disorder is not polyfactorial; i.e. unlike in humans.
  • Vitiligo for example, is not a simple, one-locus-disease, and inheritance is not its only cause. Therefore, in the case of vitiligo, animal models must be used with the knowledge that the disorder observed in the genetically defective animal will not be homologous with the disorder of the average human vitiligo patient. Thus, the study of one animal model, especially if the defect is caused by one gene locus in the model, need not be more predictive than an in vitro model.
  • screening assay for compounds which are suitable for the treatment and/or prevention of hypopigmentary disorders.
  • such screening assay is an in- vitro-model consisting of a co-culture of keratinocytes and melanocytes as described above.
  • the screening assay is an in-vitro-assay based on melanin content analysis, as described above.
  • the screening assay is based on the measurement of tyrosinase activity, as described above.
  • the screening assay is based on an animal model, as described above.
  • the l-(5-isoquinolinesulfonyl)homopiperazine and/or its active metabolites and/or its isomers and/or salts useable according to the present invention serve as positive controls in that they inhibit/prevent or induce the onset of hypopigmentary disorders,especially vitiligo and the response of the assay system towards these controls is compared with the response of the assay system towards a subject compound to be tested.
  • Figure 1 shows the influence of l-(5-isoquinolinesulfonyl)homopiperazine on dendrite formation in melanocytes in a melanocyte dendrite outgrowth assay described below.
  • Image 1 A shows control melanocytes in buffer, showing no dendrites.
  • Image IB shows melanocytes incubated with Forskolin as positive control, resulting in drendrite formation.
  • Image 1C shows melanocytes incubated with l-(5-isoquinolinesulfonyl)homopiperazine, resulting in strong dendrite formation.
  • Figure 2 shows the influence of l-(5-isoquinolinesulfonyl)homopiperazine on keratinocyte morphology as a measure for cytotoxicity.
  • Figures 2A and 2C show control HaCaT and NHEK keratinocyte cells incubated in buffer with noraial morphology.
  • Figures 2B and 2D show HaCaT and NHEK keratinocyte cells treated with l-(5- isoquinolinesulfonyl)homopiperazine. These treated cells also showed normal morphology, proving that of l-(5-isoquinolinesulfonyl)homopiperazine is not cytotoxic for keratinocytes.
  • Example 1 Effect of l-(5-isoquinolinesulfonyl)homopiperazine on melanocyte function
  • the melanocyte dendrite outgrowth assay can be performed. Vitiligo melanocytes for example have only stubby dendrites. Increasing dendricity as a prerequisite for the transfer of the melanosomes from melanocytes to the surrounding keratinocytes rescues this defect.
  • melanoma cell line (Mel-Ho) were obtained from DSMZ (Deutsche Sammlung fur Mikroorganismen und Zellkulturen) and were cultured according to the protocol provided by DSMZ.
  • DSMZ Deutsche Sammlung fur Mikroorganismen und Zellkulturen
  • the melanocytes were cultured in T- 75 flasks in melanocyte culture media (provided by the manufacturer) until they reach 70- 80% confluency.
  • the melanocytes were then trypsinized, transferred into 5-10 new T-75 flasks, and grown again to same confluency as described above. After this expansion step the melanocytes were immediately used for the Melanocyte Dendrite Outgrowth Assay or were frozen for later use.
  • the melanocytes were seeded in 24 well plates at a density of 1-5 xl04 cells/well. After 24 hours, the melanocytes were treated with 20 ⁇ M Forskolin (Sigma- Aldrich) or different concentrations of l-(5-isoquinolinesulfonyl)homopiperazine dihydrochloride (Sigma-Aldrich) for 24 hours. Forskolin is known to cause increased melanocyte dendricity and was used as a positive control. Cells treated with media only were used as a negative control. Melanocyte dendrite outgrowth was documented by digital photography (Canon G2 Powershot) after 3, 6 and 24 hours. A representative result is shown in Figure 1.
