WO2000067727A1 - Galenic formulations of antithrombotic agents for subcutaneous administration - Google Patents

Galenic formulations of antithrombotic agents for subcutaneous administration Download PDF

Info

Publication number
WO2000067727A1
WO2000067727A1 PCT/FR2000/001245 FR0001245W WO0067727A1 WO 2000067727 A1 WO2000067727 A1 WO 2000067727A1 FR 0001245 W FR0001245 W FR 0001245W WO 0067727 A1 WO0067727 A1 WO 0067727A1
Authority
WO
WIPO (PCT)
Prior art keywords
suspension
antithrombotic agent
amino
injectable suspension
subcutaneous administration
Prior art date
Application number
PCT/FR2000/001245
Other languages
French (fr)
Inventor
Frédéric Andre
Alain Cuine
Gareth Lewis
Bénédicte ROGER
Original Assignee
Sanofi-Synthelabo
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 Sanofi-Synthelabo filed Critical Sanofi-Synthelabo
Priority to AU45748/00A priority Critical patent/AU4574800A/en
Publication of WO2000067727A1 publication Critical patent/WO2000067727A1/en

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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • the present invention relates to new formulations of antithrombotic agents for subcutaneous administration.
  • the kinetics can be notably modified, in comparison with an intravenous administration. Thanks to these formulations, the diffusion of the antithrombotic agent can be slowed down from the injection site, in particular by the higher viscosity of the preparation in situ. Also, administration by the subcutaneous route is easier than intravenous administration, especially when the latter is administered by infusion. In particular, administration by the subcutaneous route may allow care at home, by a nurse or by the patient himself.
  • the Applicant then developed new galenical formulations of antithrombotic agents for subcutaneous administration.
  • antithrombotic agents for which these new galenical formulations are suitable are for example napsagatran, melagatran, inogatran or efegatran, as well as the compounds described in patent application WO 98/42700, that is to say derivatives of ⁇ / - (arginyl) benzenesulfonamide and for example (S) -N- hydrochloride [2 - [[[4 - [(aminoiminomethyl) amino] - 1 - [[(4-difluoromethylene) piperidine-1-yl] carbonyl ] butyI] amino] sulfonyl] -6-thien-2-ylphenyljpropanamide, (S) - ⁇ / - hydrochloride [2 - [[[[4- (aminoiminomethyl) amino)] - 1 - [(4-ethylpiperidin-1 - yl) carbonyl] butyl] amino] sulfonyl]
  • the injectable suspensions thus obtained have a concentration of antithrombotic agent which can be between 1 and 100 mg / ml.
  • the present invention therefore relates to a concentrated injectable suspension of antithrombotic agent for subcutaneous administration, characterized in that it contains an antithrombotic agent in the form of crystals having a diameter between 0.2 and 50 ⁇ m.
  • the formulation according to the present invention can be immediate or prolonged release. These two types of formulations, described below, form part of the invention.
  • the suspensions of the present invention can be obtained by various techniques, as described below. Their preparation can indeed go through the preparation of liquid or solid forms, before obtaining the final suspension ready for injection.
  • formulations according to the present invention can thus contain the additives usually used for the preparation
  • liquid pharmaceutical forms such as osmolarity agents, buffering agents, antioxidants and preservatives
  • - dried forms obtained by cryodessiccation, nebulization, atomization .
  • formulations according to the present invention may also contain other additional substances used for the dried forms such as cryoprotectants of lyophilisate, for example mannitol, trehalose or other oligosaccharides.
  • the formulations according to the present invention may also contain other additional substances used for liquid forms such as crystal growth inhibitors, for example povidone, lecithin, gelatin or albumin and / or agents suspension, for example, povidone.
  • the sustained release formulations are characterized in that they additionally contain a substance capable of increasing the viscosity of the suspension. Prolonged release formulations which can form a gel are particularly advantageous.
  • gelling polymers after diffusion of the organic solvent from the subcutaneous injection site such as poly (methacrylic acid) or poly (/ V- isopropyl-acrylamide-b-DL-iactide), the latter excipients which may or may not be complexed with polyethylene glycol.
  • pH-sensitive gelling polymers that is to say for which the gelling is caused by the passage from an acidic to neutral pH
  • polyvinyiacetal diethylaminoacetate examples include polyvinyiacetal diethylaminoacetate.
  • the preferred heat-sensitive polymers such as poloxamers (Lutrol F127 ®, Lutrol F68 ®, BASF).
  • the viscosity of the formulation then increases in situ thanks to the temperature differential and allows a slow release of the antithrombotic agent.
  • a mixture of the polymers described above can also be used.
  • the suspensions of antithrombotic agents ready for injection can be prepared in the following manner, in several stages:
  • the first step may consist in the preparation of a suspension of small particles, by adding the antithrombotic agent to the suspension liquid, which may contain a suspension agent and / or one or more surfactants such as, for example, poloxamers 188 and 407, with vigorous stirring.
