JP2007502791A - 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 - Google Patents

Abstract

The present invention relates to a CGRP antagonist 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 (A), or a pharmaceutically acceptable salt thereof, a powder formulation for pulmonary or nasal inhalation, a process for its production and a headache, It relates to its use for the manufacture of a medicament for the treatment of migraine and cluster headache.
[Chemical 1]

Description

The present invention relates to a CGRP antagonist 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 (A) or a pharmaceutically acceptable salt thereof, powder formulations for pulmonary or nasal inhalation, methods for their preparation and headache, It relates to their use for preparing pharmaceutical compositions for the treatment of migraine and cluster headache.

CGRP antagonist 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 (A) is known from international patent application PCT / EP97 / 04862 (published as WO 98/11128) and has the following structure:

Have
Prior art Active substance base (A) is a highly effective CGRP antagonist for the sudden treatment and prevention treatment of headaches, especially migraine and cluster headaches, which cannot be administered orally using conventional formulations. Because the substance has a very limited oral bioavailability.
In order to treat sudden attacks of migraine, it is essential that the active substance be available systemically as quickly as possible. The treatment should not be complicated for the patient to administer, and other conditions that can affect bioavailability (eg, food effects) should not limit the use of the drug for the patient.
Active substances that are intended to be systemically available are usually administered by the oral route. If this route is unsuitable or undesired due to the particular nature of the active substance or the special demands made on the application, other possible ways of systemically administering the substance are known in the art. For example, inhalation where active substances can be administered locally as well as systemically has been considered at some time. Powder inhalation is an option for substances that have proved critical due to their degradation in solution or that themselves have insufficient solubility. The absolute amount of active substance to be administered per application creates special requirements for the formulation. On the other hand, it has been found that the physical stability (eg aerodynamic particle size, dispersibility, physicochemical properties) of the active substance is an important requirement for the development and production of inhalable powders.
In powder inhaler type formulations, inhalable powders, which are packed, for example, in suitable capsules (inhalettes), are delivered to the lungs by a powder inhaler. Similarly, other systems (eg, blisters) and multidose powder systems in which the amount of powder to be administered is pre-dosed are also known. The drug may also be inhaled, for example, by use of a suitable powdered inhalation aerosol suspended in HFA134a, HFA227 or mixtures thereof as propellant gas.
In powder inhalation, fine particles of the pure active substance are administered by the inhalation method, for example, through the respiratory tract to the surface of the lung in the alveoli. These particles settle on the surface and can only be absorbed into the body after the lysis process by an active and passive transport process.
Inhalation systems are known in the literature, where the active substance is present in the form of solid particles as a finely divided suspension or in the form of a dry powder in a suitable solvent system as a carrier. Usually, powder inhalants, for example in the form of capsules for inhalation, are prepared on the basis of general teachings as described in DE-A-1792207. An important factor of this kind of multi-material system is the uniform distribution of the pharmaceutical composition in the powder mixture.

Another problem with powder inhalants is that when the active substance is administered by inhalation, only certain aerodynamic size particles reach the target organ, the lung. The average size of these lung-bound particles (inhalation fraction) is in the range of a few microns, typically 0.1 to 10 μm, preferably less than 6 μm. Such particles are usually produced by fine grinding (air jet grinding).
When finely divided formulations and excipients with special properties (carrier substances) are used, the preparations are only suitable for use as inhalation powders containing active substances, the ratio of active substance to excipient being Within a certain range, a certain amount of powder is available for its application. In addition, special climatic conditions need to be adhered to during the manufacture of the pharmaceutical composition.
In view of these basic technical requirements, the problem is that the active substance base 1- [N ^2- [3,5-dibromo-N-[[4- (3,4-dihydro-2 (1H) -oxoquinazoline- Solutions according to the special properties of 3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine (A) and its physiologically acceptable salts (it The substance can be made fully bioavailable in the form of a powder inhalant).

The present invention relates to a CGRP antagonist 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, or a physiologically acceptable salt thereof, to provide a novel and stable formulation, thereby being used biologically orally It is possible to produce adequate systemic blood levels for those substances that cannot. Similarly, the invention also includes methods for preparing such formulations and their use for preparing pharmaceutical compositions.
Active substance base 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 (A) as well as its physiologically acceptable salts are physically stable in the form of a powder mixture with excipients, Or it has been found that it can be made fully bioavailable by nasal inhalation.

