EP1663149A2

EP1663149A2 - Spray-dried amorphous bibn 4096 method for production and use thereof as inhalant

Info

Publication number: EP1663149A2
Application number: EP04764016A
Authority: EP
Inventors: Michael Trunk; Claudius Weiler
Original assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim Pharma GmbH and Co KG
Current assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2003-08-18
Filing date: 2004-08-12
Publication date: 2006-06-07
Also published as: WO2005018603A2; JP2007502789A; DE10338402A1; WO2005018603A3; CA2536047A1

Abstract

The invention relates to 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 (A), or the physiologically-acceptable salts thereof, which are stable in the amorphous state under normal conditions (T < 50 °C, relative humidity < 75%) in the form of microparticles, methods for production of microparticles of said substances and the use of said microparticles for the production of a medicament in the application form of a powder inhalant for pulmonary and nasal inhalation, in particular, for the production of a medicament for the treatment of headaches, migraines and cluster headaches.

Description

Spray-dried, amorphous BIBN 4096, process for its preparation and its use as an inhalative

The invention relates to the CGRP antagonist 1 - [/ V 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) and its physiologically tolerable salts, which in the amorphous state under normal conditions (T <50 ° C, relative humidity <75% ) are stable and in the form of microparticles, processes for the production of such microparticles from these substances and the use of these particles for the production of a medicament of the application form powder inhalant for pulmonary and nasal inhalation, in particular for the production of a medicament for the treatment of headaches, migraines and cluster headache.

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

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, the application of which is not possible by oral route using classic dosage forms, since the substance has only 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 are to be available systemically are usually made available by oral administration. If this route cannot be implemented or is desired due to special properties of the active ingredient or special requirements for the application, various other options for the systemic administration of substances are known in the prior art. For example, the inhalation route has been discussed for some time, by means of which active ingredients can also be made systemically available in addition to topical applications. Powder inhalation lends itself to substances that are critical due to their decomposition behavior in solution or have poor solubility per se. The absolute amount of the active ingredient that has to be administered in one application represents a particular challenge for the formulation. On the other hand, the physical stability (eg aerodynamic particle size, dispersibility, physicochemical properties) of the active ingredient also proves to be a critical challenge for development and manufacture 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 pre-metered (eg 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 only be absorbed by active and passive transport processes in the body after the dissolution process. Inhalation systems are known in the literature in which the active ingredient is present in the form of solid particles either as a micronized suspension in a suitable solvent system as a carrier or in the form of a dry powder. Powder inhalants, for example in the form of capsules for inhalation, are usually produced on the basis of the general teaching as described in DE-A-179 22 07. A critical factor in such multi-component systems is an even distribution of the drug in the powder mixture.

The active pharmaceutical ingredient used to manufacture the above-mentioned medicinal products should be as pure as possible and its stability during long-term storage must be guaranteed under various environmental conditions. This is imperative in order to prevent pharmaceutical compositions from being used which, in addition to the actual active ingredient, contain, for example, degradation products thereof.

In addition to the requirements stated above regarding chemical stability of the active ingredient, it should generally be taken into account that any change in the solid state of a drug or the active ingredient used, which improves its physical and chemical stability, results in a considerable advantage over less stable forms of the same drug. Different physical / physicochemical properties may, however, also bring about improved pharmacological / pharmacokinetic properties of the drug. In particular, depending on the dosage form, special morphological properties of solid particles can be advantageous for the production of a medicament.

