WO2005018609A1 - Microparticles comprising the cgrp antagonist 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 method for production and use thereof as inhalation powder - Google Patents

Abstract

The invention relates to inhalation powders in the form of spray-dried microparticles (embedding particles) for pulmonary or nasal inhalation, comprising the CGRP antagonists 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 (A), or a physiologically-acceptable salt thereof and one or more adjuncts, methods for production of said microparticles and the use thereof for the production of a powder inhalant for the treatment of headaches, migraines and cluster headaches.

Description

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- [Λ / ² - [3 ₎ 5-dibromo-Λ / - [[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.

Background of the Invention

The CGRP antagonist 1- [Λ / ² - [3,5-dibromo-Λ / - [[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:

State of the art

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.

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. On the other hand, physical stability (e.g. aerodynamic particle size, dispersibility, physicochemical properties) of the active ingredient as a critical challenge for the development and manufacture of a powder inhalant.

In the case of the powder inhalation application form, inhalation powders, which are filled, for example, into suitable capsules (inhalettes), are applied to the lungs by means of 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. As an alternative to this, 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.

In the case of powder inhalation, 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.

Inhalation systems are known in the literature in which the active ingredient is in the form of solid particles either as a micronized suspension in a suitable one

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

Basis of the general teaching, as described in DE-A-179 22 07, made.

A critical factor in such multi-component systems is an even distribution of the drug in the powder mixture.

Another important aspect of powder inhalants is that when the active ingredient is inhaled, only particles of a certain aerodynamic size enter the target organ, the lungs. The mean particle size of these respirable particles (inhalable fraction) is in the range of a few micrometers, typically between 0.1 and 10 μm, preferably below 6 μm. 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.

It is known from the literature that particles in the submicron range can be produced by spray drying. Typically, technically manageable formulations are produced from such spray drying particles based on the process cited above (DE-A-179 22 07), which have sufficient dispersibility in medical use (inhalation) [Y.-F. Maa, P.-A. Ngyuyen, JD Andya, N. Dasovich, TD Sweeny, SJ Shire, CC Hsu, Pharmaceutical Research, 15, No. 5 (1998), 768-775; MT Vidgren, PA Vidgren, TP Paronen, Int. J. Pharmaceutics, 35: 139-144 (1987); RW Niven, FD Lott, AY Ip, JM Cribbs, Pharmaceutical Research, 11, No. 8: 1101-1109 (1994)]. The spray drying of pure active substances for inhalation purposes (powder inhalation) is also described in the prior art [eg: EP 0 072 046 A1; WO 2000 000176 A1; US 6019968; A. Chawla, KMG Taylor, JM Newton, MCR Johnson, Int. J. Pharm, 108 (3), (1994), 233-240].

In addition to these examples, there are other manufacturing techniques based on spray drying processes that are primarily presented by pharmaceutical companies and that describe special formulations for powder inhalants. Examples include:

Powder preparations consisting of co-spray-dried β-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. Clark, I Gonda, M Mumenthaler, C. Hsu, Pharm Research, 14 (1997), 431-437]; spray-dried IGF1 preparations for inhalation application [WO 9955362]; Co-spray micronisates from active ingredients and physiologically harmless auxiliary substances [WO 9952506] for inhalation application; Powder preparations containing co-spray microns made from SLPI protein in physiologically harmless carrier materials [WO 9917800]; Co-spray-dried interferon with a carrier material [WO 9531479]; Co-spray microns from an active ingredient and cellulose derivatives [WO 9325198]; Co-spray micronisates, consisting of RhDNase and a physiologically acceptable auxiliary, eg lactose, whereby the primary amorphous auxiliary is converted into crystalline α-lactose monohydrate by a subsequent recrystallization [H.-K. Chan, I. Gonda, J. Pharm. Sci., 87 (5), (1998) 647-654]. In addition, the prior art also discusses special solutions for formulating active ingredients for delayed release thereof, these active ingredients being incorporated into auxiliary matrices on the basis of spray drying technology.

In addition to the solutions given above for formulating active ingredients in powder inhalants based on spray drying technology, it should generally be borne in mind that any change in the solid state of a drug or the active ingredient used, which improves its physical and chemical stability and its technical properties, compared to less stable forms of the same drug gives a significant advantage. Different physical / physicochemical properties may also result in improved pharmacological / pharmacokinetic properties of the drug.

problem

The object of the present invention is to provide a novel, stable formulation for the active ingredient base 1- [Λ / ² - [3,5-dibromo-Λ / - [[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.