  • the size of the particles of antithrombotic agent can then be reduced by conventional methods of grinding, in a liquid medium using, for example, a microbead mill, to obtain a suspension of crystals of antithrombotic agent.
  • This suspension of crystals of antithrombotic agent can be used directly for injection, but for reasons of conservation, set out below, it is preferable to carry out a second step described below.
  • a solid material containing small particles, the size of which is reduced and / or controlled for the crystals of larger diameter, either by dry grinding, for example by micronization or by selection. particle size on sieve.
  • the crystals of antithrombotic agent which are obtained in this first stage can then have a diameter of between 0.2 and 50 ⁇ m.
  • the crystals of antithrombotic agent which are obtained in this first stage may have a diameter of between 1 and 50 ⁇ m.
  • the concentrated suspension for injection of crystals of antithrombotic agent obtained, intended for subcutaneous administration is in the form of crystals having a diameter between 0.2 and 50 ⁇ m and in particular between 1 and 50 ⁇ m.
  • This suspension of crystals of antithrombotic agent can moreover have a certain instability and in particular let appear a troublesome recrystallization, that is to say a modification of the shape of the crystals and a growth of the latter.
  • the present invention therefore also relates to new stable formulations of antithrombotic agent for subcutaneous administration, as well as their methods of preparation.
  • the new stable formulations can in particular be prepared as follows:
  • the suspension of crystals of antithrombotic agent obtained above is stabilized by the addition of a hydrophilic polymer such as povidone, then a lyophilization is carried out according to techniques known to those skilled in the art.
  • a lyophilisate is obtained which can be stored in a sealed container under a controlled atmosphere.
  • Another advantage of this step is to avoid the proliferation of microorganisms in an aqueous medium.
  • the last step of obtaining suspensions ready for injection, immediate or prolonged release, according to the present invention is carried out from the lyophilisate, the nebulisate, the atomisate or the solid material obtained directly by grinding dry as described above.
  • an immediate-release suspension ready for injection by the subcutaneous route, can be obtained by extemporaneously dispersing the lyophilisate, the nebuliser, the atomisate or the solid material by adding water or any other suitable solvent. such as physiological solutions.
  • An extended-release suspension ready for subcutaneous injection, can be obtained by extemporaneously suspending the lyophilisate, nebulisate, atomisate or solid material by adding a solution containing the polymer intended to increase the viscosity of the suspension.
  • the solvent used can be water.
  • the solvent used can be a mixture of ethanol and water.
  • the medium can be a buffer solution at a pH such that the polymer is not in gelled form.
  • the solvent used can be water with 12 to 20% by weight of poloxamer.
  • concentrations of antithrombotic agent of the suspensions ready for injection thus obtained are between 1 and 100 mg / ml.
  • the reconstitution that is to say the suspension of the lyophilisate, of the nebulisate, of the atomisate or of the solid material does not cause any significant variation in the size of the particles which remains between 0.2 and 50 ⁇ m.
  • Example 1 Preparation of a suspension of microcrystals of the compound, with unmodified release, for subcutaneous administration The following constituents are dissolved:
  • the lyophilisate is reconstituted with 1 ml of ppi water. Vigorously stirred for about 30 seconds. The suspension obtained is ready for injection. After reconstitution, the compound concentration is 2.9 mg / ml and the particle size is 6 ⁇ m.
  • the compound is sieved through a 45 ⁇ m mesh sieve to remove large particles.
  • the median particle diameter is 14 ⁇ m and 90% of the particles have a size less than 36 ⁇ m. This measurement is done by size analysis granulometer Malvern Mastersizer ®.
  • Example 3 Preparation of a suspension of microcrystals of high viscosity, intended for prolonged release
  • the sample crystals 2 It is reconstituted using 1 ml of a solution of poloxamer 407 (Lutrol ®, BASF) 15.5% by weight and the suspension thus obtained, ready for injection.
  • poloxamer 407 Litrol ®, BASF
  • the concentration of compound, measured as in Example 1, is 2.9 mg / ml and the particle size, measured as in Example 1, is 15 ⁇ m.
  • the absolute viscosity is measured at 20 ° C and 35 ° C (with a Brookfield DVII + viscometer) which are 30 cP and 45,000 cP respectively.
  • the volume injected is 170 ⁇ l / kg (0.5 mg / kg) of animal.
  • a blood sample (3 ml) is taken using a 0.8 x 25 mm Insyte catheter ( France Médical Biology) implanted in the artery of the ear.
  • the thrombin time is determined chronometrically. The thrombin time is expressed in seconds.
  • TT thrombin time
  • the average percentages of increase ( ⁇ s.e.m.) are calculated for each sampling time.
  • microcrystals prolongs the anticoagulant duration of the compound compared to the effect of the aqueous solution.
  • the addition of a heat-sensitive gel to the microcrystals further prolongs the duration of anticoagulant activity.