It is known from the literature that particles in the submicron range can be produced by spray drying. Formulations which are technically manageable and which have sufficient dispersibility in medical use (inhalation) are usually prepared from such spray drying particles based on the process cited above (DE-A-179 22 07) [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)]. It is also known from the literature that so-called "large porous particles" are accessible by means of special processes, which have proven particularly suitable in their use for powder inhalants (DA Edwards, J. Hanes, G. Caponetti, J. Hrkach, A. Ben-Jebria, ML Eskew, J. Mintzes, D. Deaver, N. Lotan, R. Langer, Science, 276 (1997) 1868-1871) in which particles with an average geometric size of more than 5 μm (for example 8.5 μm to 20 μm) understood, but behave aerodynamically like particles that are smaller than 5 μm, whereby these powders are also characterized by an extremely low density (<0.4 g / cm ³ ).

problem

The complex object of the present invention was therefore primarily to provide novel, stable microparticles of the active ingredient base l-IISp-ß.δ- dibromo-Λ / - [[4- (3,4-dihydro-2 (1H) -oxoquinazoline- 3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine (A) and its physiologically tolerable salts which meet the above-mentioned high requirements for a Active pharmaceutical ingredients for a powder inhalative for pulmonary and nasal inhalation are sufficient and, compared to the conventional micronized starting material (obtainable, for example, by means of air jet grinding), have proven to be suitable in their use as powder inhalants with regard to their pharmacological / pharmacokinetic properties. According to the invention, the morphology of the microparticles was to be optimized in such a way that the formulation consisting of them preferably does not contain any auxiliaries and thus consists exclusively of the active ingredient.

The formulation according to the invention should furthermore show a rapid onset of action for the treatment of the acute pain states which occur very suddenly in the case of migraines. This means that a rapid absorption of the active ingredient and a rapid rise in the plasma level must be guaranteed.

Detailed description of the invention

A rapid onset of action for the treatment of acute pain and a high plasma level of the CGRP antagonist 1 - [/ V ² - [3,5-dibromo-A / - [[4- (3,4- dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine (A) and its physiologically tolerable salts within a very short time Time can best be realized via the lungs as the location. It has been found that when the active ingredient (A) is given by inhalation in the form of a powder inhalative, a bioavailability of about 60% based on the fine fraction of the formulation (corresponds to FPD Jine particle dose ", determined according to USP 24 Suppl. 2000) can be achieved.

The present invention therefore consists in providing novel, stable microparticles of the CGRP antagonist 1- [[/ ² - [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1H) - oxoquinazoline -3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine (A) and its physiologically tolerable salts, which are surprisingly special for the preparation of powder inhalants are suitable for pulmonary and nasal inhalation. They are characterized by special physical and physicochemical properties that lead to an improved pharmacological and pharmacokinetic effect in the inhaled use of the substance. It is surprising that by varying / optimizing the particle shape of these particles with a large specific surface area, the aerodynamic properties and the increase in dispersibility and inhalability could be improved. The invention likewise encompasses the basic procedure for the production of such microparticles and their use for the production of medicaments in the dosage form of a powder inhalant.

According to the invention, in addition to the active substance base, the corresponding physiologically compatible acid addition salts are used, which are selected, for example, from the group consisting of 1- [Λ / ² - [3,5-dibromo-Λ / - [[4- (3,4-dihydro- 2 (1 / - /) - oxochirιazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine hydrochloride, sulfate, phosphate, Hydrobromide, carbonate, methanesulfonate, p-toluenesulfonate, nitrate, citrate, malate, tatrat, lactate, succinate, gluconate, acetate, formate, propionate, capronate, oxalate, -Maleate, -Fumarate, -Mandelate and -Hydroxysuccinat, whereby the 1- [Λ / ² - [3,5-Dibrom- / V - [[4- (3,4-dihydro- 2 (1 / - /) - oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) - piperazine hydrochloride, the sulfate and the hydrobromide are preferred and the 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 in addition to the free active ingredient base are particularly preferred.

Particle geometries of the microparticles, which can be described as collapsed hollow spheres and have a wrinkle-like structure, were found to be advantageous. Geometrically, particles that are produced by the processes described below have particle shapes which, depending on the test conditions, are described between the extremes "spherical shell fragment", "thin-walled, completely collapsed sphere", "fold-like, filigree-flaky plate structure", and "rosette-like fold structure" can.