Surprisingly, the finely divided active substance 1- [N ^2- [3,5-dibromo-N-[[4- (3,4-dihydro-2 (1H) -oxoquinazoline] present in amorphous form -3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine (A), or a physiologically acceptable salt thereof, is physiologically acceptable, homogeneous Were found to be physically stable in the formulation of powder mixtures with various excipients. The powder formulations described here allow the powder to be dispersed during inhalation and make the active substance available for systemic administration by taking it in this manner. It is known that the amorphous state of a solid is thermodynamically unstable. In particular, this contributes to the fact that microparticles having amorphous parts or purely amorphous are metastable in their physicochemical properties. Typically, amorphous or partially amorphous pharmaceutically active substances and excipients, such as sugars, spontaneously recrystallize during storage under normal conditions. The process may be accelerated by an increase in relative humidity and possibly temperature. In connection with this recrystallization, the particles change their surface properties, their particle morphology and their particle size.
Surprisingly, the amorphous active substance 1- [N ^2- [3,5-dibromo-N-[[4- (3,4-dihydro--) in the form of amorphous finely divided particles prepared therefrom. 2 (1H) -Oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine (A) (X-ray crystallography / X-ray It has been found that (detected by powder diffraction) can be used to prepare stable inhalation powders. The amorphous form of the active substance is maintained over the shelf life of the drug.
According to the invention, in addition to the active substance base, for example, 1- [N ^2- [3,5-dibromo-N-[[4- (3,4-dihydro-2 (1H) -oxoquinazoline- 3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine hydrochloride, sulfate, phosphate, hydrobromide, carbonate, Methanesulfonate, p-toluenesulfonate, nitrate, citrate, malate, tartrate, lactate, succinate, gluconate, acetate, formate, propionate, caproate, An acid addition salt selected from oxalate, maleate, fumarate, mandelate and hydroxysuccinate is used, and 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 hydrochloride, Sulfuric acid Salts and hydrobromides are particularly preferred, 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 hydrochloride is particularly most preferred.

The formulations described here have a particle size X _{50 in} the range of 1 μm to 6 μm, preferably 1 μm to 3.5 μm, and at least 60% (by volume) to ensure the high active substance content of the invention. of Q _(5.8) <finely ground active substance with part of 5.8μm grain 1- [N ² - [3,5-dibromo -N - [[4- (3,4-dihydro -2 (IH ) -Oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine (A) and 1: 9 Designed to be mixed in a ratio of ~ 5: 1.
The median value X ₅₀ means the particle size that contains 50% of the amount of particles. The Q _(5.8) value describes the percentage of particles that are less than 5.8 μm in size.
In order to prepare dosages in which the dispersibility of the inhaled powder is sufficiently guaranteed for each inhalation, the finely divided active substance may be combined with coarser excipients (eg lactose) in the above ratios all right.
Such powder formulations are administered in an amount of 25 mg to 100 mg, preferably 50 mg per application by inhalation. During use, it is also possible to obtain therapeutic blood levels by multiple doses.
Thus, in a first aspect, the present invention provides a CGRP antagonist 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 (A) or physiologically acceptable salts and inertness thereof An inhalation powder for administration by pulmonary or nasal inhalation, comprising a uniform excipient,
(a) the parameter X ₅₀ relating to the particle size of the active substance is in the range from 1 μm to 6 μm, preferably from 1 μm to 3.5 μm, and
(b) relates to an inhalable powder, characterized in that the characteristic value Q _(5.8 ) for the active substance is at least 60%.

Conventional carrier materials or flowable adjuvants may be used as physiologically acceptable homogeneous excipients according to the present invention. Common carrier materials are monosaccharides (eg glucose or arabinose), disaccharides (eg lactose, saccharose, maltose, trehalose), oligosaccharides and polysaccharides (eg dextran, starch, cellulose derivatives), polyalcohols (eg Mannitol, sorbitol, xylitol), salts (eg sodium chloride, calcium carbonate), polylactide, polyglycolide and mixtures of these excipients. Flowable adjuvants include, for example, magnesium stearate, calcium stearate, stearic acid, stearyl alcohol, calcium behenate, calcium arachidnate, hydrogenated vegetable oils such as hydrogenated castor oil or hydrogenated cottonseed oil, fatty acid esters, sodium stearyl fumarate , Sodium dodecyl sulfate, magnesium dodecyl sulfate and mixtures of these fluid adjuvants.
The inhalable powders of the present invention can be used, for example, with an inhaler that dispenses a single dose from a reservoir by means of a measuring chamber (eg as described in US Pat. No. 4,706,630A) or other devices (eg as described in DE3625685A). It may be administered using. However, the inhalable powders according to the invention are preferably packaged in capsules (to form so-called inhalettes), which are used, for example, in inhalers as described in WO 94/28958.

