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WO2005018609A1 - Microparticules contenant l'antagoniste de cgrp 1-[n2-[3,5-dibromo-n-[[4-(3,4-dihydro-2(1h)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-d-tyrosyl]-l-lysyl]-4-(4-pyridinyl)-piperazine, procede de production desdites particules ainsi que leur utilisation en tant que poudre d'inhalation - Google Patents

Microparticules contenant l'antagoniste de cgrp 1-[n2-[3,5-dibromo-n-[[4-(3,4-dihydro-2(1h)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-d-tyrosyl]-l-lysyl]-4-(4-pyridinyl)-piperazine, procede de production desdites particules ainsi que leur utilisation en tant que poudre d'inhalation Download PDF

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Publication number
WO2005018609A1
WO2005018609A1 PCT/EP2004/009013 EP2004009013W WO2005018609A1 WO 2005018609 A1 WO2005018609 A1 WO 2005018609A1 EP 2004009013 W EP2004009013 W EP 2004009013W WO 2005018609 A1 WO2005018609 A1 WO 2005018609A1
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WO
WIPO (PCT)
Prior art keywords
active ingredient
weight
spray
drying gas
tyrosyl
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.)
Ceased
Application number
PCT/EP2004/009013
Other languages
German (de)
English (en)
Inventor
Michael Trunk
Claudius Weiler
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.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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 Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim International GmbH
Priority to EP04764017A priority Critical patent/EP1658051A1/fr
Priority to CA002536048A priority patent/CA2536048A1/fr
Priority to JP2006523577A priority patent/JP2007502790A/ja
Publication of WO2005018609A1 publication Critical patent/WO2005018609A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules

Definitions

  • Microparticles containing the CGRP antagonist 1- [W 2 - [3,5-dibromo- / V - [[4- (3,4-dihydro-2 (1ry) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine, process for their preparation and their use as inhalable powder
  • the invention relates to inhalation powder in the form of stable, spray-dried microparticles (embedding particles) for pulmonary or nasal inhalation, containing the CGRP antagonist 1- [ ⁇ / 2 - [3 ) 5-dibromo- ⁇ / - [[4- (3.4 -dihydro-2 (1rV) - oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine (A) or a physiologically acceptable salt thereof and one or more adjuvants, processes for producing such microparticles and the use for producing a powder inhalant for the treatment of headaches, migraines and cluster headaches.
  • the CGRP antagonist 1- [ ⁇ / 2 - [3 ) 5-dibromo- ⁇ / - [[4- (3.4 -dihydro-2 (1rV) -
  • the CGRP antagonist 1- [ ⁇ / 2 - [3,5-dibromo- ⁇ / - [[4- (3,4-dihydro-2 (1 rV) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl ] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine (A) is known from international patent application PCT / EP / 9704862 (published as WO 98/11128) and has the following structure:
  • the active ingredient base (A) is a highly effective CGRP antagonist for the acute and prophylactic treatment of headaches, especially migraines and
  • Cluster headache its application by means of classic dosage forms is not possible by oral route because the substance has a low oral bioavailability.
  • an active ingredient To treat seizure-related migraine diseases, it is necessary for an active ingredient to be available systemically as quickly as possible. It should be noted that the application is straightforward for the patient and no other conditions that can influence the bioavailability (eg "food effect") lead to a restriction of the applicability for the patient. Active ingredients that should be available systemically If this route cannot be implemented or is desired due to special properties of the active substance or special requirements for the application, various other options for the systemic administration of substances have been known in the prior art the inhalative route is discussed, by means of which active ingredients can also be made available systemically in addition to topical applications.
  • the Pul lends itself to substances which, because of their decomposition behavior in solution, prove to be critical or are poorly soluble
  • the absolute amount of active ingredient that has to be administered in one application poses a particular challenge to the formulation.
  • physical stability e.g. aerodynamic particle size, dispersibility, physicochemical properties
  • inhalation powders which are filled, for example, into suitable capsules (inhalettes), are applied to the lungs by means of powder inhalers.
  • powder inhalers Also known are other systems in which the amount of powder to be applied is predosed (e.g. blister), as well as multidose powder systems.
  • inhalative use can also be carried out by applying suitable powdered inhalation aerosols which are suspended, for example, in HFA134a, HFA227 or their mixture as propellant.
  • the microparticles of a pure active ingredient are applied through the respiratory tract on the surface of the lungs, for example in the alveoli, by means of the inhalation process. These particles sediment on the surface and can can only be absorbed by active and passive transport processes in the body after the release process.
  • Solvent system is available as a carrier or in the form of a dry powder.
  • Powder inhalants e.g. in the form of capsules for inhalation
  • a critical factor in such multi-component systems is an even distribution of the drug in the powder mixture.
  • respirable particles inhalable fraction
  • mean particle size of these respirable particles is in the range of a few micrometers, typically between 0.1 and 10 ⁇ m, preferably below 6 ⁇ m.
  • Such particles are usually generated by micronization (air jet grinding). This often means that such particles can have a complex composition with regard to their crystal properties due to this mechanical step.
  • the geometric shape of the particles of the starting material also determines the morphological properties of the micronisate. For such a formulation route, it turns out to be important to use a thermodynamically stable or the most stable form of the active ingredient in such powder preparations. This is usually a crystalline form of the active substance.
  • Powder preparations consisting of co-spray-dried ⁇ -galactosidase with trehalose [J. Broadhead, SK Edmond Rouan, CT. Rhodes, Pharm Acta Helvetiae, 70 (1995), 125-131], which can be mixed, for example, with other physiologically acceptable auxiliaries; Powder preparations consisting of a spray micronisate which consists of co-spray drying at least two active ingredients and one or more physiologically acceptable auxiliaries [WO 01/13885]; Powder preparations which have been prepared from spray-dried rhDNase, optionally co-spray-dried with salts, and either directly or in the form of a mixture with a physiologically acceptable auxiliary, for example lactose, mannitol or sodium chloride, for inhalative applications [HK Chan, A.
  • a physiologically acceptable auxiliary for example lactose, mannitol or sodium chloride
  • the object of the present invention is to provide a novel, stable formulation for the active ingredient base 1- [ ⁇ / 2 - [3,5-dibromo- ⁇ / - [[4- (3,4-dihydro-2 (1H) - oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine (A) or a physiologically acceptable salt thereof using a carrier material.
  • the formulation should preferably be composed such that the bitterness of the active ingredient is masked.
  • the CGRP antagonist 1- [ ⁇ / 2 - [3,5-dibromo- ⁇ / - [[4- (3,4-dihydro-2 (1r7) -oxoquinazoline-3- yl) - 1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine (A) or a physiologically acceptable salt thereof for the treatment of acute pain conditions in migraine and a high one
  • the best way to achieve a plasma level is via the lungs as the receiving organ.
  • the active ingredient (A) or a physiologically acceptable salt thereof physically stable as a solid in a solid matrix of an auxiliary.
  • the active ingredient can be incorporated into the solid matrix using the formulation technique according to the invention in such a way that it is stabilized by selecting a physically and chemically stable auxiliary with regard to, for example, the oxidative sensitivity of the active ingredient.
  • such embedding offers the possibility of masking the bitterness of the active ingredient during application as an inhalative.