These particles are characterized in that

(a) they have a specific surface area between 3 m ² / g and 35 m ² / g, preferably between 5 m ² / g and 30 m ² / g and particularly preferably between 10 m ² / g and 30 m ² / g

(b) the characteristic value between 50% and 100% and

(c) the parameter X _{50 is} in the range from 0.5 μm to 10 μm, preferably from 0.5 μm to 6 μm.

The wrinkle-like microparticles according to the invention are suitable for the production of powder inhalants for pulmonary and nasal inhalation, with no further auxiliaries or additives (carrier materials) being required in order to obtain a technically manageable powder which can be further processed directly and which has excellent properties with regard to dispersibility and is sufficiently easy to process with regard to its cohesive properties.

A first object of the present invention is thus a powder inhalative for pulmonary and nasal inhalation, comprising the CGRP antagonist 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 one of its physiologically compatible salts in the form of wrinkle-like microparticles, characterized in that

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

However, the wrinkle-like microparticles according to the invention are also suitable for producing powder inhalants in which the active ingredient is applied together with an auxiliary.

According to the invention, normal carrier materials or flow aids can be used as physiologically harmless, homogeneous auxiliaries. The normal carrier materials can be selected from the group consisting of monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose, trehalose), oligo- and polysaccharides (e.g. dextrans, starch, cellulose derivatives), polyalcohols (e.g. mannitol, Sorbitol, xylitol), salts (eg sodium chloride, calcium carbonate), polylactides, polyglycolides and mixtures of these auxiliaries. The flow aids can be selected, for example, from a group consisting of magnesium stearate, calcium stearate, stearic acid, stearyl alcohols, calcium behenate, calcium arachinate, hydrogenated vegetable oils such as, for example, hydrogenated castor oil or hydrogenated cottonseed oil, fatty acid esters, sodium stearyl fumurate, sodium dodecylsulfate sulfate, magnesium dodecyl sulfate, magnesium dodecyl sulfate, magnesium dodecyl sulfate, magnesium dodecyl sulfate and magnesium dodecyl sulfate.

The production process of the microparticles according to the invention is characterized in that the active ingredient is dissolved, sprayed and dried in a spray tower in a suitable manner. The particle morphology including the particle size of these microparticles can be specifically controlled by the choice of process parameters and manufacturing parameters. A second object of the present invention thus comprises a production process for the microparticles of the active ingredient base (A) according to the invention, comprising the following steps:

(a) dissolving the active ingredient (A) in an organic solvent or an organic-aqueous solvent mixture to produce a sprayable solution with an active ingredient concentration between 0.2 and 4% by weight, preferably between 0.2% by weight and 3% by weight, particularly preferably between 0.3% by weight and 2% by weight,

(b) Spraying the active ingredient solution thus obtained in a customary manner, so that a spray mist with a droplet size with the characteristic value X ₅₀ of 1 to 50 μm, preferably from 1 μm to 30 μm, particularly preferably from 1 μm to 20 μm, is achieved

(c) drying the spray thus obtained with the aid of 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

(d) separating the dried solids from the drying gas stream in a conventional manner.

The microparticles of the active ingredient base (A) according to the invention are preferably produced by a process which comprises the following steps:

(a) dissolving the active ingredient (A) in an organic solvent or an organic-aqueous solvent mixture to produce a sprayed baren solution with an active ingredient concentration between 0.2 and 4 wt .-%, preferably between 0.2 wt .-% and 3 wt .-%, particularly preferably between 0.3 wt .-% and 2 wt .-%,

(b) Spraying the active ingredient solution thus obtained in a conventional manner with a volume flow of the spray gas of 1 Nm ³ / h to 15 Nm ³ / h, so that a spray mist with a droplet size with the characteristic value X ₅₀ of 1 to 50 μm, preferably of 1 μm to 30 μm, particularly preferably from 1 μm to 20 μm, is achieved

(c) 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. and 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 and