  • Image A of Figure 1 shows the negative control with treated with media only, exhibiting no dendrites, whereas in the positive control, i.e. Forskolin-treated cells, dendrites are clearly visible.
  • the positive control i.e. Forskolin-treated cells
  • dendrites are clearly visible.
  • l-(5- isoquinolinesulfonyl)homopiperazine dihydrochloride-treated cells dendricity was strongly stimulated (Image 3 of Figure 1).
  • 100 ⁇ M were used, however also lower concentrations of l-(5-isoquinolinesulfonyl)homopiperazine dihydrochloride are sufficient to induce dendrite formation.
  • the strongly increased dendricity induced by l-(5- isoquinolinesulfonyl)homopiperazine dihydrochloride proves good suitability of the compounds useable according to the invention for treating and/or preventing hypopigmentary disorders, especially vitiligo.
  • Example 2 Effect of l-(5-isoquinolinesulfonyl homopiperazine on T cell activation
  • vitiligo is a hypopigmentary disorder with an unclear pathomechanism and various hypotheses on the causes of vitiligo exist. Possibly, several mechanisms contribute to the onset and/or progression of the disorders. It would be advantageous, if a compound useable according to the invention additionally acted on another discussed pathomechanism of vitiligo. It was therefore investigated, whether l-(5- isoquinolinesulfonyl)homopiperazine has an inhibitory effect on T cell activation.
  • l-(5- isoquinolinesulfonyl)homopiperazine is not only beneficial for supporting the dysfunctional melanocytes for regaining their functionality by increasing dendricity but has in addition an inhibitory action on T cells which, according to the autoimmune thesis, play a role in the destruction of the melanocytes.
  • T cell activation was determined by measuring cytokine secretion and BrDU incorporation, i.e. by methods well known to a person skilled in the art.
  • peripheral blood mononuclear cells PBMCs
  • PBMCs peripheral blood mononuclear cells
  • the inhibitory action of l-(5- isoquinolinesulfony ⁇ )homopiperazine on T cell activation and proliferation was determined by measuring IL-2 in the supernatant by means of ELISA (T cell activation) and by the incorporation of BrDU (T cell proliferation). It was found that l-(5- isoquinolinesulfonyl)homopiperazine dihydrochloride inhibits T cell activation and proliferation with an IC 50 of 90 ⁇ M.
  • l-(5-isoquinolinesulfonyl)homopiperazine has an inhibitory activity on T cell activation, which makes the compounds useable according to the invention especially suitable for treating and/or preventing hypopigmentary diseases in which T cell activation and proliferation plays a role, especially preferred vitiligo.
  • Example 3 Effect of l-(5-isoquinolinesulfonyl)homopiperazine on keratinocytes l-(5-isoquinolinesulfonyl)homopiperazine or its salts, active metabolites and isomers have never been tested or considered for topical application before, and hence, no data exist on the suitability of the l-(5-isoquinolinesulfonyl)homopiperazine and its salts and , active metabolites and isomers for topical application; notably, it is not known whether the substance exhibits cytotoxic effects on keratinocytes, which on the one hand represent by far the predominant cell type of the skin and on the other hand is the cell type which obtains melanin by the melanocytes by transfer via the dendrites of the melanocytes.
  • normal human epidermal keratinocytes were obtained from Clonetics (neonatal keratinocytes, NHEK) and were cultured according to the manufacturers' protocol.
  • the keratinocytes were cultured in T-75 flasks in keratinocyte culture media (provided by the manufacturer) until they reached 70-80% confluency.
  • the keratinocytes were then trypsinized, transferred into new T-75 flasks at a density of 3500 cells/cm 2 . After this expansion step the keratinocytes were immediately used for the cytotoxic assay procedure or were frozen for later use.
  • Image 2B shows HaCaT keratinocytes treated with l-(5-isoquinolinesulfonyl)homopiperazine dihydrochloride
  • Image 2A shows control HaCaT cells incubated in buffer only. No morphological changes were observed in cells treated with l-(5- isoquinolinesulfonyl)homopiperazine dihydrochloride, proving that the substance has no cytotoxic effect on the cells.