The inhalable powder of the present invention may be obtained by the method described below.
Since not only the active substance base (A) but also its salts are hygroscopic, special ambient conditions need to be maintained when weighing these substances.
After suitable comminution of the active substance, it is conditioned at a specific temperature and humidity, and in this way an equilibrium is obtained between the water content of the active substance and the relative humidity of the environment. The conditioned active substance is then suitably mixed with one or more excipients, and the resulting powder mixture to be administered takes into account the water content (modified weight) of the active substance obtained according to these conditions And packed in a single dose under specific climatic conditions (temperature and humidity). The mixture is packed into inhalettes, which are subsequently used in an inhaler suitable for this purpose. Subsequently, following preparation of the inhaled powder, powder-filled capsules are manufactured and these should be placed in their final packaging (blister bag) in a suitable manner.
Thus, in the second aspect, the present invention
(a) pulverizing the active substance,
(b) Conditioning the finely divided active substance,
(c) suitably mixed with one or more excipients of the invention, and
(d) relates to a method for preparing a powder inhalant according to the invention, characterized in that the amount of the powder mixture to be administered is packed in inhalettes as a single dose under specified climatic conditions.

The powder mixture of the present invention may be inhaled and preferably the powder is given to the patient in the form of a pre-metered pharmaceutical formulation. An example of this is an inhalation capsule system. Also possible are systems where the powder formulation is given in a single dosage form, for example, returned to the wells in a blister pack. The powder formulations described herein may be inhaled using a suitable device and thus delivered to the lungs.
Inhalable powders containing substances that can be produced from such formulations are the active substance base 1- [N ^2- [3,5-dibromo-N-[[4- (3,4-dihydro-2 (1H) -oxoquinazoline] -3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine (A) or its physiologically acceptable salts are suitable for lung penetration It has a particle size characterized by being in the form of sized microparticles. At the same time, powder mixtures such as may be obtained according to the description of this formulation are found to be sufficiently easy to process with respect to their agglomeration and produce pharmaceutical compositions reproducibly. Thus, on the one hand, during the dispersion of the powder during the course of the inhalation process by the patient, the amorphous active substance has an aerodynamic particle size that results in the precipitation of the active substance in the lung after nasal or lung inhalation, It is possible to design a powder formulation for use in pulmonary (and optionally nasal) inhalation so that the powder (consisting of finely divided active substance and carrier substance) is designed to be suitable for mechanical processing. is there. For this administration of the active substance by nasal or pulmonary inhalation in the lung, which is obtained using this technique, the active substance has sufficient systemic bioavailability.
Surprisingly, the active substance base 1- [N ^2- [3,5-dibromo-N-[[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] A pulverized formulation of carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine (A), which may be prepared by known methods such as, for example, air jet milling It has also been found to be suitable only if it has special properties with respect to the specific surface area of (A) relative to the surface area of the inert excipient of the formulation, in addition to the above conditions for particle size. Based on the total amount of powder available per application in each case, the quotient of the specific surface area of the finely divided formulation (A) to the specific surface area of the inert excipient is greater than 0.05, preferably greater than 0.1. It can be seen that the formulation is particularly suitable if it is large, particularly preferably greater than 0.5, most particularly preferably greater than 0.7 and in each case less than 22, preferably less than 15.
Air jet milled 1- [N ^2- [3,5-dibromo-N-[[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] In addition to the use of -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine (A), the pulverization of (A) present in the particle size described above, produced by another method It is also preferred to use prepared formulations. Thus, such formulations may also be prepared using, for example, a finely divided formulation of the active substance (A) or a physiologically acceptable salt thereof, Despite being obtained as a component system or in the form of spray particles consisting of the active substance and one or more excipients, they are prepared by spray drying.

Powder formulations consisting of ingredients that meet the above requirements regarding the particle size of the active substance and the ratio of the specific surface area of the active substance to the excipient are processed by methods known to produce a homogeneous powder mixture and encapsulated by known methods Or packed into other systems for pre-medication. However, such a manufacturing process is only successful if the powder is handled under strict climate control. For successful manufacturing, the bandwidth at which the maximum temperature difference and relative humidity should vary during a particular manufacturing process is important. This is because the active substance of the present invention is strongly hygroscopic. Ideally, the temperature should differ by ± 5 ° C. on either side of the freely chosen mean, preferably ± 3 ° C. or less, and the humidity should be ± 15%, preferably ±±, on both sides of the freely chosen mean. Should vary by less than 10%. Adjustment of the amount of active substance to be weighed (weight correction) should be made after adjusting the balance between the relative humidity of the environment and the water content of the active substance, depending on the hygroscopicity of the active substance.
In a third aspect, the present invention relates to the use of the inhaled powder of the invention as a pharmaceutical composition, in particular for preparing a pharmaceutical composition for the treatment of headache, migraine or cluster headache.
In a fourth aspect, the present invention relates to the use of the inhalable powder of the present invention for preparing a capsule (inhalet). Such capsules (Inhallet) are characterized by a content of 2-50 mg of the inhalable powder according to the invention.