  • the particles according to the invention are characterized in that the physicochemical properties are primarily determined by the physicochemical properties of the embedding material.
  • the bitter taste of the active ingredient is minimized or masked when the inhalable powder according to the invention is used by inhalation in comparison to the inhalation of the pure active ingredient.
  • the invention also includes corresponding manufacturing processes for producing such particles.
  • powders can be used both directly as powder inhalants (multi-dose systems, pre-metered multi-dose systems and single-dose systems) and as components that are mixed with other (e.g. coarse-grained) excipients.
  • the active ingredient 1- [ ⁇ / 2 ⁇ [3,5-dibromo- ⁇ / - [[4- (3,4-dihydro-2 (1 / - /) - oxoquinazolin-3-yl) - 1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine (A) or a physiologically tolerable salt thereof can be changed morphologically by co-spray drying with various auxiliaries such that Such a powder can be filled directly into a primary packaging material without further production steps, especially without the need for mixing with a coarser carrier material (auxiliary), and can be dispensed (inhaled) from it using a powder inhalation device.
  • auxiliary coarser carrier material
  • the micronizates produced in this way are largely insensitive to moisture and therefore correction factors which, owing to the hygroscopicity of the pure active ingredient, do not have to be taken into account further when producing a medicament from such embedding particles.
  • the production process can be controlled in such a way that the particles are of a suitable particle size, usually between 0.1 and 10 ⁇ m, and these particles have surface properties such that they can be easily swirled or dispersed.
  • the particle morphology including the particle size can be controlled in a targeted manner through the choice of process parameters and manufacturing parameters.
  • a formulation based on this manufacturing process enables the active ingredient (A) or a physiologically tolerable salt thereof to be administered to the patient by inhalation in a therapeutically relevant dose.
  • Particles which are produced by the process according to the invention are characterized by high physical stability. They are particularly suitable if, when used as a powder inhalant, a high proportion of fines is applied, technically determined e.g. by means of cascade impactor measurement (Andersenkaskaden impactor, according to USP 254 or Pharm. Eur. Suppl. 2002). Typically, the proportion of particles smaller than 5 ⁇ m (aerodynamic) using this method is greater than 15%; in some cases even fine fractions of more than 50% are achieved.
  • the powder is distinguished by the fact that it can be filled directly using conventional filling methods, but a mixture with a physiologically acceptable auxiliary is not absolutely necessary, but can be mentioned as a further variant of the present invention.
  • Powders produced in this way are characterized by the physicochemical parameters particle size, for example measured by means of laser diffraction, and specific surface area, for example measured by means of multipoint BET measurement.
  • the particle size of powders produced in this way typically lies between 50% and 100% and for the parameter X 50 in the range from 1 ⁇ m to 10 ⁇ m, preferably from 1 ⁇ m to 6 ⁇ m.
  • Particles produced by the above method thereby typically have values for the specific surface area of between 1 m 2 / g and 20 m 2 / g, ideally between 1 m 2 / g and 10m 2 / g.
  • particles that are produced according to the above method have a dependency on the chosen auxiliary Particle shapes which, depending on the test conditions, can be described between the extremes "spherical shape", “spherical shape with cavity, possibly with a hole”, “spherical shape with inward-shaped curvatures” and “collapsed hollow bodies”.
  • the surface is ⁇ - such particles largely nanostructured spherical plain or on the surface. If, for example, mannitol is used as an auxiliary, this substance spontaneously recrystallizes during the manufacturing process, so that the particle morphology also changes from spherical to rhombic shape.
  • a first object of the present invention is thus an inhalation powder for pulmonary or nasal inhalation, comprising as active ingredient the CGRP antagonist 1- [ ⁇ r - [3,5-dibromo- ⁇ / - [[4- (3,4-dihydro-2 (1f7) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) piperazine (A) or a physiologically acceptable salt thereof and one or more auxiliary substances in the form of spherically nanostructured microparticles, which are characterized in that
  • the particles have a specific surface area between 1 m 2 / g and 20 m 2 / g, preferably between 1 m 2 / g and 10 m 2 / g,
  • the parameter X 50 is in the range from 1 ⁇ m to 10 ⁇ m, preferably from 1 ⁇ m to 6 ⁇ m.
  • the physiologically tolerable acid addition salts are preferably used, which are selected, for example, from the group consisting of 1- [ ⁇ / 2 - [3,5-dibromo- ⁇ / - [[4- (3,4- dihydro-2 (1r) - oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine hydrochloride, sulfate, phosphate, Hydrobromide, carbonate, methanesulfonate, p-toluenesulfonate, nitrate, citrate, malate, tatrate, lactate, succinate, gluconate, acetate, formate, propionate, capronate, oxalate, Maleate, fumarate, almondate and hydroxysuccinate
  • suitable excipients for example, have carrier materials from the group consisting of physiologically inactive polysaccharides (such as maltodextrin, starch, cellulose, dextrans), polylactide / -glycolid (for example, Resomer ®), disaccharides (e.g., trehalose, lactose, maltose, sucrose), monosaccharides (for example fructose, glucose), polyalcohols (for example mannitol, sorbitol), amino acids (for example arginine hydrochloride), chitosan and mixtures of these carrier materials, the auxiliaries trehalose, lactose, polylactide / glycolide, sucrose, maltodextrin, mannitol and mixtures of these auxiliaries being preferred are.
  • physiologically inactive polysaccharides such as maltodextrin, starch, cellulose, dextrans
  • polylactide / -glycolid for example
  • auxiliaries which preferably influence the surface properties of the microparticles for example flow agents or lubricants.
  • examples include magnesium stearate, calcium stearate, stearic acid, stearyl alcohols, calcium behenate, calcium arachinate, hydrogenated vegetable oils (for example hydrogenated castor oil, hydrogenated cottonseed oil), fatty acid esters, sodium stearyl fumarate, sodium dodecyl sulfate, magnesium dodecyl sulfate, phosphorus lipids, or mixtures of the above-mentioned lipids.