  • Image 2D shows NHEK keratinocytes treated with l-(5- isoquinolinesulfonyl)homopiperazine dihydrochloride
  • Image 2C shows control NHEK cells incubated in buffer only.
  • Example 4 Effect of l-(5-isoquinolinesulfonyl)homopiperazine on vitiligo patients
  • 25 to 30 vitiligo vulgaris patients are treated once or twice daily with a topical formulation of l-(5-isoquinolinesulfonyl)homopiperazine (0.1%-10% preferably 0.1%-10% by weight of l-(5-isoquinolinesulfonyl)homopiperazine) for 3 to 6 months.
  • l-(5-isoquinolinesulfonyl)homopiperazine 25 to 30 vitiligo vulgaris patients are treated once or twice daily with a topical formulation of l-(5-isoquinolinesulfonyl)homopiperazine (0.1%-10% preferably 0.1%-10% by weight of l-(5-isoquinolinesulfonyl)homopiperazine) for 3 to 6 months.
  • l-(5-isoquinolinesulfonyl)homopiperazine
  • Example 5 Suitability of l-(5-isoquinolinesulfonyl)homopiperazine for topical administration l-(5-isoquinolinesulfonyl)homopiperazine) as a base and l-(5- isoquinolinesulfonyl)homopiperazine) dihydrochloride were formulated in an O/W emulsion based on Tween20/Glycerine monostearate, resulting in topical formulations Topi (3% (w/w) of the base) and Top2 (3,75% (w/w) of the dihydrochloride salt, corresponding to 3% (w/w) of the base). The penetration was studied on human reconstructed epidennis ("HRE"; Skinethic, Nice) grown to maturity.
  • HRE human reconstructed epidennis
  • HRE surface was washed and the tissues were then cut out their inserts using a scalpel and l-(5-isoquinolinesulfonyl)homopiperazine) was then extracted from the HRE and analysed by HPLC analysis.
  • l-(5-isoquinolinesulfonyl)homopiperazine) was then extracted from the HRE and analysed by HPLC analysis.
  • two HREs without product application were run in parallel and were processed exactly in the same way.
  • Topi as well as Top2 surprisingly led to considerable accumulation of active substance in the skin, thus proving excellent suitability of l-(5- isoquinolinesulfonyl)homopiperazine) and its hydrochloride salts for topical delivery, especially when formulated in an O/W emulsion:

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Abstract

L'invention concerne l'utilisation de 1-(5-isoquinolinesulfonyl)homopipérazine, de ses métabolites actifs, de ses isomères et de ses sels pour traiter et/ou prévenir l'hypopigmentation.