Abstract

The invention concerns novel antithrombotic formulations for subcutaneous administration. Said novel formulations can provide instant or prolonged release. Said formulations are in the form of antithrombotic crystals and their concentration ranges between 1 and 100 mg/ml.

Description

FORMULATIONS GALÉNIQUES D'AGENTS ANTITHROMBOTIQUES POUR ADMINISTRATION SOUS-CUTANÉE GALENIC FORMULATIONS OF ANTITHROMBOTIC AGENTS FOR SUBCUTANEOUS ADMINISTRATION
La présente invention a pour objet de nouvelles formulations d'agents antithrombotiques pour administration sous-cutanée.The present invention relates to new formulations of antithrombotic agents for subcutaneous administration.
Ces nouvelles formulations peuvent être adaptées pour augmenter la concentration de certains agents antithrombotiques.These new formulations can be adapted to increase the concentration of certain antithrombotic agents.
Elles peuvent aussi être adaptées pour augmenter leur taux plasmatique et en prolonger la durée d'action. En effet, grâce à une administration sous-cutanée, la cinétique peut être notablement modifiée, en comparaison à une administration intraveineuse. On peut obtenir, grâce à ces formulations un ralentissement de la diffusion de l'agent antithrombotique à partir du site d'injection, notamment par la viscosité plus importante de la préparation in situ. Aussi, l'administration par voie sous-cutanée est plus aisée que l'administration intraveineuse, surtout quand celle-ci est mise en oeuvre par perfusion. En particulier, l'administration par voie sous-cutanée peut permettre les soins à domicile, par une infirmière ou par le patient lui-même.They can also be adapted to increase their plasma level and prolong the duration of action. Indeed, thanks to a subcutaneous administration, the kinetics can be notably modified, in comparison with an intravenous administration. Thanks to these formulations, the diffusion of the antithrombotic agent can be slowed down from the injection site, in particular by the higher viscosity of the preparation in situ. Also, administration by the subcutaneous route is easier than intravenous administration, especially when the latter is administered by infusion. In particular, administration by the subcutaneous route may allow care at home, by a nurse or by the patient himself.
La demanderesse a alors mis au point de nouvelles formulations galéniques d'agents antithrombotiques pour administration sous-cutanée.The Applicant then developed new galenical formulations of antithrombotic agents for subcutaneous administration.
Les agents antithrombotiques pour lesquels ces nouvelles formulations galéniques conviennent sont par exemple le napsagatran, le melagatran, l'inogatran ou l'efegatran, ainsi que les composés décrits dans la demande de brevet WO 98/42700, c'est à dire des dérivés de Λ/-(arginyl)benzènesulfonamide et par exemple le chlorhydrate de (S)-N-[2-[[[4-[(aminoiminométhyl)amino]- 1-[[(4-difluorométhylène)pipéridine-1-yl]carbonyl]butyI]amino]sulfonyl]-6-thièn-2- ylphényljpropanamide, le chlorhydrate de (S)-Λ/-[2-[[[4-(aminoiminométhyl)amino]- 1 -[(4-éthylpipéridin-1 -yl)carbonyl]butyl]amino]sulfonyl]-6-thién-2-ylphényl] propanamide ou le chlorhydrate du Λ/-[2-[[[(1 S)-4-[(aminoiminométhyl)amino]-1-[[4-The antithrombotic agents for which these new galenical formulations are suitable are for example napsagatran, melagatran, inogatran or efegatran, as well as the compounds described in patent application WO 98/42700, that is to say derivatives of Λ / - (arginyl) benzenesulfonamide and for example (S) -N- hydrochloride [2 - [[[4 - [(aminoiminomethyl) amino] - 1 - [[(4-difluoromethylene) piperidine-1-yl] carbonyl ] butyI] amino] sulfonyl] -6-thien-2-ylphenyljpropanamide, (S) -Λ / - hydrochloride [2 - [[[[4- (aminoiminomethyl) amino)] - 1 - [(4-ethylpiperidin-1 - yl) carbonyl] butyl] amino] sulfonyl] -6-thien-2-ylphenyl] propanamide or Λ / - hydrochloride [2 - [[[(1 S) -4 - [(aminoiminomethyl) amino] -1- [ [4-
(trifluorométhyl)pipéridin-1-yl]carbonyl]butyl]amino]sulfonyl]-6-thién-2-ylphényl] propanamide. Ces formulations, objet de la présente invention se présentent sous la forme de suspensions de cristaux d'agent antithrombotique.(trifluoromethyl) piperidin-1-yl] carbonyl] butyl] amino] sulfonyl] -6-thien-2-ylphenyl] propanamide. These formulations, object of the present invention are in the form of suspensions of crystals of antithrombotic agent.
Les suspensions injectables ainsi obtenues présentent une concentration en agent antithrombotique pouvant être comprise entre 1 et 100 mg/ml.The injectable suspensions thus obtained have a concentration of antithrombotic agent which can be between 1 and 100 mg / ml.
La présente invention a donc pour objet une suspension injectable concentrée d'agent antithrombotique pour l'administration sous-cutanée, caractérisée en ce qu'elle contient un agent antithrombotique sous forme de cristaux présentant un diamètre compris entre 0,2 et 50 μm.The present invention therefore relates to a concentrated injectable suspension of antithrombotic agent for subcutaneous administration, characterized in that it contains an antithrombotic agent in the form of crystals having a diameter between 0.2 and 50 μm.
La formulation selon la présente invention peut être à libération immédiate ou prolongée. Ces deux types de formulations, décrites ci-après, font partie de l'invention.The formulation according to the present invention can be immediate or prolonged release. These two types of formulations, described below, form part of the invention.
Immédiates ou prolongées, les suspensions de la présente invention peuvent être obtenues par diverses techniques, comme décrit plus loin. Leur préparation peut en effet passer par la préparation de formes liquides ou solides, avant l'obtention de la suspension finale prête à l'injection.Immediate or extended, the suspensions of the present invention can be obtained by various techniques, as described below. Their preparation can indeed go through the preparation of liquid or solid forms, before obtaining the final suspension ready for injection.
Les formulations selon la présente invention peuvent ainsi contenir les additifs habituellement utilisés pour la préparationThe formulations according to the present invention can thus contain the additives usually used for the preparation
- des formes pharmaceutiques liquides, tels qu'agents d'osmolarité, agents tampons, antioxydants et conservateurs, - des formes desséchées (obtenues par cryodessiccation, nébulisation, atomisation...).- liquid pharmaceutical forms, such as osmolarity agents, buffering agents, antioxidants and preservatives, - dried forms (obtained by cryodessiccation, nebulization, atomization ...).
