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EP1173173A1 - Novel pharmaceutical compositions comprising 2-isoxazole-8-aminotetralin derivatives - Google Patents

Novel pharmaceutical compositions comprising 2-isoxazole-8-aminotetralin derivatives

Info

Publication number
EP1173173A1
EP1173173A1 EP00922748A EP00922748A EP1173173A1 EP 1173173 A1 EP1173173 A1 EP 1173173A1 EP 00922748 A EP00922748 A EP 00922748A EP 00922748 A EP00922748 A EP 00922748A EP 1173173 A1 EP1173173 A1 EP 1173173A1
Authority
EP
European Patent Office
Prior art keywords
composition according
isoxazole
derivative
aminotetralin
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00922748A
Other languages
German (de)
French (fr)
Inventor
Jacques-Pierre Moreau
Béatrice GUIMBERT
Marc Pellet
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ipsen Pharma SAS
Original Assignee
Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS filed Critical Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS
Publication of EP1173173A1 publication Critical patent/EP1173173A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

Definitions

  • the present invention relates to new pharmaceutical compositions comprising derivatives of 2-isoxazoles-8-aminotetralins.
  • compositions could be used for topical administration comprising a derivative of 2-isoxazole-8-aminotetraline.
  • an adhesive polymer system or "patch", term of English origin
  • the invention therefore relates to a matrix or reservoir pharmaceutical composition for topical administration comprising at least one 2-isoxazole-8-aminotetralin derivative in a therapeutically effective amount and one or more pharmaceutically acceptable excipients.
  • 2-isoxazole-8-aminotetralin derivative is meant in particular all those which have been described in the patents cited above.
  • Said 2-isoxazole-8-aminotetralin derivative can be in the form of a free base or in the form of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt means in particular addition salts of inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate or organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methane sulfonate, p-toluenesulfonate, pamoate, oxalate and stearate.
  • the salts formed from bases such as sodium or potassium hydroxide.
  • the 2-isoxazole-8-aminotetralin derivative will be in the form of a pharmaceutically acceptable salt.
  • a patch will be used which will contain in its matrix the derivative of 2-isoxazole-8-aminotetralin.
  • Said patch can be presented in different forms: reservoir; matrix on adhesive polymer; DIA patch (i.e. "Drugln Adhesive" in English), in other words patch in the form of a single adhesive polymer layer in which the active principle is distributed; or finally multilamellar patch.
  • DIA patch i.e. "Drugln Adhesive” in English
  • DIA patch i.e. "Drugln Adhesive” in English
  • patch in the form of a single adhesive polymer layer in which the active principle is distributed
  • multilamellar patch multilamellar patch.
  • the excipients can be polymers or copolymers or else simply monomers.
  • the composition will incorporate adhesive polymers or copolymers such as elastomers of the polyethylene vinyl acetate (EVA) type, polymers or copolymers based on styrene, polyisobutylene or acrylic polymers or copolymers, and in particular methacrylic copolymers.
  • EVA polyethylene vinyl acetate
  • plasticizers include, for example, tributylacetyl citrate or any other pharmaceutically acceptable plasticizer known to those of skill in the art.
  • a gelling agent is present in a proportion preferably of 20 to 50%.
  • the gelling agents which can be used for the topical compositions according to the invention notably comprise the cellulose derivatives, and in particular hydroxypropyl-methyl cellulose (HPMC), or the poloxamers (that is to say copolymers of polyethylene and of propylene glycol), in particular Lutrol ® F 127 (BASF).
  • the topical compositions according to the invention can also comprise other excipients in order to facilitate the transdermal passage of the 2-isoxazole-8 derivative.
  • aminotetralin in other words transdermal absorption promoters, and in particular alcohols or polyols such as ethanol, 1,3-butanediol, polyethylene glycols (PEG), fatty acid esters, in particular triglycerides of caprylic and capric acids and in particular Miglyol® (H ⁇ ls, Mari, Germany), or other surfactants or amphiphilic substances known to those skilled in the art.
  • ethanol or fatty acid esters such as Miglyol® are preferred.
  • compositions according to the invention may also comprise, where appropriate and in particular when they are in the form of an aqueous gel, a preservative, preferably propylene glycol. Likewise, they may also include an antioxidant agent, and in particular ethylenediaminetetracetic acid (EDTA).
  • a preservative preferably propylene glycol.
  • EDTA ethylenediaminetetracetic acid
  • a topical pharmaceutical composition according to the invention will preferably comprise between approximately 5 and 80 mg, more preferably between approximately 5 and 50 mg, and more particularly between approximately 5 and 20 mg, for example approximately 5 mg of 2-isoxazole-8 derivative. -aminotetralin, this mass being calculated relative to said derivative in the form of the free base. This dose should make it possible to ensure the daily treatment of a patient, but it is up to the attending physician to decide ultimately how often to apply.