Detailed description of the invention

As already mentioned above, the CGRP antagonist 1- [Λ / ² - [3,5-dibromo-Λ / - [[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 In addition to intravenous administration, the best way to achieve a plasma level is via the lungs as the receiving organ.

In the manufacture of an inhalation powder for pulmonary (or nasal) inhalation, the active ingredient (A) or a physiologically acceptable salt thereof physically stable as a solid in a solid matrix of an auxiliary. By appropriate selection of excipients that are compatible with the active ingredient, 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. In addition, 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. In particular, it proves to be advantageous here that 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. Such 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.

Surprisingly, it was found that the active ingredient 1- [Λ / ² _^ [3,5-dibromo-Λ / - [[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. It shows that 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. To produce such 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 μm, and these particles have surface properties such that they can be easily swirled or dispersed.

It was found that the particle morphology including the particle size can be controlled in a targeted manner through the choice of process parameters and manufacturing parameters.

Overall, 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 μm (aerodynamic) using this method is greater than 15%; in some cases even fine fractions of more than 50% are achieved. In addition to this key parameter for inhalants, 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. For the characteristic value Q ₍₅ β _), 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 μm to 10 μm, preferably from 1 μm to 6 μm. 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. Geometrically, 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". Scanning electron microscope, 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- [Λr - [3,5-dibromo-Λ / - [[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

(a) 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,

(b) the characteristic value Q _(5. β) is between 50% and 100% and

(c) the parameter X _{50 is} in the range from 1 μm to 10 μm, preferably from 1 μm to 6 μm.

According to the invention, in addition to the active ingredient base (A), the physiologically tolerable acid addition salts are preferably used, which are selected, for example, from the group consisting of 1- [Λ / ² - [3,5-dibromo-Λ / - [[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, the 1- [Λ / ² - [3,5-dibromo / V - [[4- (3,4-dihydro-2 (1 / - /) - oxoquinazo - lin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine hydrochloride, the sulfate and the hydrobromide are particularly preferred and the 1st - [Λ / ² - [3,5- dibromo-Λ / - [[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyI] carbonyl] -D- tyrosyl] -L-lysyl] -4- (4-pyridinyl) piperazine hydrochloride are very particularly preferred.

As according to the invention 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.

It is also possible to use 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. and 130 ° C., preferably alcohols, are used as solvents according to the invention. According to the invention, ethanol, methanol, propanol, dichloromethane, water or a mixture of these solvents are particularly preferably used. On the one hand, 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. Surprisingly, it has been shown that physically stable microparticles can be produced that allow a high proportion of active substance. There are mass ratios between Active ingredient and adjuvant possible from 1:10 to 100: 1. Ratios between 1: 3 to 20: 1 are preferred. However, 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. However, there are limits to 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.

Technically, this is implemented in which a corresponding commercial nozzle, e.g. B. two-component nozzle, which has these characteristics depending on the applied atomizing pressure and the resulting mass flow of atomizing gas and the spray rate (volume flow "spray solution"). In addition to the special conditions that must be observed in the actual spraying process in order to generate suitable droplets for the drying process, it is shown that the surface properties of the particles can also be influenced positively / specifically by the choice of drying parameters. The decisive parameters that flow into the drying step are the inlet and outlet temperature of the drying gas and its volume flow depending on the spray dryer geometry. The starting temperature must be adjusted for the process so that the powder has a sufficiently low residual solvent content and thus sufficient chemical and physical stability is achieved. This is ideally given if the initial temperature is kept in the boiling temperature range or slightly above it. On the other hand, 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.,

• an outlet temperature of the drying gas of 40 ° C to 120 ° C and

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.