Par ailleurs, les formulations selon la présente invention peuvent en outre contenir d'autres substances additionnelles utilisées pour les formes desséchées telles que des cryoprotecteurs de lyophilisât, par exemple le mannitol, le trehalose ou d'autres oligosaccharides.Furthermore, the formulations according to the present invention may also contain other additional substances used for the dried forms such as cryoprotectants of lyophilisate, for example mannitol, trehalose or other oligosaccharides.
De même, les formulations selon la présente invention peuvent en outre contenir d'autres substances additionnelles utilisées pour les formes liquides telles que des inhibiteurs de croissance cristalline, par exemple la povidone, la lécithine, la gélatine ou l'albumine et/ou des agents de suspension, par exemple, la povidone. Les formulations à libération prolongée sont caractérisées par le fait qu'elles contiennent en plus une substance capable d'augmenter la viscosité de la suspension. Les formulations à libération prolongée qui peuvent former un gel sont particulièrement avantageuses.Likewise, the formulations according to the present invention may also contain other additional substances used for liquid forms such as crystal growth inhibitors, for example povidone, lecithin, gelatin or albumin and / or agents suspension, for example, povidone. The sustained release formulations are characterized in that they additionally contain a substance capable of increasing the viscosity of the suspension. Prolonged release formulations which can form a gel are particularly advantageous.
Plusieurs types de ces substances capables d'augmenter la viscosité de la suspension peuvent être utilisés dans le cadre de la présente invention.Several types of these substances capable of increasing the viscosity of the suspension can be used in the context of the present invention.
On peut ainsi citer les polymères accroissant la viscosité tels que la povidone.Mention may thus be made of polymers increasing viscosity such as povidone.
On peut aussi citer les polymères gélifiant après diffusion du solvant organique à partir du site d'injection sous-cutanée tels que le poly(acide methacrylique) ou le poly(/V- isopropyl-acrylamide-b-DL-iactide), ces derniers excipients pouvant être complexés ou non avec le polyéthylène glycol.Mention may also be made of the gelling polymers after diffusion of the organic solvent from the subcutaneous injection site such as poly (methacrylic acid) or poly (/ V- isopropyl-acrylamide-b-DL-iactide), the latter excipients which may or may not be complexed with polyethylene glycol.
On peut encore citer les polymères gélifiant pH-sensibles (c'est à dire pour lesquels la gélification est provoquée au passage d'un pH acide vers neutre), tels que le polyvinyiacetal diethylaminoacetate.Mention may also be made of pH-sensitive gelling polymers (that is to say for which the gelling is caused by the passage from an acidic to neutral pH), such as polyvinyiacetal diethylaminoacetate.
Enfin, on préfère les polymères thermosensibles tels que les poloxamères (Lutrol® F127 ; Lutrol® F68, BASF).Finally, the preferred heat-sensitive polymers such as poloxamers (Lutrol F127 ®, Lutrol F68 ®, BASF).
La viscosité de la formulation augmente alors in situ grâce au différentiel de température et permet une libération lente de l'agent antithrombotique.The viscosity of the formulation then increases in situ thanks to the temperature differential and allows a slow release of the antithrombotic agent.
A titre de substance capable d'augmenter la viscosité de la suspension, un mélange des polymères décrits ci-dessus peut également être utilisé.As a substance capable of increasing the viscosity of the suspension, a mixture of the polymers described above can also be used.
Les suspensions d'agents antithrombotiques prêtes à l'injection, selon l'invention, peuvent être préparées de la manière suivante, en plusieurs étapes :The suspensions of antithrombotic agents ready for injection, according to the invention, can be prepared in the following manner, in several stages:
La première étape peut consister en la préparation d'une suspension de particules de faible taille, par ajout de l'agent antithrombotique au liquide de suspension, qui peut contenir un agent de suspension et/ou un ou plusieurs tensioactifs comme par exemple les poloxamères 188 et 407, sous agitation vigoureuse. La taille des particules d'agent antithrombotique peut être réduite ensuite par les méthodes classiques de broyage, en milieu liquide en utilisant par exemple un broyeur à microbilles, pour obtenir une suspension de cristaux d'agent antithrombotique.The first step may consist in the preparation of a suspension of small particles, by adding the antithrombotic agent to the suspension liquid, which may contain a suspension agent and / or one or more surfactants such as, for example, poloxamers 188 and 407, with vigorous stirring. The size of the particles of antithrombotic agent can then be reduced by conventional methods of grinding, in a liquid medium using, for example, a microbead mill, to obtain a suspension of crystals of antithrombotic agent.
Cette suspension de cristaux d'agent antithrombotique peut être utilisée directement pour l'injection, mais pour des raisons de conservation, exposées ci-après, il est préférable de procéder à une deuxième étape décrite plus loin.This suspension of crystals of antithrombotic agent can be used directly for injection, but for reasons of conservation, set out below, it is preferable to carry out a second step described below.
A titre de première étape, on peut aussi préparer un matériau solide, contenant des particules de faible taille, dont la taille est réduite et/ou contrôlée pour les cristaux de plus fort diamètre soit par broyage à sec, par exemple par micronisation soit par sélection granulométrique sur tamis.As a first step, it is also possible to prepare a solid material, containing small particles, the size of which is reduced and / or controlled for the crystals of larger diameter, either by dry grinding, for example by micronization or by selection. particle size on sieve.
Les cristaux d'agent antithrombotique que l'on obtient à cette première étape peuvent alors présenter un diamètre compris entre 0,2 et 50 μm.The crystals of antithrombotic agent which are obtained in this first stage can then have a diameter of between 0.2 and 50 μm.
En particulier les cristaux d'agent antithrombotique que l'on obtient à cette première étape peuvent présenter un diamètre compris entre 1 et 50 μm.In particular, the crystals of antithrombotic agent which are obtained in this first stage may have a diameter of between 1 and 50 μm.