  • the pH of the topical pharmaceutical composition according to the invention will preferably be between 7 and 9.5, and more preferably between 8 and 9.5 when the derivative of 2- isoxazole-8-aminotetralin is in the form of the free base.
  • the pH of the topical pharmaceutical composition according to the invention will preferably be between 5 and 7.5, and more preferably between 5.5 and 7.
  • the invention also relates to the use of a derivative of 2-isoxazole-8-aminotetralin, and in particular of 1,2,3,4-tetrahydro-8- (5-isoxazolyl) -N, N-diisopropyl- 2-naphthalenamine, for the manufacture of a medicament for transdermal administration, in particular in the treatment of irritable bowel syndrome.
  • a derivative of 2-isoxazole-8-aminotetralin and in particular of 1,2,3,4-tetrahydro-8- (5-isoxazolyl) -N, N-diisopropyl- 2-naphthalenamine
  • a patch intended for the transdermal administration of 1,2,3,4-tetrahydro-8- (5-isoxazolyl) - N, N-diisopropyl-2-naphthalenamine was prepared from a copolymer of methacrylate and ammonioalkyl according to the procedure described below.
  • the solution obtained is then spread at a rate of 100 g / m 2 on a carrier sheet (15 ⁇ m thick, Revtrans MN, Tricon GmbH, Freiburg-im-Breisgau, Germany).
  • the polymer layer is dried for 10 minutes with a flow of 1500 m 3 / h of air at 60 ° C (recycling with 80 m 3 / h of exhaust).
  • the polymer obtained can then be cut to form patches with an area of approximately 15 cm 2 , which can be used to dispense a daily dose.
  • a patch intended for the transdermal administration of 1,2,3,4-tetrahydro-8- (5-isoxazolyl) - N, N-diisopropyl-2-naphthalenamine was prepared from a copolymer of methacrylate and of ammonioalkyl according to the mode procedure described in Example 1, except that 10 g of Miglyol® 812 (Huis, Mari, Germany) were added in portions between the addition of 1,2,3,4-tetrahydro-8- (5- isoxazolyl) -N, N-diisopropyl-2-naphthalenamine and the addition of succinic acid and that after this addition of Miglyol® 812, the mixture was stirred for an additional 20 minutes.
  • Miglyol® 812 Huis, Mari, Germany
  • a patch intended for the transdermal administration of 1,2,3,4-tetrahydro-8- (5-isoxazolyl) - N, N-diisopropyl-2-naphthalenamine was prepared from a copolymer of methacrylate and of ammonioalkyl according to a method procedure similar to that described in Example 1. except that the 20 g of 1,2,3,4-tetrahydro-8- (5-isoxazolyl) -N, N-diisopropyl-2-naphthalenamine are replaced by 22.44 g of 1,2,3,4-tetrahydro- 8- (5-isoxazolyl) -N, N-diisopropyl-2-naphthalenamine hydrochloride.
  • a gel intended for the transdermal administration of 1,2,3,4-tetrahydro-8- (5-isoxazolyl) - N, N-diisopropyl-2-naphthalenamine was prepared from an aqueous dispersion of hydroxypropyl -methyl cellulose (HPMC), according to the procedure described below (to prepare 100 g of gel).
  • HPMC hydroxypropyl -methyl cellulose
  • composition of the gel is composition of the gel:
  • solution I An aqueous solution (solution I) is first prepared by dissolving 3 g of 1,2,3,4-tetrahydro-8- (5-isoxazolyl) -N, N-diisopropyl-2-naphthalenamine hydrochloride in 4 g of propylene glycol and 8 g of purified water. The solution thus obtained is then filtered on a 10 ⁇ m filter. We obtain solution I.
  • aqueous dispersion of HPMC is then prepared under vacuum by mixing 30 g of HPMC with 55 g of purified water. Still with stirring, the mixture is heated to a temperature of 50-60 ° C., for 20 min, until a gel of homogeneous appearance is obtained (gel II).
  • Solution I is added in portions to gel II, then the mixture is left for 20 min still under vacuum, with stirring and at 50-60 ° C, to obtain 100 g of drug.
  • the drug is homogenized by passing it through a die (homogenizer to die).
  • the gel thus obtained can be divided into tubes.
  • Each application will consist of a hazelnut of approximately 1 g.
  • a gel intended for transdermal administration of 1,2,3,4-tetrahydro-8- (5-isoxazolyl) - N, N-diisopropyl-2-naphthalenamine was prepared, according to the procedure described in Example 4 except that was used poloxamer Lutrol ® F 127 (BASF) as gelling agent.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to novel pharmaceutical compositions comprising 2-isoxazole-8-aminotetralin derivatives. The invention more specifically relates to compositions in the form of a patch comprising a therapeutically efficacious amount of a derivative of 2-isoxazole-8-aminotetraline, especially 1,2,3,4-tetrahydro-8-(5-isoxazolyl)-N-N-diisopropyl-2-naphtalenamine. The invention also relates to a 2-isoxazole-8-aminotetralin derivative, especially 1,2,3,4-tetrahydro-8-(5-isoxazolyl)-N,N-diisopropyl-2-naphtalenamine, which is used to produce a medicament which can be administered transdermally to treat irritable bowel syndrome.

Description

Nouvelles compositions pharmaceutiques comprenant des dérivés de New pharmaceutical compositions comprising derivatives of

2-isoxazole-8-aminotétralines2-isoxazole-8-aminotetralins

La présente invention concerne des nouvelles compositions pharmaceutiques comprenant des dérivés de 2-isoxazoles-8-aminotétralines.The present invention relates to new pharmaceutical compositions comprising derivatives of 2-isoxazoles-8-aminotetralins.