(iii) a volume flow of the drying gas of 15 Nm ³ / h to 150 Nm ³ / h and

Organic solvents, organic-aqueous solvent mixtures or water have been found to be suitable solvents for producing a sprayable solution of the active ingredient base. An alcoholic or alcoholic-aqueous solvent system is preferably used, particularly preferably a solvent mixture consisting of ethanol / methanol / water or ethanol / propanol / water and very particularly preferably the solvent mixture ethanol / water or the solvents absolute ethanol, methanol or water. A third subject of the present invention comprises a production process of the microparticles of the salts of the active substance base (A) according to the invention, comprising the following steps:

(a) Dissolving the active ingredient base (A) in water or an aqueous buffer system and adding the corresponding acid to produce a sprayable saline solution of the active ingredient with an active ingredient concentration between 0.2 and 4% by weight, preferably between 0.2% by weight and 3%. %, particularly preferably between 0.3% by weight and 2% by weight,

(b) spraying the active ingredient solution obtained in this way in a conventional manner, so that a spray mist with a droplet size with the characteristic value X ₅₀ of 1 to 50 μm, preferably from 1 μm to 30 μm, particularly preferably from 1 μm to 20 μm, is achieved,

(c) 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

The microparticles of the salts of the active ingredient base (A) according to the invention are preferably produced by a process which comprises the following steps:

(a) Dissolving the active ingredient base (A) in water or an aqueous buffer system and adding the corresponding acid to produce a sprayable saline solution of the active ingredient with an active ingredient concentration between 0.2 and 4 % By weight, preferably between 0.2% by weight and 3% by weight, particularly preferably between 0.3% by weight and 2% by weight,

(b) Spraying the active ingredient solution thus obtained in a conventional manner with a volume flow of the spray gas of 1 Nm ³ / h to 15 Nm ³ / h, so that a spray mist with a droplet size with the characteristic value X ₅₀ of 1 to 50 μm, preferably of 1 μm to 30 μm, particularly preferably from 1 μm to 20 μm, is achieved 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 drying gas of 15 Nm ³ / h to 150 Nm ³ / h and

Water or an aqueous buffer system with a pH between 6 and 8 have been found to be suitable solvents for producing a sprayable solution of the salt forms of the active ingredient base (A). According to the invention, the active ingredient in the form of the free base is brought into solution in the form of the corresponding salt in an aqueous solution, to which 0.9 to 1.1 equivalents of an acid are added, depending on the amount of active ingredient to be dissolved. According to the invention, preferred acids are inorganic acids (for example hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, carbonic acid), fruit acids (for example citric acid, malic acid, tartaric acid, lactic acid, succinic acid, gluconic acid), carboxylic acids (For example formic acid, acetic acid, propionic acid, hexanoic acid) and other organic acids such as oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, fumaric acid, mandelic acid or maleic acid, the use of hydrochloric acid, hydrobromic acid or sulfuric acid and in particular the use of hydrochloric acid being of particular importance.

The surface properties of the particles can be optimized by a certain ratio between drop size and solid concentration. A concentration between 0.2 and 4% by weight, preferably between 0.2 and 3% by weight and in a very preferred manner between 0.3 and 2% by weight, is usually selected.

The drop size is a crucial parameter for the generation of inhalable particles. Depending on the nozzle used, the spray gas throughput in combination with the solution throughput must be selected so that the desired drop size is achieved. Since there are a large number of parameter combinations of nozzle-spray gas throughput-solution throughput, which lead to a suitable drop size, a meaningful specification of the method about the drop size is made, which are determined with the same nozzle parameters with water at room temperature. This can be obtained by the characteristic value X o ₅ (median droplet size, below which 50% of the volume-based drop portion) will be described, which should be in the range from 1 .mu.m to 50 .mu.m are.

The decisive parameters that flow into the drying step are the inlet and outlet temperatures of the drying gas, as well as the volume flow of the dry gas that is passed through.