La deuxième étape, qui concerne seulement la suspension de cristaux d'agent antithrombotique obtenue ci-dessus peut alors être mise en oeuvre. Ainsi, la suspension concentrée injectable de cristaux d'agent antithrombotique obtenue, destinée à l'administration sous-cutanée, se présente sous forme de cristaux présentant un diamètre compris entre 0,2 et 50 μm et en particulier entre 1 et 50 μm.The second step, which only concerns the suspension of crystals of antithrombotic agent obtained above can then be carried out. Thus, the concentrated suspension for injection of crystals of antithrombotic agent obtained, intended for subcutaneous administration, is in the form of crystals having a diameter between 0.2 and 50 μm and in particular between 1 and 50 μm.
Cette suspension de cristaux d'agent antithrombotique peut par ailleurs présenter une certaine instabilité et notamment laisser apparaître une recristallisation gênante, c'est à dire une modification de la forme des cristaux et une croissance de ces derniers.This suspension of crystals of antithrombotic agent can moreover have a certain instability and in particular let appear a troublesome recrystallization, that is to say a modification of the shape of the crystals and a growth of the latter.
La présente invention a donc aussi pour objet de nouvelles formulations stables d'agent antithrombotique pour administration sous-cutanée, ainsi que leurs procédés de préparation. Les nouvelles formulations stables peuvent notamment être préparées comme suit :The present invention therefore also relates to new stable formulations of antithrombotic agent for subcutaneous administration, as well as their methods of preparation. The new stable formulations can in particular be prepared as follows:
On stabilise la suspension de cristaux d'agent antithrombotique obtenue ci-dessus par l'ajout d'un polymère hydrophile tel que la povidone, puis on procède à une lyophilisation selon les techniques connues de l'homme du métier.The suspension of crystals of antithrombotic agent obtained above is stabilized by the addition of a hydrophilic polymer such as povidone, then a lyophilization is carried out according to techniques known to those skilled in the art.
A la suite de cette étape on obtient un lyophilisât qui peut être conservé dans un récipient étanche sous atmosphère contrôlée.Following this step, a lyophilisate is obtained which can be stored in a sealed container under a controlled atmosphere.
D'autres procédés peuvent aussi être utilisés tels que l'atomisation ou la nébulisation, qui font également partie de l'invention.Other methods can also be used such as atomization or nebulization, which are also part of the invention.
Un autre avantage de cette étape est d'éviter la prolifération de microorganismes en milieu aqueux.Another advantage of this step is to avoid the proliferation of microorganisms in an aqueous medium.
Enfin, la dernière étape d'obtention des suspensions prêtes à l'injection, à libération immédiate ou prolongée, selon la présente invention s'effectue à partir du lyophilisât, du nébulisat, de l'atomisât ou du matériau solide obtenu directement par le broyage à sec tel que décrit plus haut.Finally, the last step of obtaining suspensions ready for injection, immediate or prolonged release, according to the present invention is carried out from the lyophilisate, the nebulisate, the atomisate or the solid material obtained directly by grinding dry as described above.
En effet, on peut obtenir une suspension à libération immédiate, prête à l'injection par voie sous-cutanée, en dispersant extemporanement le lyophilisât, le nébulisat, l'atomisât ou le matériau solide par adjonction d'eau ou de tout autre solvant approprié tel que les solutés physiologiques.In fact, an immediate-release suspension, ready for injection by the subcutaneous route, can be obtained by extemporaneously dispersing the lyophilisate, the nebuliser, the atomisate or the solid material by adding water or any other suitable solvent. such as physiological solutions.
On peut obtenir une suspension à libération prolongée, prête à l'injection par voie sous-cutanée, en mettant en suspension extemporanement le lyophilisât, le nébulisat, l'atomisât ou le matériau solide par adjonction d'une solution contenant le polymère destiné à accroître la viscosité de la suspension.An extended-release suspension, ready for subcutaneous injection, can be obtained by extemporaneously suspending the lyophilisate, nebulisate, atomisate or solid material by adding a solution containing the polymer intended to increase the viscosity of the suspension.
Pour les polymères accroissant la viscosité tels que la povidone, le solvant utilisé peut être l'eau.For viscosity-increasing polymers such as povidone, the solvent used can be water.
Pour les polymères gélifiant après diffusion du solvant organique à partir du site d'injection sous-cutanée, le solvant utilisé peut être un mélange d'éthanol et d'eau. Pour les polymères pH-sensibles le milieu peut être une solution tampon à un pH tel que le polymère n'est pas sous forme gélifiée.For the gelling polymers after diffusion of the organic solvent from the subcutaneous injection site, the solvent used can be a mixture of ethanol and water. For pH-sensitive polymers, the medium can be a buffer solution at a pH such that the polymer is not in gelled form.
Pour les polymères thermosensibles, le solvant utilisé peut être de l'eau avec 12 à 20% en poids de poloxamère.For thermosensitive polymers, the solvent used can be water with 12 to 20% by weight of poloxamer.
Les concentrations d'agent antithrombotique des suspensions prêtes à l'injection ainsi obtenues (libération immédiate ou prolongée) sont comprises entre 1 et 100 mg/ml.The concentrations of antithrombotic agent of the suspensions ready for injection thus obtained (immediate or prolonged release) are between 1 and 100 mg / ml.
La reconstitution, c'est à dire la mise en suspension du lyophilisât, du nébulisat, de l'atomisât ou du matériau solide n'entraîne pas de variation significative de la taille des particules qui reste comprise entre 0,2 et 50 μm.The reconstitution, that is to say the suspension of the lyophilisate, of the nebulisate, of the atomisate or of the solid material does not cause any significant variation in the size of the particles which remains between 0.2 and 50 μm.
Les exemples suivants illustrent la présente invention.The following examples illustrate the present invention.
Le composé utilisé pour les exemples qui suivent est décrit dans la demande de brevet WO 98/42700 en exemple 5 le chlorhydrate deThe compound used for the examples which follow is described in patent application WO 98/42700 in example 5 the hydrochloride of