Des dérivés de 2-isoxazoles-8-aminotétralines et leur utilisation en tant que médicaments ont notamment été décrits par Eli Lilly dans les demandes de brevet européen EP 385 658 et EP 471 515, ainsi que dans le brevet européen EP 498 590 qui décrit en particulier la l,2,3,4-tétrahydro-8-(5-isoxazolyl)-N,N-diisopropyl-2-naphtalènamine. L'utilisation de ces composés pour traiter le syndrome du colon irritable ^irritable bowel syndrome" en anglais) a par ailleurs été décrite dans la demande de brevet européen EP 579 507.Derivatives of 2-isoxazoles-8-aminotetralins and their use as medicaments have in particular been described by Eli Lilly in European patent applications EP 385 658 and EP 471 515, as well as in European patent EP 498 590 which describes in in particular 1,2,3,4-tetrahydro-8- (5-isoxazolyl) -N, N-diisopropyl-2-naphthalenamine. The use of these compounds to treat irritable bowel syndrome (irritable bowel syndrome) has also been described in European patent application EP 579 507.

Cependant, aucun de ces brevets ne décrit l'administration de ces produits par voie transdermique.However, none of these patents describes the administration of these products transdermally.

Or la demanderesse vient de découvrir à présent que l'on pouvait utiliser des compositions pour une administration topique comportant un dérivé de 2-isoxazole- 8-aminotétraline. En particulier, elle a mis au point un système de polymère adhésif (ou "patch", terme d'origine anglaise) comportant dans sa structure ledit dérivé de 2-isoxazole-8-aminotétraline.Now the Applicant has now discovered that compositions could be used for topical administration comprising a derivative of 2-isoxazole-8-aminotetraline. In particular, it has developed an adhesive polymer system (or "patch", term of English origin) comprising in its structure said derivative of 2-isoxazole-8-aminotetralin.

L'invention concerne donc une composition pharmaceutique matricielle ou réservoir pour une administration par voie topique comprenant au moins un dérivé de 2-isoxazole- 8-aminotétraline en quantité thérapeutiquement efficace et un ou plusieurs excipients pharmaceutiquement acceptables.The invention therefore relates to a matrix or reservoir pharmaceutical composition for topical administration comprising at least one 2-isoxazole-8-aminotetralin derivative in a therapeutically effective amount and one or more pharmaceutically acceptable excipients.

Par dérivé de 2-isoxazole-8-aminotétraline, on entend en particulier tous ceux qui ont été décrits dans les brevets cités précédemment. Ledit dérivé de 2-isoxazole-8- aminotétraline peut se présenter sous forme de base libre ou sous forme d'un sel pharmaceutiquement acceptable.By 2-isoxazole-8-aminotetralin derivative is meant in particular all those which have been described in the patents cited above. Said 2-isoxazole-8-aminotetralin derivative can be in the form of a free base or in the form of a pharmaceutically acceptable salt.

Par sel pharmaceutiquement acceptable, on entend notamment des sels d'addition d'acides inorganiques tels que chlorhydrate, sulfate, phosphate, diphosphate, bromhydrate et nitrate ou d'acides organiques tels que acétate, maléate, fumarate, tartrate, succinate, citrate, lactate, méthane sulfonate, p-toluènesulfonate, pamoate, oxalate et stéarate. Entrent également dans le champ de la présente invention, lorsqu'ils sont utilisables, les sels formés à partir de bases telles que l'hydroxyde de sodium ou de potassium. Pour d'autres exemples de sels pharmaceutiquement acceptables, on peut se référer à "Pharmaceutical salts", J. Pharm. Sci. 66: 1 (1977).The term “pharmaceutically acceptable salt” means in particular addition salts of inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate or organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methane sulfonate, p-toluenesulfonate, pamoate, oxalate and stearate. Also falling within the scope of the present invention, when they can be used, the salts formed from bases such as sodium or potassium hydroxide. For other examples of pharmaceutically acceptable salts, reference may be made to "Pharmaceutical salts", J. Pharm. Sci. 66: 1 (1977).

De préférence, le dérivé de 2-isoxazole-8-aminotétraline sera sous forme d'un sel pharmaceutiquement acceptable.Preferably, the 2-isoxazole-8-aminotetralin derivative will be in the form of a pharmaceutically acceptable salt.

Différentes formes de matrices ou de réservoirs pourront être employées. Celles-ci comprennent en particulier les crèmes, les émulsions, les gels ou encore les substances gélifiables à l'air. De préférence, on utilisera un patch qui comportera en sa matrice le dérivé de 2-isoxazole-8-aminotétraline. Ledit patch pourra se présenter sous différentes formes : réservoir ; matrice sur polymère adhésif ; patch DIA (i.e. "Drugln Adhesive" en anglais), autrement dit patch sous forme d'une simple couche polymère adhesive dans laquelle le principe actif est réparti ; ou enfin patch multilamellaire. Ces diverses formes de patch sont notamment décrites dans l'ouvrage de référence suivant : Technology Advances in drug Delivery, PJB Publications Ltd., p. 85-100 (1998). Lorsque la composition est sous forme de patch, on préférera la forme dite DIA.Different forms of dies or tanks can be used. These include in particular creams, emulsions, gels or even gelling substances in air. Preferably, a patch will be used which will contain in its matrix the derivative of 2-isoxazole-8-aminotetralin. Said patch can be presented in different forms: reservoir; matrix on adhesive polymer; DIA patch (i.e. "Drugln Adhesive" in English), in other words patch in the form of a single adhesive polymer layer in which the active principle is distributed; or finally multilamellar patch. These various forms of patch are described in particular in the following reference work: Technology Advances in drug Delivery, PJB Publications Ltd., p. 85-100 (1998). When the composition is in the form of a patch, the so-called DIA form is preferred.