A fourth object of the present invention relates to the use of the wrinkle-like microparticles produced by the methods described above for the manufacture of a powder inhalant.

A fifth object of the present invention comprises the microparticles according to the invention, obtainable according to the methods described above. Experimental part

1) Measuring method

a) Determination of the particle size using laser scanning (Frauenhoferbeuqung):

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 the particles having a size of 5.8 microns below. Measuring device: Laser diffraction spectrometer (HELOS) .Fa. Sympatec software: WINDOX 4 dispersing unit: RODOS / dispersing pressure: 3 bar focal length: 100 mm [measuring range: 0.9 175 μm] evaluation mode: HRLD (V 4)

b) Determination of the specific surface:

Measurement method: The specific surface is determined by exposing the powder sample to a nitrogen atmosphere at different pressures. By cooling the sample, the nitrogen molecules condense on the surface of the particles. The amount of condensed nitrogen is determined via the pressure drop in the system and the specific surface area of the sample is calculated using the area required by nitrogen and the sample weight.

Measuring device Tri Star Multi Point BET, Micromeritics heating station: VacPrep 061, Micromeritics heating: approx. 12 h / 40 ° C Analvsenparameter sample vessel: ^_1/2 inch; with "filier rod" analysis method: 16 point BET surface determination 0.05 to 0.20 p / pO absolute pressure tolerance: 5.0 mm Hg relative pressure tolerance: 5.0% evacuation speed: 50.0 mm Hg / second evacuation threshold: 10.0 mm Hg evacuation duration: 0.1 h Empty volume: Dewar flask lowering, t: 0.5 h holding time: 20 seconds Minimum equilibrium adjustment time: 600 seconds Adsorbent: nitrogen

c) Determination of the drop size by means of laser measurement (according to Mie):

Measuring device: Laser diffraction spectrometer (HELOS), Sympatec Software: WINDOX 4 focal length: 100 mm [measuring range: 0.9 175 μm] Measuring method: The drop size is determined by removing the nozzle from the spray dryer and the spray in the upper one Third of the spray cone is placed centrally in the laser beam. The measurement is carried out at room temperature with water as the reference medium under otherwise identical conditions. 2) Example of spray parameters

Example: Spray parameters, suitable for an alcoholic solution from (A) (NIRO spray dryer SD Micro):

3) Characterization of the solid particles obtained from the above example:

Example:

Particle size X50 1.2 μm Q (58) 99.5% Specific surface area £ m 21.5 m ² / g Brief description of the pictures

Figures 1 and 2 show the recordings of microparticles of the active ingredient base (A), which were prepared by the process according to the invention from an alcoholic spray solution.

Claims

claims

1. Powder inhalant comprising 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

or one of its physiologically tolerable salts in the form of wrinkle-like microparticles, characterized in that

(a) they have a specific surface area between 3 m ² / g and 35 m ² / g, preferably between 5 m ² / g and 30 m / g, particularly preferably between 10 m ² / g and 30 m ² / g,

(b) the characteristic value Q ( _5. ₈ ) between 50% and 100% and

(c) the parameter X _{50 is} in the range from 0.5 μm to 10 μm, preferably from 0.5 μm to 10 μm.

2. Powder inhalant according to claim 1, characterized in that the active ingredient is the free base 1- [Λ / ² - [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1H) -oxoquinazoline -3- yl) -1 -piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine (A).

3. Powder inhalant according to claim 1, characterized in that the active ingredient 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, phosphate, hydrobromide, carbonate, methanesulfonate, p-toluenesulfonate, nitrate, citrate, malate, tatrate, lactate, succinate, gluconate, acetate , Formate, propionate, capronate, oxalate, maleate, fumarate, mandelate and hydroxysuccinate.

4. Powder inhalant according to claim 1, characterized in that the active ingredient 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.