PCT/EP2004/004620 2003-04-30 2004-04-30 Utilisation de 1-(5-isoquinolinesulfonyl)homopiperazine, de ses metabolites actifs, de ses isomeres et de ses sels pour traiter et prevenir l'hypopigmentation WO2004096222A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
EP03009921A EP1479386A1 (fr) 2003-04-30 2003-04-30 Utilisation de derives de l'isoquinoline pour traiter et prevenir les troubles de la pigmentation
EP03009921.2 2003-04-30
US51994203P 2003-11-14 2003-11-14
EP03026250A EP1550446A1 (fr) 2003-11-14 2003-11-14 Utilisation de 1-(5-isoquinolinesulfonyl)homopiperazine pour le traitement et la prévention des désordres de hypopigmentation
US60/519,942 2003-11-14
EP03026250.5 2003-11-14

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006018088A1 (fr) * 2004-08-19 2006-02-23 Switch Biotech Ag Utilisation d'un inhibiteur pde5 aux fins de traitement et de prevention de troubles hypopigmentaires
EP1759700A1 (fr) * 2004-08-19 2007-03-07 Switch Biotech Aktiengesellschaft Utilisation d'inhibiteurs de PDE5 pour traiter et prévenir les maladies liées à la hypopigmentation
WO2008015001A1 (fr) 2006-08-03 2008-02-07 Universite Pierre Et Marie Curie-Paris Vi Inhibiteurs de rho/rock/p13/akt kinase pour le traitement de maladies associées aux parasites protozoaires
CN102949341A (zh) * 2012-11-20 2013-03-06 广东药学院 一种他克莫司传递体溶液及其制备方法
CN108514562A (zh) * 2018-03-22 2018-09-11 郭忠营 一种治疗白癫风乳膏及其制备方法
CN109562092B (zh) * 2016-06-03 2023-08-22 纽约市哥伦比亚大学理事会 治疗普拉德-威利综合症的方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0187371A2 (fr) * 1984-12-27 1986-07-16 Asahi Kasei Kogyo Kabushiki Kaisha Composés de sulfonylisoquinoléine substitués
EP1064944A1 (fr) * 1999-06-25 2001-01-03 Schering Aktiengesellschaft Inhibiteur de la protéine kinase N contenant du Fasudil
US6403590B1 (en) * 1995-12-21 2002-06-11 Alcon Laboratories, Inc. Use of certain isoquinolinesulfonyl compounds for the treatment of glaucoma and ocular ischemia

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0187371A2 (fr) * 1984-12-27 1986-07-16 Asahi Kasei Kogyo Kabushiki Kaisha Composés de sulfonylisoquinoléine substitués
US6403590B1 (en) * 1995-12-21 2002-06-11 Alcon Laboratories, Inc. Use of certain isoquinolinesulfonyl compounds for the treatment of glaucoma and ocular ischemia
EP1064944A1 (fr) * 1999-06-25 2001-01-03 Schering Aktiengesellschaft Inhibiteur de la protéine kinase N contenant du Fasudil

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
OHNAKA, KEIZO ET AL: "Pitavastatin enhanced BMP-2 and osteocalcin expression by inhibition of Rho-associated kinase in human osteoblasts", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS , 287(2), 337-342 CODEN: BBRCA9; ISSN: 0006-291X, 2001, XP001151646 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006018088A1 (fr) * 2004-08-19 2006-02-23 Switch Biotech Ag Utilisation d'un inhibiteur pde5 aux fins de traitement et de prevention de troubles hypopigmentaires
EP1759700A1 (fr) * 2004-08-19 2007-03-07 Switch Biotech Aktiengesellschaft Utilisation d'inhibiteurs de PDE5 pour traiter et prévenir les maladies liées à la hypopigmentation
US8268785B2 (en) 2004-08-19 2012-09-18 Switch Biotech Ag Use of a Pde 5 inhibitor for treating and preventing hypopigmentary disorders
US8329656B2 (en) 2004-08-19 2012-12-11 Switch Biotech Ag Use of a PDE5 inhibitor for treating and preventing hypopigmentary disorders
WO2008015001A1 (fr) 2006-08-03 2008-02-07 Universite Pierre Et Marie Curie-Paris Vi Inhibiteurs de rho/rock/p13/akt kinase pour le traitement de maladies associées aux parasites protozoaires
JP2009545544A (ja) * 2006-08-03 2009-12-24 ユニベルシテ ピエール エ マリー キュリー（パリ シズエム） 原生動物寄生虫に関連する疾患の治療のためのｒｈｏ／ｒｏｃｋ／ｐｉ３／ａｋｔキナーゼ阻害剤
CN102949341A (zh) * 2012-11-20 2013-03-06 广东药学院 一种他克莫司传递体溶液及其制备方法
CN109562092B (zh) * 2016-06-03 2023-08-22 纽约市哥伦比亚大学理事会 治疗普拉德-威利综合症的方法
CN108514562A (zh) * 2018-03-22 2018-09-11 郭忠营 一种治疗白癫风乳膏及其制备方法

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