Les excipients peuvent être des polymères ou copolymères ou bien simplement des monomères. De préférence, la composition incorporera des polymères ou copolymères adhésifs tels des élastomères du type polyéthylènevinylacétate (EVA), des polymères ou copolymères à base de styrène, du polyisobutylène ou des polymères ou copolymères acryliques, et en particulier des copolymères méthacryliques.The excipients can be polymers or copolymers or else simply monomers. Preferably, the composition will incorporate adhesive polymers or copolymers such as elastomers of the polyethylene vinyl acetate (EVA) type, polymers or copolymers based on styrene, polyisobutylene or acrylic polymers or copolymers, and in particular methacrylic copolymers.

Lorsque des excipients polymères ou copolymères seront inclus dans une composition selon l'invention, un ou des agents plastifiants pourront également être présents. Ces agents plastifiants incluent, par exemple, le citrate de tributylacétyle ou tout autre agent plastifiant pharmaceutiquement acceptable connu de l'homme du métier.When polymer or copolymer excipients are included in a composition according to the invention, one or more plasticizers may also be present. These plasticizers include, for example, tributylacetyl citrate or any other pharmaceutically acceptable plasticizer known to those of skill in the art.

Lorsque la composition selon l'invention est sous forme d'un gel aqueux, un agent gélifiant est présent en une proportion de préférence de 20 à 50%. Les agents gélifiants utilisables pour les compositions topiques selon l'invention comprennent notamment les dérivés cellulosiques, et en particulier l'hydroxy-propyl-méthyl cellulose (HPMC), ou les poloxamères (c'est-à-dire des copolymères de polyéthylène et de propylène glycol), en particulier le Lutrol® F 127 (BASF).When the composition according to the invention is in the form of an aqueous gel, a gelling agent is present in a proportion preferably of 20 to 50%. The gelling agents which can be used for the topical compositions according to the invention notably comprise the cellulose derivatives, and in particular hydroxypropyl-methyl cellulose (HPMC), or the poloxamers (that is to say copolymers of polyethylene and of propylene glycol), in particular Lutrol ® F 127 (BASF).

Les compositions topiques selon l'invention peuvent en outre comprendre d'autres excipients afin de faciliter le passage transdermique du dérivé de 2-isoxazole-8- aminotétraline, autrement dit des promoteurs d'absorption transdermique, et notamment des alcools ou polyols comme l'éthanol, le 1,3-butanediol, les polyéthylèneglycols (PEG), les esters d'acides gras, notamment les triglycérides des acides caprylique et caprique et en particulier le Miglyol® (Hϋls, Mari, Allemagne), ou d'autres tensioactifs ou substances amphiphiles connues de l'homme du métier. Parmi les promoteurs d'absorption transdermique, on préférera l'éthanol ou les esters d'acides gras comme le Miglyol®.The topical compositions according to the invention can also comprise other excipients in order to facilitate the transdermal passage of the 2-isoxazole-8 derivative. aminotetralin, in other words transdermal absorption promoters, and in particular alcohols or polyols such as ethanol, 1,3-butanediol, polyethylene glycols (PEG), fatty acid esters, in particular triglycerides of caprylic and capric acids and in particular Miglyol® (Hϋls, Mari, Germany), or other surfactants or amphiphilic substances known to those skilled in the art. Among the transdermal absorption promoters, ethanol or fatty acid esters such as Miglyol® are preferred.

Enfin, les compositions selon l'invention pourront également comprendre, le cas échéant et en particulier lorsqu'elles se présentent sous forme d'un gel aqueux, un agent conservateur, de préférence le propylène glycol. De même, elles pourront aussi inclure un agent antioxydant, et en particulier l'acide éthylènediaminetétracétique (EDTA).Finally, the compositions according to the invention may also comprise, where appropriate and in particular when they are in the form of an aqueous gel, a preservative, preferably propylene glycol. Likewise, they may also include an antioxidant agent, and in particular ethylenediaminetetracetic acid (EDTA).

Parmi les dérivés de 2-isoxazole-8-aminotétraline, on préférera tout particulièrement la 1,2,3, 4-tétrahydro-8-(5-isoxazolyl)-N,N-diisopropyl-2-naphtalènamine.Among the 2-isoxazole-8-aminotetralin derivatives, 1,2,3,4-tetrahydro-8- (5-isoxazolyl) -N, N-diisopropyl-2-naphthalenamine is particularly preferred.