The spraying process is additionally carried out with a volume flow of the spray gas of 1 Nm ³ / h to 15 Nm ³ / h, preferably from 3 Nm ³ / h to 15 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- [Λ / ² - [3,5-dibromo-Λ / - [[4- (3, 4-dihydro-2 (1rτ) - 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

(a) dissolving the active ingredient in water, an organic solvent or an organic-aqueous solvent mixture to produce a solution of the active ingredient with an active ingredient concentration between 1% by weight and 20% by weight, preferably between 2% by weight and 10% by weight .-%, particularly preferably between 3% by weight and 8% by weight,

(b) addition of one or more auxiliary substances in the ratio of active substance: auxiliary substance from 1:10 to 100: 1, preferably from 1: 3 to 20: 1,

(c) spraying the solution thus obtained in the usual way, so that a spray with a droplet size with (i) the characteristic value Q ( ₅ .β) between 50% and 100% and

(ii) the parameters X o ₅ microns in the range of 1 to 20, preferably from 1 micron to 8 microns, more preferably from 1 micron to 3 microns, is achieved, and

(d) drying the spray thus obtained using a drying gas using the following parameters:

(i) 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

(ii) an outlet temperature of the drying gas of 40 ° C to 120 ° C and (e) separating the dried solid particles from the drying gas stream in a conventional manner.

A method comprising the steps is preferably used according to the invention

(a) dissolving the active ingredient in water, an organic solvent or an organic-aqueous solvent mixture to produce a solution of the active ingredient with an active ingredient concentration between 1% by weight and 20% by weight, preferably between 2% by weight and 10% by weight .-%, particularly preferably between 3% by weight and 8% by weight,

(b) addition of one or more auxiliary substances in the ratio of active substance: auxiliary substance from 1:10 to 100: 1, preferably from 1: 3 to 20: 1,

(c) Spraying the solution thus obtained in the usual way, so that a spray with a droplet size

(i) the characteristic value Q ₍₅ .8) between 50% and 100% and

(ii) the parameter X _{50 is achieved} in the range from 1 to 20 μm, preferably from 1 μm to 8 μm, particularly preferably from 1 μm to 3 μm,

(d) drying the spray thus obtained using a drying gas using the following parameters:

(i) 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.,

(ii) an outlet temperature of the drying gas of 40 ° C to 120 ° C, (iii) a volume flow of the spray gas from 1 Nm ³ / h to 15 Nm ³ / h, preferably from 3 Nm ³ / h to 15 Nm ³ / h and

(iv) 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, and

(e) separating the dried solid particles from the drying gas stream in a conventional manner.

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.

Experimental part

(1) Measurement method

a) Determination of the drop size by means of laser diffraction

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 μm. 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 μm] evaluation mode: Mie (V 4)

b) Determination of the particle size by means of laser diffraction

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 μm. 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 μm] Evaluation mode: HRLD (V 4)

(2) Examples

Example 1: Spray parameters, suitable for co-spray drying with lactose from an ethanolic active ingredient solution (modified BÜCHI spray tower):

Beispiel 2: Sprühparameter, geeignet für eine Co-Sprühtrocknung mit Mannitol aus ethanolischer Wirkstofflösung (modifizierter BÜCHI-Sprühturm):

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):

Claims

claims 1. Inhalable powder for pulmonary or nasal inhalation use, comprising as active ingredient the CGRP antagonist 1 - [/ V ² - [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 H) -oxoquinazolin-3-yl) -1 -piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine

or a physiologically compatible salt thereof and one or more auxiliary substances in the form of spherically nanostructured microparticles, characterized in that (a) 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, (b) the characteristic value Q ( ₅ .β) is between 50% and 100% and (c) the parameter X _{50 is} in the range from 1 μm to 10 μm, preferably from 1 μm to 6 μm. 2. Inhalable powder according to claim 1, characterized in that the physiologically acceptable salt is selected from the group consisting of 1- [Λ / ² - [3,5-dibromo-Λ / - [[4- (3,4-dihydro- 2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D- tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine hydrochloride, sulfate, phosphate, hydrobro mid, carbonate, methanesulfonate, p-toluenesulfonate, nitrate, citrate, malate, tratate, Lactate, succinate, gluconate, acetate, formate, propionate, capronate, oxalate, maleate, fumarate, mandelate and hydroxysuccinate. 3. Inhalable powder according to claim 1, characterized in that the physiologically acceptable salt is selected from the group consisting of 1- [Λ / ² - [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 / - /) - oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D- tyrosyl] -L- lysyl] -4- (4-pyridinyl) piperazine hydrochloride, sulfate and hydrobromide. 4. Inhalable powder according to claim 1, characterized in that the physiologically acceptable salt is 1- [Λ / ² - [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 -) - oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) piperazine hydrochloride. 5. Inhalable powder according to claim 1, characterized in that the excipient or excipients are selected from the group consisting of inactive Polysaccharides, polylactide / glycolide, disaccharides, monosaccharides, polyalcohols, amino acids, chitosan and mixtures of these auxiliaries, the active ingredient: excipient mass ratio being 1:10 to 100: 1, preferably 1: 3 to 20: 1. 6. inhalation powder according to claim 1, characterized in that the excipient or excipients are selected from the group consisting of maltodextrin, starch, cellulose, dextrans, Resomer ^® , trehalose, lactose, maltose, sucrose, fructose, glucose, mannitol, sorbitol, arginine hydrochloride , Chitosan and mixtures of these auxiliaries, the mass ratio of active ingredient: excipient being 1:10 to 100: 1, preferably 1: 3 to 20: 1. 7. Inhalable powder according to claim 1, characterized in that the excipient or excipients are selected from the group consisting of trehalose, lactose, polylactide λ-glycolide, sucrose, maltodextrin, dextrans and mannitol, the mass ratio of active ingredient: excipient 1:10 to 100: 1, preferably 1: 3 to 20: 1. 8. inhalation powder according to claim 1, characterized in that the excipient or excipients are selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, stearyl alcohols, calcium behenate, calcium arachinate, hydrogenated castor oil, hydrogenated cottonseed oil, fatty acid esters, sodium stearyl fumarate, sodium dodecyl sulfate, magnesium dodecyl sulfate, phosphorus lipids and mixtures of these auxiliaries, the mass ratio of active ingredient: excipient being 50: 1 to 5000: 1, preferably 100: 1 to 1000: 1. 9. Process for the preparation of microparticles in the form of embedding particles, containing the active ingredient the CGRP antagonist 1- [Λ / ² - [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 - /) - 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 Excipients, including the steps (a) dissolving the active ingredient in water, an organic solvent or an organic-aqueous solvent mixture to produce a solution of the active ingredient with an active ingredient concentration between 1% by weight and 20% by weight, preferably between 2% by weight and 10% by weight .-%, particularly preferably between 3% by weight and 8% by weight, (b) addition of one or more auxiliary substances in the ratio of active substance: auxiliary substance from 1:10 to 100: 1, preferably from 1: 3 to 20: 1, (c) Spraying the solution thus obtained in the usual way, so that a spray with a droplet size (i) the characteristic value

between 50% and 100% and (ii) the parameter X _{50 is achieved} in the range from 1 μm to 20 μm, preferably from 1 μm to 8 μm, particularly preferably from 1 μm to 3 μm, (d) drying the spray thus obtained using a drying gas using the following parameters: (i) 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 (ii) an outlet temperature of the drying gas of 40 ° C to 120 ° C and (e) separating the dried solid particles from the drying gas stream in a conventional manner. 10. The method according to claim 9, comprising the steps (a) dissolving the active ingredient in water, an organic solvent or an organic-aqueous solvent mixture to produce a solution of the active ingredient with an active ingredient concentration between 1% by weight and 20% by weight, preferably between 2% by weight and 10% by weight .-%, particularly preferably between 3% by weight and 8% by weight, (b) addition of one or more auxiliary substances in the ratio of active substance: auxiliary substance from 1:10 to 100: 1, preferably from 1: 3 to 20: 1, (c) Spraying the solution thus obtained in the usual way, so that a spray with a droplet size with (i) the characteristic value Q < ₅ β) between 50% and 100% and (ii) the parameter X _{50 is achieved} in the range from 1 μm to 20 μm, preferably from 1 μm to 8 μm, particularly preferably from 1 μm to 3 μm, (d) drying the spray thus obtained using a drying gas using the following parameters: (ii) 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, (ii) an outlet temperature of the drying gas from 40 ° C to 120 ° C, (iii) a volume flow of the spray gas of 1 Nm ³ / h to 15 Nm ³ / h and (iv) 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, and (e) separating the dried solid particles from the drying gas stream in a conventional manner. 11. The method according to claim 9, characterized in that water or alcohol-water mixtures, preferably ethanol-water mixtures or water-dichloromethane mixtures are used as solvents. 12. Use of the embedding particles, obtainable according to one of claims 9 or 10, for the preparation of a powder inhalant.