  • Combinations of one or more carrier materials with one or more auxiliary substances which influence the surface properties of the microparticles are also possible.
  • the process for producing the microparticles or inhalation powder according to the invention is characterized in that a solution of the active ingredient (A) or a physiologically tolerable salt thereof is suitably dissolved, sprayed and dried in a spray tower with one or more auxiliaries.
  • the particles / powder can be obtained using a suitable separation process (e.g. cyclone or particle fine filter).
  • the microparticles thus produced are characterized by special values with regard to particle size, specific surface and morphology. It has been found suitable to dissolve the active ingredient in water, an organic solvent or an organic-aqueous solvent mixture with one or more auxiliary substances. In addition to water, organic solvents with a boiling point between 40 ° C.
  • the total amount of solids in solution in conjunction with the spray drying process determines the formation of the solid particles with regard to their particle size and morphology (and thus indirectly their inhalability) and, on the other hand, the relative ratio of the active ingredient to the auxiliary that the active ingredient is independent of a local or long-range order of the active substance molecules homogeneously built into the auxiliary substance, so that the active substance is physically and chemically stabilized by this "framework" of the auxiliary substance.
  • microparticles can be produced that allow a high proportion of active substance.
  • mass ratios between Active ingredient and adjuvant possible from 1:10 to 100: 1. Ratios between 1: 3 to 20: 1 are preferred.
  • micronisates are also conceivable which prefer the adjuvant, for example in the form of a flavor component or an adjuvant influences the surface properties of the microparticle (eg superplasticizer), only in traces (relative active substance: auxiliary composition in a ratio of 50: 1 to 5000: 1, preferably 100: 1 to 1000: 1).
  • the solid concentration of the spray solution is used to make the process economical.
  • the active substance concentration to be set which are predetermined by the fact that the surface properties of the particles, including the particle size, can be optimized by a specific ratio between the droplet size and the solids concentration.
  • a concentration is usually between 1% by weight and 20% by weight, preferably between 2% by weight and 10% by weight, in a very preferred manner between 3% by weight and 8% by weight .-% to choose.
  • Droplet size to be chosen in the process by the parameters X 5 o, of microns in the range of 1 micron to 20, preferably from 1 micron to 8 microns and more preferably from 1 micron to 3 microns, is located, and the characteristic value Q (5.8) , which is between 30% and 100% and preferably between 60% and 100%, is characterized.
  • the inlet temperature of the drying gas should be selected so that in combination with the parameter volume flow "drying gas" and spray rate, the drying process is so gentle that particles with suitable surface properties are created. Particles according to the invention can be obtained by means of this method using the following parameters:
  • Inlet temperature of the drying gas from 100 ° C. to 350 ° C., preferably from 120 ° C. to 250 ° C. and particularly preferably from 130 ° C. to 200 ° C.,
  • a volume flow of the drying gas from 15 Nm 3 / h to 1500 Nm 3 / h, preferably from 15 Nm 3 / h to 150 Nm 3 / h.
  • a second subject of the present invention is thus a process for the production of microparticles in the form of embedding particles containing the active ingredient the CGRP antagonist 1- [ ⁇ / 2 - [3,5-dibromo- ⁇ / - [[4- (3, 4-dihydro-2 (1r ⁇ ) - oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine (A) or a physiologically acceptable salt thereof and one or more adjuvants comprising the steps
  • an inlet temperature of the drying gas from 100 ° C to 350 ° C, preferably from 120 ° C to 250 ° C and particularly preferably from 130 ° C to 200 ° C and
  • a method comprising the steps is preferably used according to the invention.
  • the parameter X 50 is achieved in the range from 1 to 20 ⁇ m, preferably from 1 ⁇ m to 8 ⁇ m, particularly preferably from 1 ⁇ m to 3 ⁇ m,
  • an inlet temperature of the drying gas from 100 ° C. to 350 ° C., preferably from 120 ° C. to 250 ° C. and particularly preferably from 130 ° C. to 200 ° C.,
  • Suitable excipients which can be used in the above-mentioned process are, for example, the carrier materials or those auxiliaries which influence the surface properties of the microparticles, which are already listed under the first subject of the invention.
  • a third object of the present invention is the use of the embedding particles, that is to say microparticles consisting of the active ingredient and one or more auxiliaries, obtainable according to the process described above, for producing a powder inhalant.
  • Measurement method To determine the drop size, the spray cone (spray) of the nozzle is analyzed directly in the laser measuring zone with regard to the drop size distribution.
  • the median value X 5 o means the drop size below which 50% of the drop amount lies.
  • the Q ⁇ 5 . 8 ) - Value describes the percentage of drops that have a size below 5.8 ⁇ m. H 2 O is used as the solution.
  • Measuring device Laser diffraction spectrometer (HELOS) .Fa.
  • Sympatec software WINDOX version 4 dispersing unit: RODOS / dispersing pressure: 3 bar focal length: 100 mm [measuring range: 0.9 175 ⁇ m] evaluation mode: Mie (V 4)
  • Measurement method To determine the particle size, the powder is fed to a laser diffraction spectrometer using a dispersing unit.
  • the median value X 50 means the particle size below which 50% of the particle quantity lies.
  • the Q (5.8) value describes the percentage of particles that are smaller than 5.8 ⁇ m.
  • Measuring device Laser diffraction spectrometer (HELOS), Fa.
  • Sympatec software WINDOX version 4 dispersing unit: RODOS / dispersing pressure: 3 bar focal length: 50 mm [measuring range: 0.9 175 ⁇ m] Evaluation mode: HRLD (V 4)
  • Example 1 Spray parameters, suitable for co-spray drying with lactose from an ethanolic active ingredient solution (modified BÜCHI spray tower):
  • Example 2 Spray parameters, suitable for co-spray drying with mannitol from an ethanolic active ingredient solution (modified BÜCHI spray tower):
  • Example 3 Spray parameters, suitable for co-spray drying with trehalose from an aqueous active ingredient solution (modified BÜCHI spray tower):