La préparation des dérivés de 2-isoxazole-8-aminotétraline, et en particulier de la 1,2,3, 4-tétrahydro-8-(5-isoxazolyl)-N,N-diisopropyl-2-naphtalènamine, est décrite dans les brevets ou demandes de brevet EP 385 658, EP 471 515, EP 498 590 et EP 579 507. Ces composés peuvent être salifiés si nécessaire selon les méthodes habituelles connues de l'homme du métier.The preparation of derivatives of 2-isoxazole-8-aminotetralin, and in particular of 1,2,3,4-tetrahydro-8- (5-isoxazolyl) -N, N-diisopropyl-2-naphthalenamine, is described in the Patents or patent applications EP 385 658, EP 471 515, EP 498 590 and EP 579 507. These compounds can be salified if necessary according to the usual methods known to those skilled in the art.

Une composition pharmaceutique topique selon l'invention comprendra de préférence entre environ 5 et 80 mg, plus préférentiellement entre environ 5 et 50 mg, et plus particulièrement entre environ 5 et 20 mg, par exemple environ 5 mg de dérivé de 2-isoxazole-8-aminotétraline, cette masse étant calculée par rapport audit dérivé sous forme de base libre. Cette dose devrait permettre d'assurer le traitement journalier d'un patient, mais c'est au médecin traitant qu'il reviendra en définitive de décider de la fréquence d'application.A topical pharmaceutical composition according to the invention will preferably comprise between approximately 5 and 80 mg, more preferably between approximately 5 and 50 mg, and more particularly between approximately 5 and 20 mg, for example approximately 5 mg of 2-isoxazole-8 derivative. -aminotetralin, this mass being calculated relative to said derivative in the form of the free base. This dose should make it possible to ensure the daily treatment of a patient, but it is up to the attending physician to decide ultimately how often to apply.

Enfin, afin d'assurer un taux de passage transdermique optimal, le pH de la composition pharmaceutique topique selon l'invention sera de préférence compris entre 7 et 9,5, et plus préférentiellement entre 8 et 9,5 lorsque le dérivé de 2-isoxazole-8-aminotétraline est sous forme de base libre. Lorsque le dérivé de 2-isoxazole-8-aminotétraline est sous forme de sel, le pH de la composition pharmaceutique topique selon l'invention sera de préférence compris entre 5 et 7,5, et plus préférentiellement entre 5,5 et 7.Finally, in order to ensure an optimal transdermal passage rate, the pH of the topical pharmaceutical composition according to the invention will preferably be between 7 and 9.5, and more preferably between 8 and 9.5 when the derivative of 2- isoxazole-8-aminotetralin is in the form of the free base. When the 2-isoxazole-8-aminotetralin derivative is in the salt form, the pH of the topical pharmaceutical composition according to the invention will preferably be between 5 and 7.5, and more preferably between 5.5 and 7.

L'invention concerne aussi l'utilisation d'un dérivé de 2-isoxazole-8-aminotétraline, et en particulier de la l,2,3,4-tétrahydro-8-(5-isoxazolyl)-N,N-diisopropyl-2-naphtalènamine, pour fabriquer un médicament permettant une administration transdermale, notamment dans le traitement du syndrome du colon irritable. A moins qu'ils ne soient définis d'une autre manière, tous les termes techniques et scientifiques utilisés ici ont la même signification que celle couramment comprise par un spécialiste ordinaire du domaine auquel appartient cette invention. De même, toutes les publications, demandes de brevets, tous les brevets et toutes autres références mentionnées ici sont incorporées par référence.The invention also relates to the use of a derivative of 2-isoxazole-8-aminotetralin, and in particular of 1,2,3,4-tetrahydro-8- (5-isoxazolyl) -N, N-diisopropyl- 2-naphthalenamine, for the manufacture of a medicament for transdermal administration, in particular in the treatment of irritable bowel syndrome. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as that commonly understood by an ordinary specialist in the field to which this invention belongs. Likewise, all publications, patent applications, all patents and all other references mentioned herein are incorporated by reference.

Les exemples ci-après sont présentés pour illustrer les compositions pharmaceutiques décrites ci-dessus et ne doivent en aucun cas être considérés comme une limite à la portée de l'invention.The examples below are presented to illustrate the pharmaceutical compositions described above and should in no way be considered as limiting the scope of the invention.

EXEMPLE 1EXAMPLE 1

Un patch destiné à l'administration transdermale de l,2,3,4-tétrahydro-8-(5-isoxazolyl)- N,N-diisopropyl-2-naphtalènamine a été préparé à partir de copolymère de méthacrylate et d'ammonioalkyle selon le mode opératoire décrit ci-après.A patch intended for the transdermal administration of 1,2,3,4-tetrahydro-8- (5-isoxazolyl) - N, N-diisopropyl-2-naphthalenamine was prepared from a copolymer of methacrylate and ammonioalkyl according to the procedure described below.