5. Powder inhalant according to claim 1, characterized in that the active ingredient 1- [Λ / ² - [3,5-dibromo-Λ / - [[4- (3,4-dihydro-2 (1 / - -oxoquinazoline-3 -yl) -1-piperidynyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine hydrochloride.

6. Powder inhalant according to one of claims 1 to 5, characterized in that it is applied together with one or more physiologically acceptable carrier materials and / or flow aids.

7. Powder inhalant according to claim 6, characterized in that the carrier materials used are monosaccharides, disaccharides, oligo- and polysaccharides, polyalcohols, salts, polylactides, polyglycolides or mixtures of these carrier materials.

8. Powder inhalant according to claim 6, characterized in that the carrier materials used are glucose, arabinose, lactose, or sucrose, maltose, trehalose, dextrans, starch, cellulose derivatives, mannitol, sorbitol, xylitol, sodium chloride, calcium carbonate, polylactides, polyglycolides or mixtures of these carrier materials Find.

9. inhalation powder according to claim 6, characterized in that as flow aids magnesium stearate, calcium stearate, stearic acid, stearyl alcohols, calcium behenate, calcium arachinate, hydrogenated vegetable oils, fatty acid esters, Sodium stearyl fumurate, sodium dodecyl sulfate, magnesium dodecyl sulfate or mixtures of these flow aids are used.

10. The method for producing the wrinkle-like microparticles of the active ingredient base (A) according to claim 1 comprises the following steps:

(a) Dissolving the active ingredient (A) in an organic solvent or an organic-aqueous solvent mixture to produce a sprayable solution with an active ingredient concentration between 0.2% by weight and 4% by weight, preferably between 0.2% by weight and 3% by weight .-%, particularly preferably between 0.3% by weight and 2% by weight,

(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 from 40 ° C to 120 ° C and

11. The method for producing the wrinkle-like microparticles of the active ingredient base (A) according to claim 1 comprises the following steps: (a) dissolving the active ingredient (A) in an organic solvent or an organic-aqueous solvent mixture to produce a sprayable solution with an active ingredient concentration between 0.2 and 4% by weight, preferably between 0.2% by weight and 3% by weight, particularly preferably between 0.3% by weight and 2% by weight,

(b) Spraying the active ingredient solution thus obtained in a conventional manner with a volume flow of the spray gas of 1 Nm ³ / h to 15 Nm ³ / h, so that a spray mist with a droplet size with the characteristic value X ₅ o of 1 to 50 μm, preferably of 1 μm to 30 μm, particularly preferably from 1 μm to 20 μm,

(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) a fermentation temperature of the drying gas from 40 ° C to 120 ° C,

(iii) a volume flow of the drying gas of 15 Nm ³ / h to 150 Nm ³ / h and

12. A method for producing the wrinkle-like microparticles of the salts of the active ingredient base (A) according to claim 1, comprising the following steps:

(b) Spraying the active ingredient solution thus obtained in a customary manner, so that a spray mist with a droplet size with the characteristic value X ₅ o of 1 to 50 μm, preferably of 1 μm to 30 μm, particularly preferably of 1 μm to 20 μm, is achieved .

(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

13. A method for producing the wrinkle-like microparticles of the salts of the active ingredient base (A) according to claim 1, comprising the following steps:

(b) spraying the active ingredient solution thus obtained in a conventional manner with a volume flow of the spray gas of 1 Nm ³ / h to 15 Nm ³ / h, so that a spray mist with a droplet size with the characteristic value X ₅₀ of 1 to 50 μm, preferably from 1 μm to 30 μm, particularly preferably from 1 μm to 20 μm,

(ii) an outlet temperature of the drying gas of 40 ° C to 120 ° C and

(iii) a volume flow of the drying gas of 15 Nm ³ / h to 150 Nm ³ / h and

14. Use of the wrinkle-like microparticles produced according to claims 10 to 13 for producing a powder inhalant according to claim 1.

15. Microparticles obtainable according to a method described in claims 10 to 13.