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Abstract

Poudre d'inhalation sous forme de microparticules stables, séchées par pulvérisation (particules d'incrustation) pour l'inhalation pulmonaire ou nasale, qui contient l'antagoniste de CGRP 1[N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-pipéridinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-pipérazine (A) ou un sel physiologiquement acceptable dudit composé, ainsi qu'un ou plusieurs adjuvants. La présente invention concerne également des procédés de production desdites microparticules ainsi que leur utilisation pour la préparation d'une substance pulvérulente à inhaler, destinée à traiter les céphalées, la migraine et l'algie vasculaire de la face.
PCT/EP2004/009013 2003-08-18 2004-08-12 Microparticules contenant l'antagoniste de cgrp 1-[n2-[3,5-dibromo-n-[[4-(3,4-dihydro-2(1h)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-d-tyrosyl]-l-lysyl]-4-(4-pyridinyl)-piperazine, procede de production desdites particules ainsi que leur utilisation en tant que poudre d'inhalation Ceased WO2005018609A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP04764017A EP1658051A1 (fr) 2003-08-18 2004-08-12 Microparticules contenant l'antagoniste de cgrp 1-¬n 2 - ¬3,5-dibromo- n-¬¬ 4-(3,4-dihydro-2(1h)-oxoquinazolin-3-yl)-1-piperidinyl|carbonyl|-d-tyrosyl|-l-lysyl|-4-(4-pyridinyl)-piperazine, procede de production desdites particules ainsi que leur utilisation en tant que poudr
CA002536048A CA2536048A1 (fr) 2003-08-18 2004-08-12 Microparticules contenant l'antagoniste de cgrp 1-[n2-[3,5-dibromo-n-[[4-(3,4-dihydro-2(1h)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-d-tyrosyl]-l-lysyl]-4-(4-pyridinyl)-piperazine, procede de production desdites particules ainsi que leur utilisation en tant que poudre d'inhalation
JP2006523577A JP2007502790A (ja) 2003-08-18 2004-08-12 Ｃｇｒｐアンタゴニスト１−〔ｎ２−〔３，５−ジブロモ−ｎ−〔〔４−（３，４−ジヒドロ−２（１ｈ）−オキソキナゾリン−３−イル）−１−ピペリジニル〕カルボニル〕−ｄ−チロシル〕−ｌ−リシル〕−４−（４−ピリジニル）−ピペラジンを含む微粒子、その調製方法及び吸入粉末としてのその使用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10338399A DE10338399A1 (de) 2003-08-18 2003-08-18 Mikropartikel, enthaltend den CGRP-Antagonisten 1-[N2-[3,5-Dibrom-N-[[4-(3,4-dihydro-2(1H)-oxochinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-Iysyl]-4-(4-pyridinyl)-piperazin, Verfahren zu deren Herstellung sowie deren Verwendung als Inhalaltionspulver
DEDE10338399.9 2003-08-18