On mélange 20 g d'acétone, 2 g d'alcool isopropylique et 11 g d'éthanol dans un récipient. Le mélange est agité et 39 g d'EUDRAGIT® E 100 (fournisseur : Rohm GmbH, Darmstadt. Allemagne) sont ajoutés par petites portions et à intervalles réguliers sur une période d'une heure et demie, l'agitation étant suffisamment importante pour que l'EUDRAGIT® E 100 ne se dépose pas. On ajoute ensuite 19 g de citrate de triburylacétyle et on agite encore pendant 20 minutes. 20 g de 1.2,3,4-tétrahydro-8-(5-isoxazolyl)-N,N-diisopropyl-2-naphtalènamine (préparée comme décrit dans le brevet européen EP 498 590) sont ajoutés en plusieurs fois, l'agitation étant maintenue durant 30 minutes. Enfin, tout en agitant puissamment le mélange, on ajoute en plusieurs portions 1,5 g d'acide succinique et on maintient l'agitation durant encore 20 minutes.20 g of acetone, 2 g of isopropyl alcohol and 11 g of ethanol are mixed in a container. The mixture is stirred and 39 g of EUDRAGIT® E 100 (supplier: Rohm GmbH, Darmstadt. Germany) are added in small portions and at regular intervals over an hour and a half period, the agitation being sufficient enough for EUDAGIT® E 100 does not deposit. Then 19 g of triburylacetyl citrate are added and the mixture is stirred for another 20 minutes. 20 g of 1,2,3,4-tetrahydro-8- (5-isoxazolyl) -N, N-diisopropyl-2-naphthalenamine (prepared as described in European patent EP 498 590) are added several times, with stirring being maintained for 30 minutes. Finally, while vigorously stirring the mixture, 1.5 g of succinic acid are added in several portions and stirring is continued for another 20 minutes.

La solution obtenue est ensuite étalée à raison de 100 g/m2 sur une feuille porteuse (15 μm d'épaisseur, Revtrans MN, Tricon GmbH, Freiburg-im-Breisgau, Allemagne). On sèche la couche de polymère pendant 10 minutes avec un flux de 1500 m3/h d'air à 60 °C (recyclage avec 80 m3/h d'échappement).The solution obtained is then spread at a rate of 100 g / m 2 on a carrier sheet (15 μm thick, Revtrans MN, Tricon GmbH, Freiburg-im-Breisgau, Germany). The polymer layer is dried for 10 minutes with a flow of 1500 m 3 / h of air at 60 ° C (recycling with 80 m 3 / h of exhaust).

Le polymère obtenu peut ensuite être découpé pour former des patchs d'une surface d'approximativement 15 cm2, utilisables pour dispenser une dose journalière. EXEMPLE 2The polymer obtained can then be cut to form patches with an area of approximately 15 cm 2 , which can be used to dispense a daily dose. EXAMPLE 2

Un patch destiné à l'administration transdermale de l,2,3.4-tétrahydro-8-(5-isoxazolyl)- N,N-diisopropyl-2-naphtalènamine a été préparé à partir de copolymère de méthacrylate et d'ammonioalkyle selon le mode opératoire décrit dans l'exemple 1 , excepté que l'on a ajouté par portions 10 g de Miglyol® 812 (Huis, Mari, Allemagne) entre l'ajout de l,2,3,4-tétrahydro-8-(5-isoxazolyl)-N,N-diisopropyl-2-naphtalènamine et l'ajout d'acide succinique et qu'après cette addition de Miglyol® 812, le mélange a été agité pendant 20 minutes supplémentaires.A patch intended for the transdermal administration of 1,2,3,4-tetrahydro-8- (5-isoxazolyl) - N, N-diisopropyl-2-naphthalenamine was prepared from a copolymer of methacrylate and of ammonioalkyl according to the mode procedure described in Example 1, except that 10 g of Miglyol® 812 (Huis, Mari, Germany) were added in portions between the addition of 1,2,3,4-tetrahydro-8- (5- isoxazolyl) -N, N-diisopropyl-2-naphthalenamine and the addition of succinic acid and that after this addition of Miglyol® 812, the mixture was stirred for an additional 20 minutes.

EXEMPLE 3EXAMPLE 3

Un patch destiné à l'administration transdermale de 1.2,3,4-tétrahydro-8-(5-isoxazolyl)- N,N-diisopropyl-2-naphtalènamine a été préparé à partir de copolymère de méthacrylate et d'ammonioalkyle selon un mode opératoire analogue à celui décrit dans l'exemple 1. excepté que les 20 g de l,2,3,4-tétrahydro-8-(5-isoxazolyl)-N,N-diisopropyl- 2-naphtalènamine sont remplacés par 22,44 g de chlorhydrate de 1,2,3,4-tétrahydro- 8-(5-isoxazolyl)-N,N-diisopropyl-2-naphtalènamine.A patch intended for the transdermal administration of 1,2,3,4-tetrahydro-8- (5-isoxazolyl) - N, N-diisopropyl-2-naphthalenamine was prepared from a copolymer of methacrylate and of ammonioalkyl according to a method procedure similar to that described in Example 1. except that the 20 g of 1,2,3,4-tetrahydro-8- (5-isoxazolyl) -N, N-diisopropyl-2-naphthalenamine are replaced by 22.44 g of 1,2,3,4-tetrahydro- 8- (5-isoxazolyl) -N, N-diisopropyl-2-naphthalenamine hydrochloride.