(S)-N-[2-[[[4-[(aminoiminométhyl)amino] -1-[[(4-difluorométhylène)pipéridine- 1-yI]carbonyl]butyl]amino]sulfonyl]-6-thièn-2-ylphényl]propanamide, qui sera nommé "le composé" dans le cadre des exemples.(S) -N- [2 - [[[4 - [(aminoiminomethyl) amino] -1 - [[(4-difluoromethylene) piperidine- 1-yI] carbonyl] butyl] amino] sulfonyl] -6-thièn-2 -ylphenyl] propanamide, which will be named "the compound" in the context of the examples.
Exemple 1 : préparation d'une suspension de microcristaux du composé, à libération non-modifiée, pour administration sous-cutanée Les constituants suivants sont mis en solution :Example 1: Preparation of a suspension of microcrystals of the compound, with unmodified release, for subcutaneous administration The following constituents are dissolved:
Figure imgf000008_0001
Figure imgf000008_0001
1 commercialisé sous la marque Kollidon 17 PF par BASF 1 marketed under the brand Kollidon 17 PF by BASF
On réduit la taille des particules du composé par broyage de la solution dans un broyeur à micro-billes Dyno Mill® type KDL, pendant 5 minutes. La taille moyenne (diamètre médian) des particules est de 6 μm et 90% des particules ont une taille inférieure à 18 μm. On effectue cette mesure par analyse granulométrique au granulomètre Maivern Mastersizer®. La suspension est ensuite lyophilisée avec un lyophilisateur Sérail CS3-0.25. Chaque flacon contient 3 mg en composé.Reducing the compound particle size by grinding of the solution in a micro-ball mill Dyno ® Mill Type KDL, during 5 minutes. The average particle size (median diameter) is 6 μm and 90% of the particles have a size less than 18 μm. This measurement is done by size analysis particle size Maivern Mastersizer ®. The suspension is then lyophilized with a Sérail CS3-0.25 lyophilizer. Each bottle contains 3 mg of compound.
On reconstitue le lyophilisât avec 1 ml d'eau ppi. On agite vigoureusement pendant environ 30 secondes. La suspension obtenue est prête à l'injection. Après reconstitution, la concentration en composé est de 2,9 mg/ml et la taille des particules est de 6 μm.The lyophilisate is reconstituted with 1 ml of ppi water. Vigorously stirred for about 30 seconds. The suspension obtained is ready for injection. After reconstitution, the compound concentration is 2.9 mg / ml and the particle size is 6 μm.
Exemple 2 : préparation d'une suspension de microcristaux à libération non- modifiée, pour administration sous-cutanéeExample 2 Preparation of a Suspension of Unmodified Release Microcrystals for Subcutaneous Administration
Le composé est tamisé sur tamis de mailles de 45 μm pour éliminer les grosses particules. Le diamètre médian des particules est de 14 μm et 90% des particules ont une taille inférieure à 36 μm. On effectue cette mesure par analyse granulométrique au granulomètre Malvern Mastersizer®.The compound is sieved through a 45 μm mesh sieve to remove large particles. The median particle diameter is 14 μm and 90% of the particles have a size less than 36 μm. This measurement is done by size analysis granulometer Malvern Mastersizer ®.
Exemple 3 : préparation d'une suspension de microcristaux de forte viscosité, destinée à la libération prolongéeExample 3: Preparation of a suspension of microcrystals of high viscosity, intended for prolonged release
On utilise les cristaux d'exemple 2. On le reconstitue avec 1 ml d'une solution de poloxamère 407 (Lutrol®, BASF) à 15,5% en poids et obtient ainsi la suspension prête à l'injection.The sample crystals 2. It is reconstituted using 1 ml of a solution of poloxamer 407 (Lutrol ®, BASF) 15.5% by weight and the suspension thus obtained, ready for injection.
La concentration en composé, mesurée comme dans l'exemple 1 , est de 2,9 mg/ml et la taille des particules, mesurée comme dans l'exemple 1 , est de 15 μm.The concentration of compound, measured as in Example 1, is 2.9 mg / ml and the particle size, measured as in Example 1, is 15 μm.
On mesure la viscosité absolu à 20°C et à 35°C (avec un viscosimètre Brookfield DVII+) qui sont respectivement de 30 cP et 45000 cP.The absolute viscosity is measured at 20 ° C and 35 ° C (with a Brookfield DVII + viscometer) which are 30 cP and 45,000 cP respectively.
Exemple 4 : durée d'action de l'activité anticoagulante des suspensions des exemples 1 , 2 à 3EXAMPLE 4 Duration of Action of the Anticoagulant Activity of the Suspensions of Examples 1, 2 to 3
MÉTHODEMETHOD
Pour chaque formulation testée, 5 à 6 lapins mâles vigiles ESD (2,5 à 3,5 kg) sont traités. Les suspensions sont administrées par voie sous-cutanée au niveau du cou. Une solution du composé dans l'eau ppi, de concentration 3 mg/ml est aussi testée par injection sous-cutanée.For each formulation tested, 5 to 6 vigorous male ESD rabbits (2.5 to 3.5 kg) are treated. The suspensions are administered subcutaneously at the level of the neck. A solution of the compound in ppi water, with a concentration of 3 mg / ml is also tested by subcutaneous injection.
Le volume injecté est de 170 μl/kg (0,5 mg/kg) d'animal.The volume injected is 170 μl / kg (0.5 mg / kg) of animal.
A différents temps (0, 15, 30, 60, 120, 240, et 360 minutes), on effectue le prélèvement d'un échantillon sanguin (3 ml) à l'aide d'un cathéter 0,8 x 25 mm Insyte (France Médical Conseil) implanté dans l'artère de l'oreille. On détermine le temps de thrombine chronometriquement. Le temps de thrombine est exprimé en secondes.At different times (0, 15, 30, 60, 120, 240, and 360 minutes), a blood sample (3 ml) is taken using a 0.8 x 25 mm Insyte catheter ( France Médical Conseil) implanted in the artery of the ear. The thrombin time is determined chronometrically. The thrombin time is expressed in seconds.
On calcule pour chaque lapin traité le pourcentage d'augmentation du temps de thrombine (TT) des prélèvements réalisés post-administration par rapport au prélèvement réalisé juste avant administration (chaque lapin est son propre témoin).The percentage increase in thrombin time (TT) of the samples taken post-administration compared to the sample taken just before administration is calculated for each rabbit treated (each rabbit is its own control).
Pour chaque formulation testée, on calcule les pourcentages moyens d'augmentation (± s.e.m.) pour chaque temps de prélèvement.For each formulation tested, the average percentages of increase (± s.e.m.) are calculated for each sampling time.
RÉSULTATSRESULTS
Les résultats sont rassemblés dans le tableau. L'utilisation de microcristaux, prolonge la durée anticoagulante du composé par rapport à l'effet de la solution aqueuse. L'ajout d'un gel thermosensible aux microcristaux prolonge encore la durée d'activité anticoagulante. The results are collated in the table. The use of microcrystals prolongs the anticoagulant duration of the compound compared to the effect of the aqueous solution. The addition of a heat-sensitive gel to the microcrystals further prolongs the duration of anticoagulant activity.
TableauBoard
Figure imgf000011_0001
Figure imgf000011_0001