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WO2005018609A1 true WO2005018609A1 (fr) 2005-03-03

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PCT/EP2004/009013 Ceased WO2005018609A1 (fr) 2003-08-18 2004-08-12 Microparticules contenant l'antagoniste de cgrp 1-[n2-[3,5-dibromo-n-[[4-(3,4-dihydro-2(1h)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-d-tyrosyl]-l-lysyl]-4-(4-pyridinyl)-piperazine, procede de production desdites particules ainsi que leur utilisation en tant que poudre d'inhalation

Country Status (6)

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EP (1) EP1658051A1 (fr)
JP (1) JP2007502790A (fr)
CA (1) CA2536048A1 (fr)
DE (1) DE10338399A1 (fr)
UY (1) UY28474A1 (fr)
WO (1) WO2005018609A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005018603A3 (fr) * 2003-08-18 2005-07-21 Boehringer Ingelheim Int Bibn 4096 amorphe seche par pulverisation, procede de production dudit compose ainsi que son utilisation en tant que substance a inhaler
WO2005018604A3 (fr) * 2003-08-18 2005-07-21 Boehringer Ingelheim Int Nouvelle poudre à inhaler contenant l'antagoniste de cgrp 1-[n2-[3,5-dibromo-n-[[4-(3,4-dihydro-2(1h)-oxoquinazolin-3-yl)-1-pipéridinyl]carbonyl]-d-tyrosyl]-l-lysyl]-4-(4-pyridinyl)-pipérazine
WO2024211881A1 (fr) * 2023-04-06 2024-10-10 Navinta, Llc Suspension de rimégépant
WO2024220974A1 (fr) * 2023-04-21 2024-10-24 Navinta, Llc Films à dissolution rapide de rimégépant pour administration orale

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EP3673895A1 (fr) * 2018-12-28 2020-07-01 Université Libre de Bruxelles Formulation d'inhalateur en poudre sèche et son utilisation pour le traitement thérapeutique des poumons

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DE10139410A1 (de) * 2001-08-17 2003-02-27 Boehringer Ingelheim Pharma Verwendung von BIBN4096 in Kombination mit anderen Arzneistoffen gegen Migräne für die Behandlung von Migräne
WO2003070753A1 (fr) * 2002-02-19 2003-08-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Procede de production d'un inhalant en poudre contenant un sel de l'antagoniste du cgrp bibn4096

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Publication number Priority date Publication date Assignee Title
WO2005018603A3 (fr) * 2003-08-18 2005-07-21 Boehringer Ingelheim Int Bibn 4096 amorphe seche par pulverisation, procede de production dudit compose ainsi que son utilisation en tant que substance a inhaler
WO2005018604A3 (fr) * 2003-08-18 2005-07-21 Boehringer Ingelheim Int Nouvelle poudre à inhaler contenant l'antagoniste de cgrp 1-[n2-[3,5-dibromo-n-[[4-(3,4-dihydro-2(1h)-oxoquinazolin-3-yl)-1-pipéridinyl]carbonyl]-d-tyrosyl]-l-lysyl]-4-(4-pyridinyl)-pipérazine
WO2024211881A1 (fr) * 2023-04-06 2024-10-10 Navinta, Llc Suspension de rimégépant
WO2024220974A1 (fr) * 2023-04-21 2024-10-24 Navinta, Llc Films à dissolution rapide de rimégépant pour administration orale

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CA2536048A1 (fr) 2005-03-03
UY28474A1 (es) 2005-03-31
EP1658051A1 (fr) 2006-05-24
JP2007502790A (ja) 2007-02-15

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