EXEMPLE 4EXAMPLE 4

Un gel destiné à l'administration transdermale de l,2,3,4-tétrahydro-8-(5-isoxazolyl)- N,N-diisopropyl-2-naphtalènamine a été préparé à partir d'une dispersion aqueuse de hydroxy-propyl-methyl cellulose (HPMC), selon le mode opératoire décrit ci-après (afin de préparer 100 g de gel).A gel intended for the transdermal administration of 1,2,3,4-tetrahydro-8- (5-isoxazolyl) - N, N-diisopropyl-2-naphthalenamine was prepared from an aqueous dispersion of hydroxypropyl -methyl cellulose (HPMC), according to the procedure described below (to prepare 100 g of gel).

Composition du gel :Composition of the gel:

• chlorhydrate de l,2,3.4-tétrahydro-8-(5-isoxazolyl)-N,N- 3 g diisopropyl-2-naphtalènamine• 1,2,3,4-tetrahydro-8- (5-isoxazolyl) -N, N- 3 g hydrochloride 3 g diisopropyl-2-naphthalenamine

• Propylène glycol 4 g• Propylene glycol 4 g

• HPMC 30 g• HPMC 30 g

• Eau purifiée qsp 100 g Préparation du gel :• Purified water qs 100 g Gel preparation:

On prépare d'abord une solution aqueuse (solution I) en solubilisant 3 g de chlorhydrate de 1 ,2,3,4-tétrahydro-8-(5-isoxazolyl)-N,N-diisopropyl-2-naphtalènamine dans 4 g de propylène glycol et 8 g d'eau purifiée. La solution ainsi obtenue est alors filtrée sur filtre 10 μm. On obtient la solution I.An aqueous solution (solution I) is first prepared by dissolving 3 g of 1,2,3,4-tetrahydro-8- (5-isoxazolyl) -N, N-diisopropyl-2-naphthalenamine hydrochloride in 4 g of propylene glycol and 8 g of purified water. The solution thus obtained is then filtered on a 10 μm filter. We obtain solution I.

On prépare ensuite sous vide une dispersion aqueuse de HPMC en mélangeant 30 g de HPMC à 55 g d'eau purifiée. Toujours sous agitation, on chauffe le mélange à une température de 50-60 °C, pendant 20 min, jusqu'à obtention d'un gel d'apparence homogène (gel II).An aqueous dispersion of HPMC is then prepared under vacuum by mixing 30 g of HPMC with 55 g of purified water. Still with stirring, the mixture is heated to a temperature of 50-60 ° C., for 20 min, until a gel of homogeneous appearance is obtained (gel II).

On ajoute par portions la solution I au gel II, puis on laisse le mélange pendant 20 min toujours sous vide, sous agitation et à 50-60 °C, afin d'obtenir 100 g de médicament.Solution I is added in portions to gel II, then the mixture is left for 20 min still under vacuum, with stirring and at 50-60 ° C, to obtain 100 g of drug.

Le médicament est homogénéisé en le passant à travers une filière (homogénéisateur à filière).The drug is homogenized by passing it through a die (homogenizer to die).

Après refroidissement, le gel ainsi obtenu peut être réparti en tubes. Chaque application consistera en une noisette d'environ 1 g.After cooling, the gel thus obtained can be divided into tubes. Each application will consist of a hazelnut of approximately 1 g.

EXEMPLE 5EXAMPLE 5

Un gel destiné à l'administration transdermale de l,2,3,4-tétrahydro-8-(5-isoxazolyl)- N,N-diisopropyl-2-naphtalènamine a été préparé, selon le mode opératoire décrit dans l'exemple 4, excepté que l'on a utilisé le poloxamère Lutrol® F 127 (BASF) comme agent gélifiant. A gel intended for transdermal administration of 1,2,3,4-tetrahydro-8- (5-isoxazolyl) - N, N-diisopropyl-2-naphthalenamine was prepared, according to the procedure described in Example 4 except that was used poloxamer Lutrol ® F 127 (BASF) as gelling agent.