Experimental part
1) Measurement method
a) Measurement of particle size by laser diffraction (Frauen-Hoffer diffraction) Measurement method: To measure the particle size, the powder is supplied to a laser diffraction spectrophotometer using a dispersion unit. Median X ₅₀ represents a particle size enter 50% of the amount of the particles. The Q _(5.8) value describes the percentage of particles that are less than 5.8 μm in size.
Measuring device: Sympatec Laser Diffraction Spectrophotometer (HELOS)
Software: WINDOX version 3.3 / REL 1
Dispersion unit: RODOS / Dispersion pressure: 3 bar Focal length: 100mm [Measuring range: 0.9 ..... 175μm]
Evaluation method: HRLD (V 3.3 Rel. 1)
b) Measurement method for specific surface area : The specific surface area is measured by exposing a powder sample to a nitrogen atmosphere at different pressures. Cooling the sample causes nitrogen molecules to condense on the particle surface. The amount of condensed nitrogen is measured by the pressure drop in the system and the surface of the sample is calculated by the surface nitrogen demand and the weight of the sample.
Measuring equipment: Tri-Star Multi-Point BET manufactured by Micromeritics
Heating station: VacPrep 061 manufactured by Micromeritics
Heating: about 12 hours / 40 ° C

Analysis parameters Sample tube: 1.27cm (1/2 inch) with filter rod Analysis method: 10-point BET surface measurement
0.1 ~ 0.20 p / p0
Absolute pressure tolerance: 6.67hPa (5.0 mm Hg)
Relative pressure tolerance: 5.0%
Pumping speed: 66.67 hPa / s (50.0 mm Hg / s)
Exhaust threshold: 13.33 hPa (10.0 mm Hg)
Exhaust time: 0.1 hours Free space: Low dewar, t: 0.5 hours Retention time: 20 seconds Minimum equilibrium delay: 600 seconds Adsorption: Nitrogen

2) Example
a) 50 g of (anhydrous) air jet milled active substance with a specific surface area of 20.2 m ² / g is conditioned for 8 hours at 25 ° C. and 45% relative humidity, with a specific surface area of 0.96 m ² / g Mix with 450 g of Toose (registered trademark) 200M (manufactured by Danone) (sieving for each layer, Turbula mixer). The mixture is transferred to a single capsule under the same ambient conditions as starting material preparation and mixing of the individual components. A filling of 20.12 mg of the powder mixture having the above composition corresponds to a content of 2 mg of finely divided active substance (anhydrous) per capsule.
b) 100 g of (anhydrous) air-jet milled active substance with a specific surface area of 20.2 m ² / g is conditioned for 8 hours at 25 ° C. and 45% relative humidity, with a specific surface area of 0.25 m ² / g Mix with 200 g of Tose (registered trademark) 325M (manufactured by DMV) (sieving for each layer, Turbula mixer). The mixture is transferred to a single capsule under the same ambient conditions as starting material preparation and mixing of the individual components. Filling 48.96 mg of powder mixture having the above composition corresponds to a content of finely divided active substance (anhydrous) of 16 mg per capsule.

c) ²⁰⁰ g of (anhydrous) spray-dried active substance with a specific surface area of 7.8 m ² / g are conditioned for 8 hours at 25 ° C. and 30% relative humidity, and a lactochem with a specific surface area of 0.75 m ² / g ( (Registered trademark) Super fine powder (Bokuro) 200g is mixed (sieving by layer, Turbula mixer). The mixture is transferred to a single capsule under the same ambient conditions as starting material preparation and mixing of the individual components. A filling of 51 mg of powder mixture having the above composition corresponds to a content of 25 mg of finely divided active substance (anhydrous) per capsule.
d) 400 g (anhydrous) spray-dried active substance with a specific surface area of 1.4 m ² / g are conditioned for 8 hours at 25 ° C. and 30% relative humidity and with a specific surface area of 0.96 m ² / g (Registered trademark) 200M (manufactured by Danone) is mixed with 100 g (screened for each layer, Turbula mixer). The mixture is transferred to a single capsule under the same ambient conditions as starting material preparation and mixing of the individual components. A filling of 51.6 mg of a powder mixture having the above composition corresponds to a content of finely divided active substance (anhydrous) of 40 mg per capsule.