Claims

revendications claims
1. Suspension injectable concentrée d'agent antithrombotique pour l'administration sous-cutanée, caractérisée en ce qu'elle contient un agent antithrombotique sous forme de cristaux présentant un diamètre compris entre 0,2 et 50 μm.1. Concentrated injectable suspension of antithrombotic agent for subcutaneous administration, characterized in that it contains an antithrombotic agent in the form of crystals having a diameter between 0.2 and 50 μm.
2. Suspension injectable concentrée d'agent antithrombotique pour l'administration sous-cutanée selon la revendication 1 , caractérisée en ce que le diamètre des cristaux est compris entre 1 et 50 μm.2. Concentrated injectable suspension of antithrombotic agent for subcutaneous administration according to claim 1, characterized in that the diameter of the crystals is between 1 and 50 μm.
3. Suspension injectable selon la revendication 1 ou 2, caractérisée en ce que la concentration en agent antithrombotique est comprise entre 1 et 100 mg/ml.3. Injectable suspension according to claim 1 or 2, characterized in that the concentration of antithrombotic agent is between 1 and 100 mg / ml.
4. Suspension injectable selon l'une quelconque des revendications 1 à 3, caractérisée en ce que l'agent antithrombotique est choisi parmi le napsagatran, le melagatran, l'inogatran, l'efegatran, le chlorhydrate de4. Injectable suspension according to any one of claims 1 to 3, characterized in that the antithrombotic agent is chosen from napsagatran, melagatran, inogatran, efegatran, hydrochloride
(S)-N-[2-[[[4-[(aminoiminométhyl)amino]-1-[[(4-difluorométhylène)pipéridine- 1 -yl]carbonyl]butyl]amino]sulfonyl]-6-thièn-2-ylphényl]propanamide, le chlorhydrate de (S)-Λ/-[2-[[[4-(aminoiminométhyl)amino]-1 -[(4-éthylpipéridin-1 -yl)carbonyl]butyl] amino]sulfonyl]-6-thién-2-ylphényl]propanamide et le chlorhydrate du ^-[2-[[[(1 S)-4-[(aminoiminométhyl)amino]-1-[[4-(trifluorométhyl)pipéridin-1- yl]carbonyl]butyl]amino]sulfonyl]-6-thién-2-ylphényl]propanamide.(S) -N- [2 - [[[4 - [(aminoiminomethyl) amino] -1 - [[(4-difluoromethylene) piperidine- 1 -yl] carbonyl] butyl] amino] sulfonyl] -6-thièn-2 -ylphenyl] propanamide, (S) -Λ / - hydrochloride [2 - [[[4- (aminoiminomethyl) amino] -1 - [(4-ethylpiperidin-1 -yl) carbonyl] butyl] amino] sulfonyl] - 6-thien-2-ylphenyl] propanamide and the hydrochloride of ^ - [2 - [[[(1 S) -4 - [(aminoiminomethyl) amino] -1 - [[4- (trifluoromethyl) piperidin-1- yl] carbonyl] butyl] amino] sulfonyl] -6-thien-2-ylphenyl] propanamide.
5. Suspension d'agent antithrombotique selon l'une quelconque des revendications 1 à 4, caractérisée en ce qu'elle contient un agent de suspension et/ou un ou plusieurs tensioactifs.5. Antithrombotic agent suspension according to any one of claims 1 to 4, characterized in that it contains a suspending agent and / or one or more surfactants.
6. Suspension injectable selon la revendication 5, caractérisée en ce que l'agent de suspension est la povidone et le tensioactif est choisi parmi les poloxamères 188 et 407.6. Injectable suspension according to claim 5, characterized in that the suspending agent is povidone and the surfactant is chosen from poloxamers 188 and 407.
7. Suspension d'agent antithrombotique selon l'une quelconque des revendication 1 à 6, caractérisée en ce qu'elle contient un inhibiteur de croissance cristalline. 7. Suspension of antithrombotic agent according to any one of claims 1 to 6, characterized in that it contains a crystal growth inhibitor.
8. Suspension injectable selon la revendication 7, caractérisée en ce que l'inhibiteur de croissance cristalline est choisi parmi la povidone, la lécithine, la gélatine ou l'albumine.8. Injectable suspension according to claim 7, characterized in that the crystal growth inhibitor is chosen from povidone, lecithin, gelatin or albumin.
9. Suspension injectable selon l'une quelconque des revendications 1 à 8, caractérisée en ce qu'elle contient un ou plusieurs cryoprotecteurs choisis parmi le mannitol, le trehalose ou tout autre oligosaccharide.9. Suspension for injection according to any one of claims 1 to 8, characterized in that it contains one or more cryoprotectors chosen from mannitol, trehalose or any other oligosaccharide.
10. Suspension injectable selon l'une quelconque des revendications 1 à 9, pour la libération prolongée, caractérisée en ce qu'elle contient une substance capable d'augmenter la viscosité.10. Suspension for injection according to any one of claims 1 to 9, for prolonged release, characterized in that it contains a substance capable of increasing viscosity.
11. Suspension injectable selon la revendication 10, caractérisé en ce que la substance capable d'augmenter la viscosité est choisie parmi la povidone, les polymères gélifiant après diffusion du solvant organique à partir du site d'injection sous-cutanée, les polymères gélifiant pH-sensibies ou les polymères thermosensibles ou un mélange de ces derniers polymères.11. Injectable suspension according to claim 10, characterized in that the substance capable of increasing the viscosity is chosen from povidone, the gelling polymers after diffusion of the organic solvent from the subcutaneous injection site, the gelling polymers pH -sensitivity or thermosensitive polymers or a mixture of these latter polymers.
12. Suspension injectable selon la revendication 11 , caractérisée en ce que le polymère gélifiant après diffusion du solvant organique à partir du site d'injection sous-cutanée peut être le poly(acide methacrylique) ou le poly(N-isopropyl-acrylamide-b-DL-lactique) qui peuvent être complexés avec le polyéthylène glycol.12. Injectable suspension according to claim 11, characterized in that the gelling polymer after diffusion of the organic solvent from the subcutaneous injection site can be poly (methacrylic acid) or poly (N-isopropyl-acrylamide-b -DL-lactic) which can be complexed with polyethylene glycol.
13. Suspension injectable selon la revendication 1 1 , caractérisée en ce que le polymère gélifiant pH-sensible peut être le polyvinylacetal diethylaminoacetate.13. Suspension for injection according to claim 1 1, characterized in that the pH-sensitive gelling polymer can be polyvinylacetal diethylaminoacetate.
14. Suspension injectable selon la revendication 11 , caractérisée en ce que le polymère thermosensible peut être un poloxamère.14. Suspension for injection according to claim 11, characterized in that the thermosensitive polymer can be a poloxamer.
15. Lyophilisât, nébulisat ou atomisât contenant de l'agent antithrombotique, caractérisé en ce qu'il est obtenu par lyophilisation, atomisation ou nébulisation de la suspension selon l'une quelconque des revendications 1 à 9. 15. Lyophilisate, nebulisate or atomisate containing antithrombotic agent, characterized in that it is obtained by lyophilization, atomization or nebulization of the suspension according to any one of claims 1 to 9.
16. Matériau solide contenant de l'agent antithrombotique, caractérisé en ce que l'agent antithrombotique est sous forme de cristaux présentant un diamètre compris entre 0,2 et 50 μm.16. Solid material containing the antithrombotic agent, characterized in that the antithrombotic agent is in the form of crystals having a diameter between 0.2 and 50 μm.
17. Matériau solide selon la revendication 16, caractérisé en ce qu'il est obtenu soit par broyage à sec soit par sélection granulométrique sur tamis.17. Solid material according to claim 16, characterized in that it is obtained either by dry grinding or by particle size selection on a sieve.
18. Suspension injectable concentrée d'agent antithrombotique, à libération immédiate, pour l'administration sous-cutanée, caractérisée en ce qu'elle est préparée extemporanement en dispersant le lyophilisât, le nébulisat ou l'atomisât selon la revendication 15 ou le matériau solide selon la revendication 16 ou 17, par adjonction d'eau ou de tout autre solvant approprié.18. Concentrated injectable suspension of antithrombotic agent, for immediate release, for subcutaneous administration, characterized in that it is prepared extemporaneously by dispersing the lyophilisate, the nebulisate or the atomisate according to claim 15 or the solid material according to claim 16 or 17, by adding water or any other suitable solvent.
19. Suspension injectable concentrée d'agent antithrombotique, à libération prolongée, pour l'administration sous-cutanée, caractérisée en ce qu'elle est préparée extemporanement en dispersant le lyophilisât, le nébulisat ou l'atomisât selon la revendication 15 ou le matériau solide selon la revendication 16 ou 17, par adjonction d'une solution contenant la substance capable d'augmenter la viscosité. 19. Concentrated injectable suspension of antithrombotic agent, with sustained release, for subcutaneous administration, characterized in that it is prepared extemporaneously by dispersing the lyophilisate, the nebulisate or the atomisate according to claim 15 or the solid material. according to claim 16 or 17, by adding a solution containing the substance capable of increasing the viscosity.
PCT/FR2000/001245 1999-05-11 2000-05-09 Galenic formulations of antithrombotic agents for subcutaneous administration WO2000067727A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU45748/00A AU4574800A (en) 1999-05-11 2000-05-09 Galenic formulations of antithrombotic agents for subcutaneous administration