Claims

Revendications claims 1. Composition pharmaceutique matricielle ou réservoir pour une administration par voie topique comprenant au moins un dérivé de 2-isoxazole-8-aminotétraline en quantité thérapeutiquement efficace et un ou plusieurs excipients pharmaceutiquement acceptables.1. Pharmaceutical matrix composition or reservoir for topical administration comprising at least one 2-isoxazole-8-aminotetralin derivative in a therapeutically effective amount and one or more pharmaceutically acceptable excipients. 2. Composition pharmaceutique selon la revendication 1. caractérisée en ce qu'au moins un des excipients pharmaceutiquement acceptables est un polymère ou un copolymère.2. Pharmaceutical composition according to claim 1. characterized in that at least one of the pharmaceutically acceptable excipients is a polymer or a copolymer. 3. Composition pharmaceutique selon la revendication 2. caractérisée en ce qu'elle comprend également un agent plastifiant, par exemple le citrate de tributylacétyle.3. Pharmaceutical composition according to Claim 2. characterized in that it also comprises a plasticizer, for example citrate tributylacétyle. 4. Composition pharmaceutique selon l'une des revendications 1 à 3. caractérisée en ce qu'elle est sous la forme d'un patch.4. A pharmaceutical composition according to one of Claims 1 to 3. characterized in that it is in the form of a patch. 5. Composition selon la revendication 4, caractérisée en ce que le patch se présente sous la forme d'une simple couche polymère adhesive dans laquelle le dérivé de 2-isoxazole- 8-aminotétraline est réparti.5. Composition according to claim 4, characterized in that the patch is in the form of a single adhesive polymer layer in which the 2-isoxazole-8-aminotetraline derivative is distributed. 6. Composition pharmaceutique selon la revendication 1. caractérisée en ce qu'il s'agit d'une crème ou d'un gel aqueux.6. Pharmaceutical composition according to claim 1. characterized in that it is an aqueous cream or gel. 7. Composition pharmaceutique selon la revendication 6. caractérisée en ce qu'il s'agit d'un gel aqueux d'hydroxy-propyl-méthyl cellulose (HPMC) ou d'un poloxamère.7. A pharmaceutical composition according to claim 6. characterized in that it is an aqueous gel of hydroxy-propyl-methyl cellulose (HPMC) or a poloxamer. 8. Composition selon l'une des revendications précédentes, caractérisée en ce qu'elle contient un agent conservateur, en particulier du propylène glycol.8. Composition according to one of the preceding claims, characterized in that it contains a preservative, in particular propylene glycol. 9. Composition selon l'une des revendications précédentes, caractérisée en ce qu'elle contient un agent antioxydant, en particulier de l'acide éthylènediaminetétracétique (EDTA).9. Composition according to one of the preceding claims, characterized in that it contains an antioxidant agent, in particular ethylenediaminetetracetic acid (EDTA). 10. Composition selon l'une des revendications précédentes, caractérisée en ce que le dérivé de 2-isoxazole-8-aminotétraline est présent sous forme d'un sel pharmaceutiquement acceptable. 10. Composition according to one of the preceding claims, characterized in that the 2-isoxazole-8-aminotetralin derivative is present in the form of a pharmaceutically acceptable salt. 11. Composition selon l'une des revendications 1 à 9, caractérisée en ce que le dérivé de 2-isoxazole-8-aminotétraline est la l,2,3,4-tétrahydro-8-(5-isoxazolyl)- N,N-diisopropyl-2-naphtalènamine ou un de ses sels pharmaceutiquement acceptables.11. Composition according to one of claims 1 to 9, characterized in that the 2-isoxazole-8-aminotetralin derivative is l, 2,3,4-tetrahydro-8- (5-isoxazolyl) - N, N -diisopropyl-2-naphthalenamine or one of its pharmaceutically acceptable salts. 12. Composition selon l'une des revendications précédentes, caractérisée en ce qu'elle comprend un promoteur d'absorption transdermique.12. Composition according to one of the preceding claims, characterized in that it comprises a transdermal absorption promoter. 13. Composition selon la revendication 12, caractérisée en ce que le promoteur d'absorption transdermique est choisi parmi le groupe composé des alcools, en particulier l'éthanol, des polyols comme le 1,3-butanediol et les polyéthylèneglycols (PEG), les esters d'acides gras, notamment les triglycérides des acides caprylique et caprique et en particulier le Miglyol®, ainsi que d'autres tensioactifs ou substances amphiphiles.13. Composition according to claim 12, characterized in that the transdermal absorption promoter is chosen from the group consisting of alcohols, in particular ethanol, polyols such as 1,3-butanediol and polyethylene glycols (PEG), fatty acid esters, in particular the triglycerides of caprylic and capric acids and in particular Miglyol ® , as well as other surfactants or amphiphilic substances. 14. Composition selon l'une des revendications précédentes, caractérisée en ce qu'elle entre 5 et 80 mg, et de préférence entre 5 et 50 mg, de dérivé de 2-isoxazole- 8-aminotétraline, cette masse étant calculée par rapport audit dérivé sous forme de base libre.14. Composition according to one of the preceding claims, characterized in that it between 5 and 80 mg, and preferably between 5 and 50 mg, of 2-isoxazole-8-aminotetralin derivative, this mass being calculated relative to said derivative in free base form. 15. Utilisation d'un dérivé de 2-isoxazole-8-aminotétraline pour fabriquer un médicament permettant une administration transdermale.15. Use of a 2-isoxazole-8-aminotetralin derivative to manufacture a medicament for transdermal administration. 16. Utilisation selon la revendication 15, caractérisée en ce que le dérivé de 2-isoxazole- 8-aminotétraline est employé sous forme d'un sel pharmaceutiquement acceptable.16. Use according to claim 15, characterized in that the 2-isoxazole-8-aminotetralin derivative is used in the form of a pharmaceutically acceptable salt. 17. Utilisation selon la revendication 15, caractérisée en ce que le dérivé de 2-isoxazole- 8-aminotétraline employé est la l,2,3,4-tétrahydro-8-(5-isoxazolyl)-N.N-diisopropyl-2- naphtalènamine ou un de ses sels pharmaceutiquement acceptables. 17. Use according to claim 15, characterized in that the 2-isoxazole-8-aminotetralin derivative used is l, 2,3,4-tetrahydro-8- (5-isoxazolyl) -NN-diisopropyl-2-naphthalenamine or a pharmaceutically acceptable salt thereof.
EP00922748A 1999-04-26 2000-04-26 Novel pharmaceutical compositions comprising 2-isoxazole-8-aminotetralin derivatives Withdrawn EP1173173A1 (en)

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