Claims (18)

CGRP antagonist 1- [N ^2- [3,5-dibromo-N-[[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl as active substance ] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine

Or an inhalable powder for administration by pulmonary or nasal inhalation comprising a physiologically acceptable salt thereof and an inert, homogeneous excipient,
(a) the parameter X ₅₀ relating to the particle size of the active substance is in the range from 1 μm to 6 μm, preferably from 1 μm to 3.5 μm, and
(b) An inhalable powder characterized by a characteristic value Q _(5.8 ) for the active substance of at least 60%. Active substance base 1- [N ^2- [3,5-dibromo-N-[[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D 2. Inhalable powder according to claim 1, characterized in that -tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine (A) is present in the form of an amorphous finely divided preparation. The physiologically acceptable salt is 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 hydrochloride, sulfate, phosphate, hydrobromide, carbonate, methanesulfonate, p-toluenesulfonic acid Salt, nitrate, citrate, malate, tartrate, lactate, succinate, gluconate, acetate, formate, propionate, caproate, oxalate, maleate, fumaric acid 2. Inhalable powder according to claim 1, characterized in that it is selected from among salts, mandelate and hydroxysuccinate. The physiologically acceptable salt is 1- [N ^2- [3,5-dibromo-N-[[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] Inhalable powder according to claim 1, characterized in that it is selected from among:] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine hydrochloride, sulphate and hydrobromide . The physiologically acceptable salt is 1- [N ^2- [3,5-dibromo-N-[[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] Inhalation according to claim 1, characterized in that it is a non-crystalline finely divided preparation which is] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine hydrochloride Powder.   2. The excipient used is a monosaccharide, disaccharide, oligosaccharide and polysaccharide, polyalcohol, salt, polylactide, polyglycolide or a mixture of these excipients with one another. Inhalation powder.   The excipients used are glucose, arabinose, lactose or saccharose, maltose, trehalose, dextran, starch, cellulose derivatives, mannitol, sorbitol, xylitol, sodium chloride, calcium carbonate, polylactide, polyglycolide or each other of these excipients. 7. Inhalable powder according to claim 6, characterized in that it is a mixture of   Inhalable powder according to claim 1, characterized in that a flowable adjuvant is used as an excipient.   The flowable adjuvant used is magnesium stearate, calcium stearate, stearic acid, stearyl alcohol, calcium behenate, calcium arachidate, hydrogenated vegetable oil, fatty acid ester, sodium stearyl fumarate, sodium dodecyl sulfate, magnesium dodecyl sulfate or these 9. Inhalable powder according to claim 8, characterized in that it is a mixture of flowable adjuvants.   Inhalation powder according to claim 1, characterized in that the ratio of active substance to excipient is from 1: 9 to 5: 1.   The quotient of the specific surface area of the active substance versus the specific surface area of the inert excipient, in each case based on the total amount of powder available per application, is greater than 0.05, preferably greater than 0.1, particularly preferably greater than 0.5. Inhalable powder according to claim 1, characterized in that it is large, most particularly preferably greater than 0.7 and less than 22, preferably less than 15. (a) pulverizing the active substance,
(b) Conditioning the finely divided active substance,
(c) suitably mixed with one or more excipients of the invention, and
12. Inhalation powder preparation according to one of claims 1 to 11, characterized in that (d) the dose of the powder mixture thus obtained is packed in inhalettes in a single dose under specified ambient climatic conditions Method.   12. Inhalable powder according to any one of claims 1 to 11, obtained according to claim 12.   Use of the inhalable powder according to any one of claims 1 to 11 or claim 13 as a pharmaceutical composition.   Use of the inhalable powder according to any one of claims 1 to 11 or claim 13 for the preparation of a pharmaceutical composition for the treatment of headache, migraine or cluster headache.   Use of an inhalable powder according to any one of claims 1 to 11 or claim 13 for the preparation of capsules (inhalettes).   Capsule (Inhalet) characterized by comprising a filling of 2 mg to 50 mg of inhalable powder according to any one of claims 1 to 11. 1- [N ^2- [3,5-Dibromo-N-[[4- (3,4-Dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] [18] Capsule (Inhalet) according to claim 17, characterized in that it contains 2 mg to 50 mg of -L-lysyl] -4- (4-pyridinyl) -piperazine (A).