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR9905975A FR2793418B1 (en) 1999-05-11 1999-05-11 GALENIC FORMULATIONS OF ANTITHROMBOTIC AGENTS FOR SUBCUTANEOUS ADMINISTRATION
FR99/05975 1999-05-11

Publications (1)

Publication Number Publication Date
WO2000067727A1 true WO2000067727A1 (en) 2000-11-16

Family

ID=9545447

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/FR2000/001245 WO2000067727A1 (en) 1999-05-11 2000-05-09 Galenic formulations of antithrombotic agents for subcutaneous administration

Country Status (3)

Country Link
AU (1) AU4574800A (en)
FR (1) FR2793418B1 (en)
WO (1) WO2000067727A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6479078B1 (en) 1999-07-02 2002-11-12 Astrazeneca Ab Substantially crystalline form of melagatran

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3356732A (en) * 1966-03-29 1967-12-05 Gen Electric 2-[p-(phenylsulfonyl) phenyl]-1, 3-indanedione and its tautomer
US4474752A (en) * 1983-05-16 1984-10-02 Merck & Co., Inc. Drug delivery system utilizing thermosetting gels
GB2201089A (en) * 1987-01-30 1988-08-24 Ciba Geigy Ag Parenteral suspensions of diclofenac
US5534270A (en) * 1995-02-09 1996-07-09 Nanosystems Llc Method of preparing stable drug nanoparticles
WO1997039770A1 (en) * 1996-04-24 1997-10-30 Astra Aktiebolag New pharmaceutical formulation of a thrombin inhibitor for parenteral use
WO1998042700A1 (en) * 1997-03-20 1998-10-01 Sanofi-Synthelabo N-(arginyl)benzenesulphonamide derivatives and use thereof as antithrombotic agents

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3356732A (en) * 1966-03-29 1967-12-05 Gen Electric 2-[p-(phenylsulfonyl) phenyl]-1, 3-indanedione and its tautomer
US4474752A (en) * 1983-05-16 1984-10-02 Merck & Co., Inc. Drug delivery system utilizing thermosetting gels
GB2201089A (en) * 1987-01-30 1988-08-24 Ciba Geigy Ag Parenteral suspensions of diclofenac
US5534270A (en) * 1995-02-09 1996-07-09 Nanosystems Llc Method of preparing stable drug nanoparticles
WO1997039770A1 (en) * 1996-04-24 1997-10-30 Astra Aktiebolag New pharmaceutical formulation of a thrombin inhibitor for parenteral use
WO1998042700A1 (en) * 1997-03-20 1998-10-01 Sanofi-Synthelabo N-(arginyl)benzenesulphonamide derivatives and use thereof as antithrombotic agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
S. BUDAVARI ET AL.: "THE Merck INDEX twelth edition", 1996, MERCK & CO., INC., WHITEHOUSE STATION NJ (US), XP002127652 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6479078B1 (en) 1999-07-02 2002-11-12 Astrazeneca Ab Substantially crystalline form of melagatran
EP1196431B1 (en) * 1999-07-02 2006-09-13 AstraZeneca AB A substantially crystalline form of melagatran

Also Published As

Publication number Publication date
FR2793418A1 (en) 2000-11-17
FR2793418B1 (en) 2001-07-27
AU4574800A (en) 2000-11-21

Similar Documents

Publication Publication Date Title
EP1007030B3 (en) Solid pharmaceutical composition containing benzofurane derivatives
EP0608207B1 (en) Nanocapsule containing pharmaceutical compositions
CA2377909C (en) Pharmaceutical composition containing fenofibrate and preparation method
WO1998043635A1 (en) Pharmaceutical composition for oral administration of a n-piperidino- 3-pyrazolecarboxamide derivative, its salts and their solvates
LU87675A1 (en) NEW PHARMACEUTICAL COMPOSITIONS BASED ON CYCLOSPORINS
JP2001505928A (en) Solid pharmaceutical composition comprising cyclosporin and an anionic surfactant
SK97199A3 (en) Oral cyclosporin formulations
JPH11512115A (en) Pharmaceutical composition for oral administration
CN114787200A (en) Method for forming inclusion complex using hydrophilic beta-cyclodextrin derivatives and compositions thereof
EP0376852B1 (en) Microgranules essentially consisting of triglycerides of saturated fatty acids loaded with an active substance, and their topical therapeutical use
EP0244315B1 (en) Process for preparing an aquous pharmaceutical solution of an organic acid as the active ingredient
US20100056644A1 (en) Pharmaceutical compositions containing anhydrous calcipotriene
JPH10509462A (en) Oral cyclosporine preparation
FR2753376A1 (en) PHARMACEUTICAL COMPOSITIONS COMPRISING AMISULPRIDE AND THERAPEUTIC APPLICATIONS THEREOF
FR2462424A1 (en) COMPOSITION BASED ON BENZYL PEROXIDE, IN PARTICULAR FOR THE TREATMENT OF ACNE
EP0290299B1 (en) Galenic formulation based on dry extracts of plants
CH644015A5 (en) AQUEOUS INJECTABLE OXYTETRACYCLINE SOLUTION.
CA2273990A1 (en) Pharmaceutical compositions containing n-sulphonyl indolin derivatives
WO2000067727A1 (en) Galenic formulations of antithrombotic agents for subcutaneous administration
WO1999030728A1 (en) Pharmaceutical compositions based on dalforpristin and quinupristin and preparation
EP1835906A1 (en) Injectable or orally deliverable formulations of azetidine derivatives
BE1011413A4 (en) Pharmaceutical composition for lowering blood pressure and method of preparation.
FR2793412A1 (en) GALENIC ARGATROBAN FORMULATIONS FOR SUBCUTANEOUS ADMINISTRATION
AU2011302885B2 (en) Non-aqueous oily injectable formulation exhibiting preservative efficacy
FI118953B (en) Inflammatory, nimesulide containing substance for external use

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP