EP2299990A1

EP2299990A1 - Novel embedment particles for inhalation

Info

Publication number: EP2299990A1
Application number: EP09761699A
Authority: EP
Inventors: Michael Krueger; Marc Egen; Elke Jahr; Regis Cartier; Anja Enderle; Thierry Bouyssou
Original assignee: Boehringer Ingelheim International GmbH
Current assignee: Boehringer Ingelheim International GmbH
Priority date: 2008-06-09
Filing date: 2009-06-08
Publication date: 2011-03-30
Also published as: CA2727309A1; JP2011522859A; WO2009150136A1; JP5552118B2; US20110311630A1

Abstract

The invention relates to the preparation of inhalation powders comprising a delayed active ingredient release, and a method for the manufacture thereof, as well as the medicines producible using said inhalation powders.

Description

NEW EMBEDDED PARTICLES FOR INHALATION

The invention relates to methods for the preparation of sustained-release medicaments and to medicaments obtainable by means of these methods for inhalative use. In particular, the invention relates to poly (lactide-co-glycolide) -based

Dry powder formulations which have a delayed release of active ingredient. The invention also relates to the use of these medicaments for the treatment of respiratory diseases, in particular for the treatment of COPD (chronic obstructive pulmonary disease) and asthma.

Background of the invention

For a reproducible and constant release of active ingredient, it may be necessary to delay the release of active ingredient by means of special formulation techniques.

Particularly in the case of inhalative applications in which the active substance, after inhalative administration, is finely distributed on the lung surface for absorption, a rapid absorption of active substance is observed. This is reflected in a pharmacokinetic

Behavior corresponding to that of an intravenous dose.

From the field of oral dosage forms is known (R.H.Müller and G.E.

Hildebrand: "Pharmaceutical technology: Modern dosage forms", scientific publishing company mbH Stuttgart, 1997, ISBN 3-8047-1504-4), that the use of special auxiliary substances, one for the process of the drug release additional

Diffusion barrier can form or impede the distribution of the drug.

This can be achieved by

(i) that the excipient forms a coating of drug particles or drug microcompartments, or

(ii) that the excipient interacts with the drug to be molecularly dispersed in an adjuvant matrix.

Active ingredients are usually made accessible by oral administration. Unless this route is due to specific properties of the active ingredient or special

Requirements for the application is not feasible or is desired, in the prior art various other ways to administer substances known.

In the application form powder inhalation, inhalation powders, which are filled, for example, into suitable capsules (inhalettes), are applied by means of powder inhalers in the lungs. Likewise, other systems in which the amount of powder to be applied is pre-dosed (eg blister), as well as multi-dose powder systems known. Alternatively, inhalative application may also be effected by administration of suitable powdered inhalation aerosols, which are suspended, for example, in HFA134a, HFA227 or their mixture as propellant gas. In the case of powder inhalation, the microparticles of the pure active substance are usually applied by the respiratory tract to the lung surface, for example in the alveoli, by means of the inhalation process. These particles sediment on the surface and are absorbed by active and passive transport processes in the body directly after the dissolution process.

Known in the literature are inhalation systems in which the active ingredient is present in the form of solid particles either as a micronized suspension in a suitable solvent system as carrier or in the form of a dry powder. Usually, powder inhalants, e.g. In the form of capsules for inhalation, based on the general teaching, as described in DE-A-179 22 07 prepared.

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

Another important aspect of powder inhalation is that only particles of a certain aerodynamic size reach the target organ lung during the inhalative application of the active ingredient. The average particle size of these respirable particles (inhalable fraction) is in the range of a few micrometers, typically between 0.1 and 10 .mu.m, preferably below 6 .mu.m. Such particles are usually produced by micronization (air jet milling).

It is known from the literature that particles in the range of a few micrometers can be produced by means of spray drying. Conventionally, from such spray-drying particles, based on the above-cited process (DE-A-179 22 07), technically manageable formulations are prepared which have sufficient dispersibility in medical application (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 (1987), 139-144; RW Niven, FD Lott, AY Ip, JM Cribbs, Pharmaceutical Research, 11, no. 8 (1994), 1101-1109]. The spray-drying of pure active ingredients for inhalation purposes (powder inhalation) has also been 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, especially by pharmaceutical companies presented manufacturing techniques based on spray drying processes that describe special formulations for powder inhalants. Examples which may be mentioned are: powder preparations consisting of co-spray-dried β-galactosidase with trehalose [J. Broadhead, S.K. Edmond Rouan, CT. Rhodes, Pharm Acta Helvetiae, 70 (1995), 125-131], which can be mixed, for example, with other physiologically acceptable excipients; Powder preparations consisting of a spray micronisate, which by co-spray drying of at least two active substances and one or more physiologically acceptable excipients [WO 01/13885]; Powder preparations consisting of spray-dried rhDNase, optionally co-spray-dried with salts, and either directly or in the form of a mixture with a physiologically acceptable excipient, e.g. Lactose, mannitol or sodium chloride were provided for inhalation applications [H. K. 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 of active ingredients and physiologically acceptable excipients [WO 9952506] for inhalation application; Powder preparations containing co-spray micronisates of SLPI protein in physiologically acceptable carrier materials [WO 9917800]; Co-spray-dried interferon with a carrier material [WO 9531479]; Co-spray micronisates of an active ingredient and cellulose derivatives [WO 9325198]; Co-spray micronisates consisting of RhDNase and a physiologically acceptable excipient, e.g. Lactose, which is converted by a subsequent recrystallization of the primary amorphous excipient in crystalline α-lactose monohydrate [H. -K. Chan, I. Gonda, J. Pharm. Sci., 87 (5), (1998) 647-654].

Object of the invention

Conventional production technologies for the provision of embedding particles for inhalative administration are based on the use of physiologically acceptable auxiliaries. In the prior art serve the excipients used in Pulverinhalativa be primarily, the task that with the help of the excipients, a uniform mixture and thus dilution of the active ingredient can be done.

The object of the invention is that a controlled release of the active ingredient is made possible by means of the inhalable powder according to the invention. It is therefore the task of

Invention to provide inhalable powder, which delayed a time

Dissolution rate (retardation) in comparison to particles of the pure active substance.

A specific object of the invention is to provide inhalation powders having a retardation characterized in that a maximum of 60% of the

Active ingredient in a maximum of 30 minutes, and a maximum of 80% of the active ingredient in a maximum of 10

Hours is released.

By retarding is to be understood here that particles according to the invention are such

Release behavior show that particles in a diffusion cell according to Franz show a delayed dissolution behavior. As a result, a slower and at the same time prolonged release of a drug substance from the inhalable powder according to the invention, preferably from particles which have an aerodynamic size of less than 5 μm, is observed.

It is therefore an object of the invention to provide inhalable powders which have a delayed dissolution rate in comparison to the pure active substance particles and to processes for their preparation. In particular, it is an object of the invention to provide the abovementioned inhalable powders for low molecular weight active compounds, as well as for water-soluble active substances. Another aspect of the invention is to provide retarded inhalable powders containing a biodegradable, chemically modified polymer and methods for their preparation.

In addition, it is an object of the invention to provide retarded inhalable powders which consist exclusively of a low molecular weight active substance and a biodegradable polymer and to processes for their preparation.

It is likewise an object of the invention to provide medicaments containing inhalable powders according to the invention. Detailed description of the invention

Inhalable powders according to the invention contain microparticles in which one or more active substances are incorporated in an auxiliary substance matrix of a biodegradable polymer. In the production of an inhalation powder for pulmonary (or nasal) inhalation, the active ingredient (or a physiologically acceptable salt thereof) is physically stably incorporated as a solid in a solid matrix of an excipient (biodegradable polymer).

By appropriate selection of excipients, with the formulation technique according to the invention, the active ingredient can be incorporated into the solid matrix in such a way that it has a delayed release. According to the invention, this is to be understood as meaning that the dissolution behavior of the inhalable particles in a release medium, determined in a diffusion cell according to Franz, is delayed in comparison to inhalable particles of the pure active substance.

By a microparticle are meant inhalable particles. According to the invention, the inhalable microparticles contain an active substance and, according to the definition of the present invention, represent inhalable, active ingredient-containing microparticles (active substance particles).

The inhalable fraction represents the amount of inhalable active ingredient particles (particles <5 μm), as described on the basis of Pharm. Eur. 2.9.18 (European Pharmacopoeia, 6th edition 2008, Apparatus D - Andersen Cascade Impactor) or USP30-NF25 < 601> is determinable. The inhalable fraction is also referred to in the context of the present invention as FPD (Fine Particle Dose).

Surprisingly, it has been found that the inhalable particles of the inhalable powders according to the invention achieve the abovementioned objects if the active substance or several active substances is / are incorporated in an auxiliary substance matrix of a biodegradable polymer. By a biodegradable polymer is meant a polymer which is decomposed by the organism. In particular, it is understood that during the residence time of the polymer in the human body no cell change and no toxic effect in vivo results. In particular, the object is achieved if the active substance or several active substances is / are incorporated in an auxiliary substance matrix from a biodegradable polymer and the excipient (biodegradable polymer) is selected from the group consisting of PLGA (which is understood to mean co-polymers of the type poly). (lactide-co Glycolide)), PEG-modified (poly (lactide-co-glycolide)) based polymers, and PEG-modified (poly-lactides).

For the purposes of the present invention, the group consisting of PEG-modified PLGA and PEG-modified poly-lactides comprises block co-polymers which are selected from the substance class of the PEG [lactide co-glycolides] and the substance class of the PEGs. [poly-lactide]. Block copolymers according to the invention are characterized in that they contain at least one hydrophilic and one hydrophobic block. The chemical compounds of the PLGAs (not PEG-modified) do not represent block co-polymers, but correspond to simple co-polymers.

By block copolymers is meant polymers consisting of longer sequences or blocks of each monomer (e.g., block A corresponds to aaaaaaaaaaaaaa ...; block B corresponds to bbbbbbbbbbb ...). Each lower case letter stands for one

Monomer unit. Depending on the number of blocks one also speaks of diblock, triblock copolymers.

A diblock structure (A-B) or triblock structure (A-B-A) is to be understood as meaning that the polymer is made up of different units which repeat regularly at the molecular level and consist of two or three blocks. Thus, the block A consists of successive monomer units aaaaaaaaa ... of a first polymer and the block B of successive monomer units bbbbbbbbbbb ... of the second polymer.

For example, polymers from the class of block co-polymers can be selected for the production of the inhalable powders according to the invention. These include at least one water-soluble block (block B) and at least one non-water-soluble block (block A). As water-soluble block B, PEG (polyethylene glycol) is used to a particular degree. As non-water-soluble block A, a polyester compound is chosen in particular. For example, as the polyester block, the polymer class of the poly (lactide-co-glycolides) is used. Thus, the monomer units a of block A in the case of the (i) PEG- [lactide-co-glycolides] both lactide units a ¹ and glycolide units a ² , wherein the monomer units "lactide unit a ¹ " and "glycolide unit a ² " either statistically randomly distributed within the block or even occur alternately or alternately in the course of the block or in the case of

(ii) PEG- [poly-lactides] exclusively lactide units a ¹ on.

The lactide units can represent D-lactide as well as L-lactide.

A specific embodiment of the invention is the use of block co-polymers which have a di-B lock structure.

Of particular importance are the listed in Table 1 Nos. 2 to 9 listed PEG- [lactide co-glycolides] and PEG [poly-lactides] as emulsifiers for W / O (water in oil) emulsions according to the invention, while the Polymer of the current No. 1 is not a suitable polymer.

Table 1: Embedding materials suitable for the production of inhalable powders according to the invention (manufacturer: Boehringer Ingelheim); Mw = molecular weight in [kD] (calculated theoretically after the preparation process on the basis of the monomer amounts used), T _g = glass transition temperature in [ ⁰ C]; the percentages given in the column Composition represent the mass-related% values of the building blocks PEG, D / L-lactides and glycolides, 100% being based on the total mass of the copolymer; "Nd" stands for "not determined".

The object of the invention is fulfilled by inhalable powders, which are characterized in that a maximum of 60% of the active ingredient in a maximum of 30 minutes, and a maximum of 80% of the active ingredient is released in a maximum of 10 hours, wherein the inhalable powder contains microparticles, in which one or more active ingredients in an excipient matrix of a biodegradable polymer is incorporated.

According to the invention, the inhalable powders containing microparticles in which one or more active substances are incorporated in an excipient matrix of a biodegradable polymer are characterized in a further embodiment in that a maximum of 90% of the active ingredient has dissolved after 10 hours, preferably at most 90% of the active ingredient is solved after 12 hours.

Here, the solution behavior of the inhalable fraction of the inhalable powder according to the invention serves as a measure of the retardation of the active ingredient. This solution behavior can be determined using a Franz diffusion cell (see Figure 1). In this case, a lower compartment is filled with a freely selectable release medium (preferably PBS buffer) and the membrane (here o filter membrane) placed on the surface of the medium, whereby air bubbles are no longer present between the release medium and the membrane. The upper part of the cell closes the system and forms an air compartment. In such an embodiment, the lower compartment is with hoses to a pump connected, which direct the medium to a device for measuring data acquisition, for example, a UV detector or a fluorescence detector. With such detectors, an active ingredient can be detected quantitatively. Finally, the release medium is mixed with a stirring system, such as a magnetic stirrer, to better distribute an active substance contained in the release medium within the chamber.

[Figures refer to Figure 1 in the following section] The inhalable fraction of the inhalable powders according to the invention is deposited in finely distributed form on a filter membrane 1 in a Franz diffusion cell. Below the membrane 1, a first compartment 2 for receiving a liquid release medium is arranged free of air bubbles, which continuously, as indicated by the terminals 3 and the flow arrow D, implemented and a means for measuring data acquisition, such as a UV or fluorescence detector supplied. Above the membrane 1 is formed as a second compartment 4, an air chamber and the entire diffusion cell 5 (Franz cell) is surrounded by a heat insulation 6 and can be controlled by a hotplate 7 in the desired manner. For mixing the release medium, a magnetic stirrer 8 is used.

The inhalable fraction of the inhalable powders according to the invention may preferably be deposited on a cellulose membrane. The deposition of the inhalable fraction can be effected by placing this filter on the filter plate of the Andersen cascade impactor. The application is then carried out in accordance with Pharm. Eur. 2.9.18 (European Pharmacopoeia, 6th edition 2008, Apparatus D - Andersen Cascade Impactor), with only the deposition plates are inserted into the cascade impactor, not for the deposition of particles from 0 microns to 5 microns, so that all particles smaller than 5 microns are deposited on the filter. Preferably, a filter is used, which is made of regenerated cellulose.

Specific embodiments fulfill the object of the invention in the use of active compounds which have a water solubility of more than 0.01 g per 100 ml (FaIIA) which have a solubility of more than 0.01 g per 100 ml in an organic solvent which is completely miscible with water (case B) which has a solubility in an organic solvent, preferably dichloromethane of more than 0.01 g per 100 ml (case C) according to the following information: Compositions according to the invention FaIlA:

In a specific embodiment, the object of the present invention is achieved by the use of active ingredients having a water solubility of more than 0.01 g per 100 ml if inhalation powders containing microparticles are embedded in a polymer, the biodegradable polymer being a Substance selected from the substance classes of PEG [lactide co-glycolides] or PEG- [poly-lactides] represents. Such substances are available under the name Resomer® (Boehringer Ingelheim Pharma GmbH & Co. KG, Germany). In particular, polymers of these two classes of substances are suitable if they have the properties (a), (b), (c), (d) and (e):

(a) a PEG content of 1-15% (mass% based on the total molecular weight of the biodegradable polymer),

(b) a molecular mass between 37.5-150 kDa,

(c) a diblock structure, (d) a glycolide fraction of 0-5%, preferably 0% (mass% based on the

Molecular mass, 100% being based on the molecular mass of the polymer block A of the co-polymer),

(e) a lactide content of 95-100%, preferably 100% (mass% based on the molecular mass and 100% based on the molecular mass of the polymer block A of the co-polymer) and the lactide content of the components L -Lactide and D-lactide may contain and the D-lactide to L-lactide maximally in the ratio of n: 4 and n is a number less than or equal to 1, possibly the lactide portion consists exclusively of L-lactide.

In a particularly specific embodiment, the object of the invention is fulfilled when using active ingredients having a water solubility of more than 0.01 g per 100 ml when inhalation powders containing microparticles are embedded in a polymer, the biodegradable polymer a substance selected from the substance classes of the PEG [lactide co-glycolides] or the PEG [poly-lactides] represents. Such substances are called Resomer®

(Boehringer Ingelheim Pharma GmbH & Co. KG, Germany). In particular, polymers of these two classes of substances are suitable if they have the properties (f), (g), (h), (i) and (j):

(f) a PEG content of 1-15% (mass% based on the total molecular weight of the biodegradable polymer),

(g) a molecular mass between 37.5-150 kDa, (h) a triblock structure,

(i) a glycolide fraction of 0-15%, preferably 0% (mass% based on molecular mass, where 100% is based on the molecular mass of polymer block A of the co-polymer), (J) a lactide moiety from 85 to 100%, preferably 100% (% by mass based on the

Molecular mass and 100% based on the molecular mass of the polymer block A of the co-polymer) and thereby the lactide portion may contain the components L-lactide and D-lactide and the D-lactide to L-lactide maximally in the ratio n: A is present and n is a number less than or equal to 1, optionally the lactide portion consists exclusively of L-lactide.

Compositions of the invention Case B:

In a further specific embodiment, the object of the invention is fulfilled when using active ingredients which have a solubility of more than 0.01 g per 100 ml in an organic solvent which is completely miscible with water, if inhalation powders containing microparticles embedded in a polymer, wherein the biodegradable polymer is a substance selected from the class of PEG- [lactide-co-glycolides]. Such substances are known as Resomer® (Boehringer Ingelheim Pharma GmbH & Co. KG,

Germany) available. In particular, polymers of this class of substances are suitable if they have the properties (k), (1), (m), (n) and (o): (k) a PEG content of 10 - 15% (mass) % related to

Total molecular weight of the biodegradable polymer), (1) a molecular mass between 37.5-150 kDa,

(m) a diblock structure or triblock structure,

(n) a glycolide fraction of 20-50% (mass% based on molecular mass, 100% being based on the molecular mass of polymer block A of the co-polymer), (o) a lactide content of 50-80 % (Mass% based on the molecular mass and 100% based on the molecular mass of the polymer block A of the co-polymer) and thereby the lactide portion may contain the components L-lactide and D-lactide and the D-lactide for L Lactide is present in the ratio n: 4 at most and n is a number less than or equal to 1, optionally the lactide portion consists exclusively of L-lactide. Compositions of the invention Case C:

In a further specific embodiment, the object according to the invention is fulfilled when using active substances which have a solubility in an organic solvent, preferably dichloromethane, of more than 0.01 g per 100 ml, when inhalable powders containing microparticles are transformed into a polymer be embedded, wherein the biodegradable polymer is a substance from the class of PEG- [lactide co-glycolides]. Such substances are available under the name Resomer® (Boehringer Ingelheim Pharma GmbH & Co. KG, Germany). In particular, polymers are suitable if they have the properties (p), (q), (r), (s) and (t):

(p) a PEG content of 1-15%, preferably 10-15% or 1-9.9% (mass% based on the total molecular weight of the biodegradable polymer),

(q) a molecular mass between 15-150 kDa, (r) a diblock structure or triblock structure,

(s) a glycolide fraction of 15-50% (mass% based on molecular mass, 100% being based on the molecular mass of polymer block A of the co-polymer),

(t) a lactide content of 50-85% (mass% based on molecular mass and 100% based on the molecular mass of polymer block A of the co-polymer) and thereby the lactide content of the components L-lactide and D. -Laktid may contain and the D-lactide to L-lactide maximally in the ratio n: 4 and n is a number less than or equal to 1, optionally, the lactide portion consists exclusively of L-lactide.

In a further specific embodiment, the object of the invention is embedded in a polymer when using active substances which have a solubility in an organic solvent, preferably dichloromethane, of more than 0.01 g per 100 ml, when inhalable powders containing microparticles are embedded wherein the biodegradable polymer is a substance of the class of PLGA and the

Polymer PLGA has a modified end group, wherein the end group of the polymer is selected from the group consisting of -COOH or a terminal alkyl group. Here, a terminal alkyl group is understood as meaning an end group of the structure - (CH ₂ ) _n -CH ₃ , where n may be a number selected from 8, 9, 10, 11, 12, 13, 14, 15. Preferably, n = 11. Likewise, polymer blends of these polymers with the end groups consisting of -COOH or a terminal alkyl group can be used as embedding material.

Another specific embodiment is additionally characterized in that a maximum of 80% of the active ingredient is released in a maximum of 18 hours. These

Inhalable powders are characterized in that these inhalable powders contain microparticles embedded in a polymer, the biodegradable polymer being a substance of the class PLGA and the polymer PLGA having a modified end group, the end group of the polymer corresponding to the structure -COOH.

Another specific embodiment is further characterized in that more than 80% of the active ingredient is released in a maximum of 18 hours. These inhalable powders are characterized in that these inhalable powders contain microparticles embedded in a polymer, the biodegradable polymer being a substance of the class PLGA and the polymer PLGA having a modified end group, the end group of the polymer having the structure - (CHi ) _n -CHs, where n can be a number selected from 8, 9, 10, 11, 12, 13, 14, 15. preferably n = 11.

Furthermore, the invention relates to methods by means of which the objects according to the invention are achieved. The invention includes corresponding part Hers process for the production of inhalable powder according to the invention. Such powders can be used both directly as powder inhalants (multi-dose systems, pre-metered multi-dose and single-dose systems) and as components blended with other (e.g., coarse) excipient.

To produce such particles, the production process can be controlled so that the particles are present in a suitable particle size, usually between 0.1 and 10 .mu.m, and these particles have such surface properties that they are easily fluidizable or dispersible.

Overall, a formulation based on this preparation method allows the active ingredient or a physiologically acceptable salt thereof to be administered to the patient by inhalation in a therapeutically relevant dose as a delayed-release drug. The particles of the inhalable powders according to the invention which are prepared by the process according to the invention are characterized by a high physical stability. In particular, they are suitable when used as Pulverinhalativum a high fines content during the application, technically determined, for example by means of cascade impactor measurement arises. Typically, the proportion of particles by this method that are less than 5 μm (aerodynamic) is greater than 15%; preferably more than 30%, particularly preferably more than 50% achieved.

Characterized are powder thus produced by a particle size, for example, as measured by laser diffraction, by an average particle size X ₅₀ in the range of 1 .mu.m to 10 .mu.m, preferably from 1 .mu.m to 6 .mu.m. The term "average particle size X _50" as used herein refers to the 50% value from the volume distribution measured by a laser diffractometer according to the dry dispersion method.

The manufacturing method of the microparticles or the inhalable powder according to the invention is characterized in that a solution or emulsion of the active ingredient or a physiologically acceptable salt thereof with an excipient selected from the group consisting of PLGA (which is understood to mean co-polymers of the type poly (lactide co-

Glycolide), PEG-modified (poly (lactide-co-glycolide)) based polymers and PEG-modified (poly-lactides) are suitably dissolved or emulsion-processed, sprayed and dried in a spray tower. By means of a suitable separation method (for example cyclone or fine particle filter), it is possible to recover the particles / powder. The microparticles produced in this way are characterized by special values in terms of particle size.

Specific manufacturing method for microparticles according to FaIlA:

For active substances which have a solubility in water of more than 0.01 g per 100 ml, it has proved suitable for the preparation of microparticles in the form of embedded particles of inhalable powders according to the invention to use a process which comprises the following steps:

(i) dissolving the active ingredient in water, optionally with the addition of a salt, preferably NaCl in a concentration of 10-50 mM,

(ii) preparing a (W / O) emulsion, wherein the organic phase used is preferably dichloromethane in which a biodegradable polymer (see compositions according to the invention, J * OllA ") is dissolved, (Iii) spraying the thus obtained emulsion in a conventional manner, so that a

There is a spray mist with a droplet size with the characteristic value X ₅₀ between 7 μm and 25 μm,

(Iv) drying of the spray thus obtained with the aid of a drying gas

Application of the following parameters: an inlet temperature of the drying gas of 3O ⁰ C to 35O ⁰ C, preferably from 4O ⁰ C to 25O ⁰ C and particularly preferably from 45 ⁰ C to 15O ⁰ C and - a starting temperature of the drying gas from 3O ⁰ C to 12O ⁰ C and

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

Specific Production Method for Microparticles According to Case B:

For active substances which have a solubility of more than 0.01 g per 100 ml in an organic solvent which is completely miscible with water, it has proved to be suitable if a process is used to prepare microparticles in the form of embedding particles of inhalable powders according to the invention which includes the following steps:

(i) preparing a solution of organic solvent which is immiscible with water indefinitely, by dissolving the active substance (s) with a biodegradable polymer (see compositions "Case B" according to the invention) in the solvent,

(Ii) spraying the solution thus obtained in the usual way, so that a

(Iii) drying of the spray thus obtained by means of a drying gas using the following parameters: an inlet temperature of the drying gas from 30 ⁰ C to 35O ⁰ C, preferably from 40 ⁰ C to 25O ⁰ C and particularly preferably from 145 ⁰ C to 15O ⁰ C. and a starting temperature of the drying gas of 3O ⁰ C to 12O ⁰ C and (iv) separating the dried solid particles from the drying gas stream in the usual way.

Specific Production Method for Microparticles According to Case C: For active substances which have a solubility in an organic solvent, preferably dichloromethane of more than 0.01 g per 100 ml, it has proved to be suitable if lo according to the invention is used for the preparation of microparticles in the form of embedding particles Inhalation powder, a method is used which comprises the following steps:

(i) preparing a solution, wherein the one or more active ingredients and a biodegradable

Polymer (see compositions of the invention, J * Oll C ") are dissolved in the organic solvent,

(Ii) spraying the solution thus obtained in the usual way, so that a

Spray mist with a droplet size with the characteristic value X ₅₀ between 7 μm and 25 μm is present, 20

(Iii) drying of the spray thus obtained by means of a drying gas using the following parameters: an inlet temperature of the drying gas from 30 ⁰ C to 35O ⁰ C, preferably from 40 ⁰ C to 25O ⁰ C and particularly preferably from 145 ⁰ C to 25 15 ⁰ C and a starting temperature of the drying gas from 3O ⁰ C to 12O ⁰ C and

(iv) separating the dried solid particles from the drying gas stream in the usual way. 30

The particle sizes were determined in the context of the present invention by means of laser diffraction (Fraunhoferbeugung). Here, the mean particle size X ₅₀ in the sense used here is understood to mean the 50% value from the volume distribution. More detailed information can be found in the experimental descriptions of the invention. 35 According to the invention, the inhalable powders thus obtained can be used for the preparation of a medicament. Preference is given to the production of a medicament for the treatment of respiratory diseases, in particular for the treatment of COPD and / or asthma. Likewise, the invention relates to the use of the inhalable powders thus obtained for the manufacture of a medicament for inhalation use to a particular extent for the preparation of a medicament for inhalation use, which enables a delayed release of the active ingredient.

The chemical compounds (active substances) listed below can be used alone or in combination as a drug-relevant constituent of the inhalable powders according to the invention.

In the compounds listed below, W is a pharmacologically active agent and (for example) selected from the group consisting of betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, HIV antihistamines, PAF- Antagonists and PI3 kinase inhibitors. Furthermore, two- or three-fold combinations of W can be combined and used for application in the device according to the invention. Exemplary combinations of W would be:

W represents a betamimetics combined with an anticholinergic, corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists,

W represents an anticholinergic agent combined with a betamimetics, corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists, W represents a corticosteroid combined with a PDE4 inhibitor, EGFR inhibitors or LTD4 antagonists - W represents a PDE4 Inhibitors combined with an EGFR inhibitor or LTD4 antagonist W represents an EGFR inhibitor combined with a LTD4 antagonist.

Preferred betamimetics for this purpose are compounds selected from the group consisting of albuterol, arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharines, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol , Orciprenaline, Pirbuterol, Procaterol, Reproterol, Rimiterol, Ritodrine, Salmefamol, Salmeterol, Soterenol, Sulphone terol, Terbutaline, Tiaramide, Tolubuterol, Zinterol, CHF-1035, HOKU-81, KUL-1248 and 3- (4- {6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethyl-amino] -hexyloxy} -butyl) -benzyl-sulfonamide

5- [2- (5,6-diethyl-indan-2-ylamino) -l-hydroxy-ethyl] -8-hydroxy-1H-quinolin-2-one 4-hydroxy-7- [2- {2- {[3- (2-phenylethoxy) propyl] sulphonyl} ethyl] amino} ethyl] -2 (3H) -benzothiazolone

1- (2-Fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol 1- [3- (4-methoxybenzylamino) -4-hydroxyphenyl] - 2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3 - (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino] ethanol

- 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino] ethanol

- 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino] ethanol - 1 - [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl] -2- [4- [3- (4-methoxyphenyl) -1,2,4-triazole-3-one yl] -2-methyl-2-butylamino Jethanoi

5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1,4-benzoxazine-3- (4H) -on- (4-amino-3-chloro-5-trifluoromethylphenyl) -2-tert .-butylamino) ethanol 6-hydroxy-8- {1-hydroxy-2- [2- (4-methoxyphenyl) -1,1-dimethylethylamino] ethyl} -4H-benzo [1,4] oxazine -3-one

6-Hydroxy-8- {1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -l, l-dimethyl-ethylamino] -ethyl} -4 H -benzo [1,4] oxazin-3-one

6-Hydroxy-8- {1-hydroxy-2- [2- (4-phenoxyacetic acid) -1,1-dimethylethylamino] ethyl} -4H-benzo [1,4-oxazin-3-one 8- {2- [1,1-dimethyl-2- (2,4,6-trimethylphenyl) ethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4-oxazine-3-] on

6-hydroxy-8- {1-hydroxy-2- [2- (4-hydroxyphenyl) -1,1-dimethyl-ethylamino] -ethyl} -

4H-benzo [l, 4] oxazin-3-one

6-Hydroxy-8- {1-hydroxy-2- [2- (4-isopropylphenyl) -1,1-dimethyl-ethylamino] -ethyl} -4H-benzo [1,4-oxazin-3-one

8- {2- [2- (4-ethylphenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one

8- {2- [2- (4-Ethoxy-phenyl) -l, 1-dimethyl-ethylamino] -1-hydroxy-ethyl} -6-hydroxy-4H-benzo [1,4] oxazin-3-one 4- (4- {2- [2-Hydroxy-2- (6-hydroxy-3-oxo-3,4-dihydro-2H-benzo [l, 4] oxazin-8-yl) ethylamino] -2- methyl-propyl} -phenoxy) -butyric acid 8- {2- [2- (3,4-difluorophenyl) -1,1-dimethylethylamino] -1-hydroxyethyl} -6-hydroxy

4H-benzo [1,4] oxazin-3-one 1- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tert -butylamino) ethanol

2-Hydroxy-5- (1-hydroxy-2- {2- [4- (2-hydroxy-2-phenyl-ethylamino) -phenyl] -ethylamino} -ethyl) -benzaldehyde

N- [2-hydroxy-5- (1-hydroxy-2- {2- [4- (2-hydroxy-2-phenyl-ethylamino) -phenyl] -ethylamino} -ethyl) -phenyl] -formamide

8-Hydroxy-5- (1-hydroxy-2- {2- [4- (6-methoxy-biphenyl-3-ylamino) -phenyl] -ethylamino} -ethyl) -1H-quinolin-2-one - 8- hydroxy-5- [(6-phenethylamino-hexylamino) -ethyl l-hydroxy-2-] -lH-quinolin-2-one

5- [2- (2- {4- [4- (2-amino-2-methyl-propoxy) -phenyl-amino] -phenyl} -ethyl-amino) -1-hydroxy-ethyl] -8-hydroxy-1H-quinoline 2-one

[3- (4- {6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -hexyloxy} -butyl) -5-methylphenyl] -urea f - 4- ( 2- {6- [2- (2,6-dichloro-benzyloxy) -ethoxy] -hexylamino} -1-hydroxy-ethyl) -2-hydroxymethyl-phenol

3- (4- {6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -hexyloxy} -butyl) -benzylsulfonamide

3- (3- {7- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -heptyloxy} -propyl) -benzylsulfonamide

4- (2- {6- [4- (3-Cyclopentanesulfonylphenyl) -butoxy] -hexylamino} -1-hydroxyethyl) -2-hydroxymethyl-phenol

N-Adamantan-2-yl-2- (3- {2- [2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -propyl} -phenyl) -acetamide

optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, the acid addition salts of the betamimetics are preferably selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro- toluenesulfonate.

As anticholinergic compounds are preferably used here, which are selected from the group consisting of tiotropium salts, preferably the

Bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, ipratropium salts, preferably the bromide salt, glycopyrronium salts, preferably the bromide salt, trospium salts, preferably the chloride salt, tolterodine. In the above-mentioned salts, the cations are the pharmacologically active ingredients. As anions, the aforementioned salts may preferably contain chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate , Benzoate or p-toluenesulfonate, with chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate being preferred as counterions. Of all the salts, the chlorides, bromides, iodides and methanesulfonates are particularly preferred.

Likewise preferred anticholinergics are selected from the salts of the formula AC-I

wherein X ^{~ is} a single negatively charged anion, preferably an anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-Toluenesulfonate, preferably a singly negatively charged anion, more preferably an anion selected from the group consisting of fluoride, chloride, bromide, methanesulfonate and p-toluenesulfonate, most preferably bromide, optionally in the form of their racemates, enantiomers or hydrates. Of particular importance are those drug combinations which contain the enantiomers of the formula AC-I-ene

contain, wherein X ^{~ can have} the meanings given above. Further preferred anticholinergics are selected from the salts of the formula AC-2

may have the above mentioned meanings wherein R is either methyl or ethyl and wherein X ^~. In an alternative embodiment, the compound of the formula AC-2 may also be present in the form of the free base AC-2-base.

Further named compounds are:

2,2-Diphenylpropionic acid-tropol ester-methobromide 2,2-diphenylpropionic acid copoprene-methobromide 2-fluoro-2,2-diphenylacetic acid-co-ester methobromide 2-fluoro-2,2-diphenylacetic acid-tropol ester-methobromide - 3,3 ', 4,4'-tetrafluorobenzilic acid-tropol ester-methobromide 3,3 ', 4,4'-Tetrafluorobenzilic Acid Copoester Methobromide 4,4'-Difluorobenzilic Acid Sterol Ester Methobromide 4,4'-Difluorobenzilic Acid Copoester Methobromide 3,3'-Difluorobenzilic Acid Sterol Ester Methobromide - 3,3'-Difluorobenzilic Acid Copoprene Methobromide

9-Hydroxy-fluorene-9-carboxylic acid-tropol ester-methobromide 9-Fluoro-fluorene-9-carboxylic acid-tropol ester-methobromide 9-Hydroxy-fluorene-9-carboxylic acid-co-ester methobromide 9-fluoro-fluoren-9-carboxylic acid-co-ester methobromide - 9-methyl-fluorene -9-carboxylic acid tropol ester methobromide 9-methyl-fluorene-9-carboxylic acid copoester methobromide Benzylic acid cyclopropyltropine ester methobromide 2,2-Diphenylpropionic acid cyclopropyltropine ester methobromide 9-Hydroxy-xanthene-9-carboxylic acid cyclopropyltropine ester methobromide 9-Methyl-fluorene-9-carboxylic acid cyclopropyltropine ester methobromide - 9-methyl-xanthene-9-carboxylic acid cyclopropyltropine ester methobromide 9-hydroxyfluorene 9-carboxylic acid cyclopropyltropine ester methobromide 4,4'-difluorobenzilate methylcyclopropyltropine ester methobromide 9-hydroxy-xanthene-9-carboxylic acid tropol ester methobromide 9-hydroxy-xanthene-9-carboxylic acid copolyester-methobromide - 9-methyl-xanthene-9-carboxylic acid-tropol ester-methobromide 9-methyl -xanthene-9-carboxylic acid-co-ester methobromide 9-ethyl-xanthene-9-carboxylic acid-tropol ester-methobromide 9-difluoromethyl-xanthene-9-carboxylic acid-tropol ester-methobromide 9-hydroxymethyl-xanthene-9-carboxylic acid-co-ester methobromide The compounds mentioned above are within the scope of the present invention Invention can also be used as salts, in which instead of the Methobromids, the Salts Metho-X are used, wherein X may have the meanings given above for X ^" .

Preferred corticosteroids here are compounds selected from the group consisting of beclomethasone, betamethasone, budesonide, butixocort, ciclesonide, deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, rofleponide, triamcinolone, RPR - 106541, NS-126, ST-26 and

6,9-Difluoro-17 - [(2-furanylcarbonyl) oxy] -ll-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionic acid (S) -fluoromethyl ester

6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionic acid (S) - (2-oxo-tetrahydrofuran-3S-yl) esters,

6α, 9α-difluoro-LLβ-hydroxy-16α-methyl-3-oxo-17α- (2,2,3,3-tertamethylcyclopropylcarbonyl) oxy-androsta-1,4-diene-17β-carboxylic acid cyanomethyl ester, optionally in Form of their racemates, enantiomers or diastereomers and optionally in the form of their salts and derivatives, their solvates and / or hydrates. Any reference to steroids includes reference to their optional salts or derivatives, hydrates or solvates. Examples of possible salts and derivatives of steroids may be: alkali metal salts, such as, for example, sodium or potassium salts, sulphobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates,

Dihydrogen phosphates, palmitates, pivalates or furoates. Preferred PDE4 inhibitors here are compounds selected from the group consisting of enprofylline, theophylline, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, arofylline, atizoram, D-4418, bay 198004, BY343, CP-325,366, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V- 11294A, Cl-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and

N- (3,5-dichloro-1-oxo-pyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide - (-) p - [(4αR *, 10bS *) - 9-ethoxy-1,2 3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzo [s] [l, 6] naphthyridin-6-yl] -N, N-diisopropylbenzamide (R) - (+) - l- (4) Bromobenzyl) -4 - [(3-cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidone 3- (cyclopentyloxy-4-methoxyphenyl) -1- (4-N '- [N-2-cyano-S-methylisothioureido ] benzyl) -2-pyrrolidone - cis [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid] 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxy) phenyl) cyclohexane-1-one cis [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol] (R) - (+) - ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl ) pyrrolidin-2-ylidene] acetate - (S) - (-) - ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene] acetate

9-cyclopentyl-5,6-dihydro-7-ethyl-3- (2-thienyl) -9H-pyrazolo [3,4-c] -1,4,4-triazolo [4,3-a] pyridine

9-cyclopentyl-5,6-dihydro-7-ethyl-3- (tert -butyl) -9H-pyrazolo [3,4-c] -1,4,4-triazolo [4,3-a] pyridine, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, the acid addition salts of the PDE4 inhibitors are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-hydroxybenzene. toluenesulfonate.

Preferred LTD4 antagonists here are compounds selected from the group consisting of montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078 , VUF-K-8707, L-

733321 and - l - (((R) - (3- (2- (6,7-Difluoro-2-quinolinyl) ethenyl) phenyl) -3- (2- (2-hydroxy-2-propyl) phenyl) thio) methylcyclopropane -acetic acid,

- l - (((l (R) -3 (3- (2- (2,3-dichlorothieno [3,2-b] pyridin-5-yl) - (E) -ethenyl) phenyl) -3- ( 2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropaneacetic acid - [2 - [[2- (4-tert-butyl-2-thiazolyl) -5-benzofuranyl] oxymethyl] phenyl] acetic acid optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,

Hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate. Examples of salts or derivatives which the LTD4 antagonists are able to form are understood as meaning alkali salts, such as, for example, sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.

The EGFR inhibitors used are preferably compounds selected from the group consisting of cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and - 4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxyquinazoline

- 4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-diethylamino) -l-oxo-2-buten-1-yl] -amino} -7-cyclopropylmethoxy quinazoline

- 4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -7-cyclopropylmethoxyquinazoline

- 4 - [(R) - (1-Phenylethyl) amino] -6- {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7-cyclopentyloxy -quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {[4- ((R) -6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-butene - 1 -yl] amino} -7-cyclopropylmethoxy-quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [4 - ((R) -6-methyl-2-oxo] morpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7 - [(S) - (tetrahydrofuran-3-yl) oxy] quinazoline 4 - [(3-chloro-4- fluorophenyl) amino] -6- {[4- ((R) -2-methoxymethyl-6-oxomorpholin-4-yl) -1-oxo-2-buten-1-yl] amino} -7- cyclopropylmethoxy-quinazoline 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2 - ((S) -6-methyl-2-oxomorpholin-4-yl) -ethoxy] - 7 methoxy-quinazoline 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl-amino] -l-oxo-2-butene-1-yl } amino) -7-cyclopropylmethoxyquinazoline 4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino} -V-cyclopentyloxy-quinazoline

5 - 4 - [(R) - (1-Phenyl-ethyl) -amino] -6- {[4- (N, N-bis (2-methoxy-ethyl) -amino] -l-oxo-2-butene - 1 -yl] amino} -V-cyclopropylmethoxy-quinazoline

- 4 - [(R) - (1-Phenyl-ethyl) -amino] -6 - ({4- [N- (2-methoxyethyl) -N-ethyl-amino] -l-oxo-2-butene 1 -yl} amino) -7-cyclopropylmethoxy-quinazoline

- 4 - [(R) - (1-Phenyl-ethyl) -amino] -6 - ({4- [N- (2-methoxy-ethyl) -N-methyl-amino] -l-oxo-2-O-butene - l-yl} amino) -7-cyclopropylmethoxy-quinazoline

- 4 - [(R) - (1-phenylethyl) amino] -6 - ({4- [N- (tetrahydropyran-4-yl) -N-methylamino] -l-oxo-2-butene 1 -yl} amino) -7-cyclopropylmethoxyquinazoline 4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -l-oxo-2-butene-1 - yl] amino} -7 - ((R) -tetrahydrofuran-3-yloxy) quinazoline 5 - 4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino ) -l -oxo-2-buten-1-yl] amino} -7 - ((S) -tetrahydrofuran-3-yloxy) quinazoline

4 - [(3-Chloro-4-fluorophenyl) amino] -6 - ({4- [N- (2-methoxyethyl) -N-methyl-amino] -l-oxo-2-butene-1-yl } amino) -7-cyclopentyloxy-quinazoline 4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N-cyclopropyl-N-methyl-amino) -l-oxo-2-o-butene - 1 -yl] amino} -7-cyclopentyloxy-quinazoline

4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -l-oxo-2-buten-1-yl] amino} -7 - [(R) - (tetrahydrofuran-2-yl) methoxy] quinazoline

4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -l-oxo-2-butenyl-1-yl] amino} -7- [(S) - (tetrahydrofuran-2-yl) methoxy] quinazoline 5 - 4 - [(3-ethynylphenyl) amino] -6,7-bis (2-methoxyethoxy) quinazoline

4 - [(3-chloro-4-fluorophenyl) amino] -7- [3- (morpholin-4-yl) -propyloxy] -6 - [(vinylcarbonyl) amino] quinazoline

4 - [(R) - (l-Phenyl-ethyl) amino] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2,3-d] pyrimidine

3-cyano-4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (N, N-dimethylamino) -1-oxo-2-buten-0 1-yl] amino} -7 ethoxy-quinoline

4- {[3-Chloro-4- (3-fluoro-benzyloxy) -phenyl] -amino} -6- (5- {[(2-methanesulfonyl-ethyl) -amino] -methyl} -furan-2-yl) -quinazoline

- 4 - [(R) - (1-phenylethyl) amino] -6- {[4- ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-ol butene-1-yl] amino} -7-methoxy-quinazoline 5 - 4 - [(3-chloro-4-fluorophenyl) amino] -6- {[4- (morpholin-4-yl) -l-oxo-2 buten-l-yl] amino} -

7 - [(tetrahydrofuran-2-yl) methoxy] -quinazoline 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N, N-bis (2-methoxy-ethyl) amino] -1-oxo-2-buten-1-yl } amino) -7 - [(tetrahydrofuran-2-yl) methoxy] -quinazoline

4 - [(3-Ethynyl-phenyl) -amino] -6- {4- (5,5-dimethyl-2-oxomorpholin-4-yl) -1-oxo-2-but-1-yl] -amino } -quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -

7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -

7 - [(R) - (tetrahydrofuran-2-yl) methoxy] -quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] - 6 - [(S) - (tetrahydrofuran-2-yl) methoxy] -quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {2- [4- (2-oxo-morpholin-4-yl) -piperidin-1-yl] -ethoxy} -7-methoxy -quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline-4 - [(3-chloro-4-yl) 4-fluoro-phenyl) amino] -6- (trans-4-amino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-3-yloxy) -7-methoxyquinazoline-4 - [(3-chloro-4-fluoro-phenyl) -amino] - 6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1- (morpholin-4-yl) -carbonyl] -piperidin-4-yl-oxy} -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(methoxymethyl) -carbonyl] -piperidin-4-yl-oxy} -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) amino] -6- (piperidin-3-yloxy) -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- [1- (2-acetylamino-ethyl) -piperidin-4-yloxy] -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7-ethoxy-quinazoline-4 - [(3-chloro-4-fluoro-phenyl) -amino] - 6 - ((S) -tetrahydrofuran-3-yloxy) -7-hydroxyquinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(dimethylamino) -sulfonyl-amino] -cyclohexane-1-yloxy} -7-methoxy-quinazoline 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(morpholin-4-yl) carbonylamino] -cyclohexane-1-yloxy} -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {trans-4 - [(morpholin-4-yl) sulfonylamino] -cyclohexane-1-yloxy} -7-methoxy-quinazoline-4- [(3-chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-acetylamino-ethoxy) -quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (tetrahydropyran-4-yloxy) -7- (2-methanesulfonylamino-ethoxy) -quinazoline

4- [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(piperidine-1-yl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-aminocarbonylmethyl-piperidin-4-yloxy) -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(tetrahydropyran-4-yl) -carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy ) -7-methoxyquinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) -carbonyl] -N-methyl- amino} -cyclohexan-1-ylxy) -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(morpholin-4-yl) -sulfonyl] -N-methyl-amino} -cyclohexan-1-yloxy ) -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-ethanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-ethoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline-4 - [(3-chloro 4-fluoro-phenyl) amino] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy] -7- (2-methoxyethoxy) -quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4-acetylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

4 - [(3-Ethynylphenyl) amino] -6- [1- (tert-butyloxycarbonyl) -piperidin-4-yloxy] -7-methoxy-quinazoline

4 - [(3-ethynyl-phenyl) amino] -6- (tetrahydropyran-4-yloxy] -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(piperidin-1-yl) -carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy ) -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (cis-4- {N - [(4-methylpiperazin-1-yl) carbonyl] -N-methyl-amino} -cyclohexane - 1-yloxy) -7-methoxy-quinazoline 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {cis-4 - [(morpholin-4-yl) carbonylamino] -cyclohexane-1-yloxy} -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1- [2- (2-oxopyrrolidin-1-yl) -ethyl] -piperidin-4-yloxy} -7-methoxy-quinazoline - 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7- (2-methoxy-ethoxy) - quinazoline

4 - [(3-ethynylphenyl) amino] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline 4 - [(3-ethynyl-phenyl) -amino] -6- methyl-piperidin-4-yloxy) -7-methoxy-quinazoline 4 - [(3-ethynyl-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methyl-piperidin-4-yloxy) -7 (2-methoxy-ethoxy) -quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-isopropyloxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline-4 - [(3-chloro-4-fluoro-phenyl ) amino] -6- (cis-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {cis-4- [N- (2-methoxy-acetyl) -N-methyl-amino] -cyclohexane-1-yloxy} -7 -methoxy-quinazoline 4 - [(3-ethynyl-phenyl) -amino] -6- (piperidin-4-yloxy) -7-methoxy-quinazolin-4 - [(3-ethynyl-phenyl) -amino] -6- [l - (2-methoxy-acetyl) -piperidin-4-yloxy] -7-methoxy-quinazoline

4 - [(3-ethynylphenyl) amino] -6- {1- (morpholin-4-yl) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(cis-2,6-dimethyl-morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7- methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(2-methyl-morpholin-4-yl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(S, S) - (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) carbonyl] -piperidin-4-yloxy} -7-methoxyquinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- {1 - [(N-methyl-N-2-methoxyethyl- amino) carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-ethyl-piperidin-4-yloxy) -7-methoxy-quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(2-methoxyethyl) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline 4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- {1 - [(3-methoxy-propyl-amino) -carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [cis-4- (N-acetyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4-dimethylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (trans-4- {N - [(morpholin-4-yl) -carbonyl] -N-methyl-amino} -cyclohexan-1-yloxy ) -7-methoxy-quinazoline - 4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy] -

7 - [(S) - (tetrahydrofuran-2-yl) methoxy] -quinazoline

4 - [(3-Chloro-4-fluoro-phenyl) -amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline

4 - [(3-chloro-4-fluoro-phenyl) -amino] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.

Preferred dopamine agonists are compounds selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole,

Terguride and Viozan, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate,

Hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, Hydrobenzoate and hydro-p-toluenesulfonate.

As Hl antihistamines here preferably compounds are used, which are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene, clemastine, bamipine, Cexchlorpheniramin, pheniramine, doxylamine, chlorphenoxamine , Dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclocine, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.

As pharmaceutically active substances, substance formulations or

Substance mixtures are used for all inhalable compounds, e.g. also inhalable macromolecules, as disclosed in EP 1 003 478. Preferably, substances, substance formulations or substance mixtures are used for the treatment of respiratory diseases, which are used in the inhalation area.

Furthermore, the compound may be derived from the group of derivatives of ergot alkaloids, triptans, CGRP inhibitors, phosphodiesterase V inhibitors, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts, their solvates and / or or hydrates.

As derivatives of ergot alkaloids: dihydroergotamine, ergotamine.

Experimental part

(7) measuring method

a) Particle size determination by laser diffraction (average particle size X:

Meter and settings:

The operation of the equipment was carried out in accordance with the operating instructions of the manufacturer. Measuring instrument: laser diffraction s-spectrometer (HELOS), Sympatec (particle size determination by means of fraunhof diffraction)

Dispersing unit: Dry disperser RODOS with suction funnel, Sympatec

Sample amount: 200 mg + 150 mg

Product feed: vibrating trough Vibri, Fa. Sympatec

Frequency d. Vibrating trough: up to 100% rising

Duration of sample feeding: 15 to 25 sec. (in the case of 200 mg)

Focal length: 100 mm (measuring range: 0.9 - 175 μm)

Measuring time / waiting time: approx. 15 s (in the case of 200 mg)

Cycle time: 20 ms

Start / Stop at: 1% on channel 28

Dispersing gas: compressed air

Pressure: 3 bar

Negative pressure: maximum

Evaluation mode: HRLD

Sample preparation / product feed: Approx. 200 mg of the test substance are weighed on a map sheet.

With another map sheet, all larger agglomerates are crushed.

The powder is then placed on the front half of the vibrating trough (from about 1 cm from the front

Rand) scattered finely distributed.

After the start of the measurement, the frequency of the vibrating trough is varied so that the supply of the sample is as continuous as possible. The amount of product must not be too large so that adequate dispersion is achieved.

b) Determination of Drop Size by Laser Diffraction (Average Droplet Size X ₅₀ )

Measuring method: To determine the droplet size, the spray cone (spray) of the nozzle is analyzed directly in the laser measuring zone with respect to the droplet size distribution. The median value X ₅₀ is the drop size below which 50% of the drop quantity lies. H ₂ O is used as a test solution to determine suitable nozzle parameters. Measuring instrument: Laser diffraction spectrometer (HELOS) _{5 from} 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)

c) Determination of emulsion drop size (hydrodynamic diameter) by means of photon correlation spectroscopy (Zetasizer, Malvern) Measuring instrument: Zetasizer, Malvern, type Zetasizer Nano ZS

Software: Dispersion Technology Software Version 4.10 (Malvern)

Measurement conditions / measurement parameters Procedure: Measurement procedure as specified by the equipment manufacturer. The meter calculates the hydrodynamic diameter (Dh) of a suspension and gives the size distribution (volume-related determination mode). The measurement results listed below correspond to the respective main peaks of the determined size distributions (for the purposes of this invention, the droplet size of the main peak corresponds to the hydrodynamic

Diameter).

(2) Examples a) Dry powder formulations containing a water-soluble active ingredient

The preparation was carried out with the aid of a Büchi spray drier, type mini spray drier B-290. In this case, those listed in Table 2 were

Dry powder formulations obtained by preparing w / o (water in DCM) emulsions which were spray dried. The emulsions are prepared by means of an ultrasound apparatus (Sonics & Materilas Inc., type Vibra Cell, equipped with a 3 mm tip). For the preparation of the emulsion, the tip is immersed 0.5 2 cm in the solution and the ultrasonic apparatus at 30% operated.

b) Dry Powder Formulations Containing a Non-Water-Soluble Active Substance The dry powder formulations listed in Table 3 are obtained by spray-drying solutions of the polymer and the active ingredient budesonide.

Table 3: Dry powder formulations with budesonide

Release Behavior of Inventive Inhalable Powders The inhalable fraction of the inhalable powders according to the invention was investigated in a dissolution model (diffusion cell according to Franz) with respect to controlled release of the salbutamol or budesonide. (In order to consider the particle fraction that would deposit in a human application from the HandiHaler ^® in the lung, by inserting the cascade impactor stages 0 and 1 has been discriminated particles> 5 micrometers.)

The inhalable powders discussed in the following Examples 1 to 5, identified by the respective identification code, were obtained by means of spray-drying technology. The respective process parameters are listed in Table 4.

Table 4: Process parameters for the inhalable powders discussed in Examples 1-5.

Example 1 (Production method according to case A):

From the active substance salbutamol, inhalable embedding particles were prepared by spray-drying together with various triblock copolymers (identification code SR 2.8, SR 11, SR 14, SR 1.3).

In Figure 2, the release behavior (37 ⁰ C, release medium PBS buffer (phosphate-buffered-solution)) of the active ingredient in the inhalable fraction of the inhalable powder according to the invention is shown. The triblock copolymers used were LGP t 8546; LP t 52; LGP t 5046 and LRP 17046 are used. All particles showed retardation over 24 hours.

Example 2 (Production method according to case A):

From the active substance salbutamol, inhalable embedding particles were prepared by spray-drying together with various diblock-co-polymers

(Identification code SR 12.0, SR 13.0, SR 6.1).

In Figure 3, the release behavior is 37 ⁰ C, release medium PBS buffer

(Phosphate-buffered-solution)) of the active ingredient in the inhalable fraction of the inhalable powder according to the invention. The diblock co-polymers used were 2 o LGP d 8555; LRP d 7055 and RGP d 5055 are used. All particles showed retardation over 24 hours.

Example 3:

From the active ingredient salbutamol were together with the triblock co-polymer means

25 spray-drying made inhalable embedding particles. This was done in the

Sample with the identification code SBR 2.0, the spray drying such that from a homogeneous solution of the active ingredient and the polymer (embedding material: triblock copolymer LGP t 8546) in acetone, the spray drying was carried out. The pattern with the identification code SR 2.8, on the other hand, was made in such a way that

30 a W / O emulsion was prepared, wherein the active ingredient was dissolved in the aqueous phase and as the organic phase dichloromethane (dissolved therein: embedding material: Triblock co-polymer LGP t 8546) was used.

The pattern with the identification code SRME was prepared by adding additional ethanol to the W / O emulsion (water / dichloromethane) until

35 clarified the emulsion. Measurements by means of dynamic light scattering with a device of the Malvern, type Zetasizer nano ZS, showed that double peaks characteristic of microemulsions were observed at 12 nm and 300 nm, which were stable for at least 45 minutes.

In Figure 4, the release behavior 37 ⁰ C, release medium PBS buffer (phosphate-buffered-solution)) of the active ingredient in the inhalable fraction of the inhalable powder according to the invention is shown.

Example 4:

From the active substance salbutamol, together with the diblock co-polymer RGP d 5055, further inhalable embedding particles were prepared by spray drying (identification code SBR 3.0, SR 6.1).

In Figure 5, the release behavior 37 ⁰ C, release medium PBS buffer (phosphate-buffered-solution)) of the active ingredient in the inhalable fraction of the inhalable powder according to the invention is shown.

Example 5:

From the active ingredient budesonide were together with the triblock co-polymers LP t 52; LRP 17046 and LGP t 8546 produced further inhalable embedding particles by means of spray drying (identification code BR 3.0, BR 2.0, BR 1.2, bud micronisate corresponds to pure, jet-ground budesonide).

In Figure 6, the release behavior 37 ⁰ C, release medium PBS buffer (phosphate buffered solution)) of the active ingredient in the inhalable fraction of the inhalable powder according to the invention is shown.

Example 6 (Production method according to case B):

Embedding particles were prepared according to the "Case B" preparation method with a composition as indicated in Table 5. The composition of these embedding particles is listed in Table 5. In Figure 7 (Identification Code SBR 2.0, SBR 3.0, SBR 1.0) the release behavior is 37 ^° C, release medium PBS buffer (phosphate buffered solution) of the active ingredient in the inhalable fraction of the inhalable powder according to the invention.

Example 7 (Production Method according to Case C):

Embedding particles were prepared according to the manufacturing method "Case B" with a composition as indicated in Table 5. The composition of these embedding particles is listed in Table 5. In Figure 8 this is Release behavior 37 ^° C., release medium PBS buffer (phosphate-buffered solution) of the active ingredient in the inhalable fraction of the inhalable powder according to the invention. The polymer RG503H corresponds to a PLGA polymer having an end group -COOH and the polymer RG503S corresponds to a PLGA polymer having an end group of an alkyl radical.

Table 5: Compositions of the microparticles of Examples 1, 2, 6 and 7 (% - data correspond to mass per volume (w / v) in grams per declared volume). The current Nos. 1-4 correspond to Example 1, the current Nos. 5-7 correspond to Example 2, the current Nos. 8-10 correspond to Example 6, and the consecutive Nos. 11-15 correspond to Example 7.

Claims

claims

1. Inhalable powders for pulmonary or nasal inhalation use, characterized in that a maximum of 60% of the active ingredient in a maximum of 30 minutes, and a maximum of 80% of the active ingredient is released in a maximum of 10 hours, wherein the inhalable powder contains microparticles, in which one or more active ingredients embedded in an adjuvant matrix of a biodegradable polymer.

2. Inhalable powder according to claim 1, characterized in that the active substance has a water solubility of more than 0.01 g per 100 ml and the biodegradable polymer is a substance selected from the substance classes of PEG-

[Lactide-co-glycolides] or the PEG- [poly-lactides], wherein the polymer (i) has a PEG content of 1-15% (mass% based on the

Total molecular weight of the biodegradable polymer), (ii) has a molecular mass between 37.5-150 kDa, (iii) has a diblock structure,

(iv) a glycolide fraction of 0-5%, preferably 0% (mass% based on molecular mass, 100% being based on the molecular mass of polymer block A of the co-polymer),

(v) a lactide content of 95-100%, preferably 100% (mass% based on the molecular mass and 100% based on the molecular mass of the polymer

Block A of the co-polymer) contains and

(vi) the lactide moiety may contain the components L-lactide and D-lactide and the D-lactide to the L-lactide maximally in the ratio n: A and n is a number less than or equal to 1, optionally the lactide portion exclusively made of L-lactide or the polymer

(I) a PEG content of 1 - 15% (% by mass based on the

Total molecular weight of the biodegradable polymer), (ii) has a molecular mass between 37.5-150 kDa, (iii) has a triblock structure,

(iv) a glycolide fraction of 0-15%, preferably 0% (mass% based on molecular mass, with 100% being based on the molecular mass of polymer block A of the co-polymer),

(v) a lactide content of 85-100%, preferably 100% (mass% based on the molecular mass and 100% based on the molecular mass of the polymer

Block A of the co-polymer) contains and (vi) the lactide moiety may contain the components L-lactide and D-lactide and the D-lactide to the L-lactide is at a maximum of n: 4 and n is a number less than or equal to 1, optionally the lactide moiety exclusively made of L-lactide.

3. Inhalable powder according to claim 1, characterized in that the active ingredient has a solubility of more than 0.01 g per 100 mL in an organic solvent which is completely miscible with water, and the biodegradable polymer is a substance selected from the class of PEG -

[Lactide-co-glycolides], where the polymer

(I) a PEG content of 10 - 15% (% by mass based on the

Total molecular weight of the biodegradable polymer), (ii) has a molecular mass between 37.5-150 kDa, (iii) has a diblock structure or triblock structure,

(iv) a glycolide content of 20-50% (% by weight based on the

(v) a lactide content of 50-80% (mass% based on molecular mass and 100% based on the molecular mass of the polymer block

A of the co-polymer) contains and

(vi) the lactide moiety may contain the components L-lactide and D-lactide and the D-lactide to the L-lactide is at a maximum of n: 4 and n is a number less than or equal to 1, optionally the lactide moiety exclusively made of L-lactide.

4. Inhalable powder according to claim 1, characterized in that the active substance has a solubility in an organic solvent, preferably dichloromethane of more than 0.01 g per 100 ml and the biodegradable polymer is a substance selected from the class of PEG- [lactide-co-polymer]. Glycolide], wherein the

polymer

(I) a PEG content of 10 - 15% (% by mass based on the

Total molecular weight of the biodegradable polymer), (ii) has a molecular mass between 15-150 kDa, (iii) has a diblock structure or triblock structure, (iv) a glycolide content of 15-50% (% by weight based on the

(v) a lactide content of 50-85% (mass% based on molecular mass and 100% based on the molecular mass of the polymer block

A of the co-polymer) contains and

(vi) the lactide moiety may contain the components L-lactide and D-lactide and the D-lactide to the L-lactide is at a maximum of n: 4 and n is a number less than or equal to 1, optionally the lactide moiety exclusively consists of L-lactide or the polymer is a substance of the class PLGA with a modified end group, wherein the end group of the polymer is selected from the group consisting of -COOH and a terminal alkyl group.

5. Inhalable powder according to one of claims 1 to 4, characterized in that it is produced by means of a spray-drying process.

6. A process for the preparation of microparticles in the form of embedding particles according to claim 2, comprising one or more active substances which have a water solubility of more than 0.01 g per 100 ml, the process comprising the steps

(i) preparing a (W / O) emulsion, wherein the active substance (s) are dissolved in water and, as the organic phase, preferably dichloromethane is used, in which the polymer is dissolved, (ii) spraying the solution thus obtained in a customary manner, so that one

Spray mist with a droplet size with the characteristic X ₅₀ between 7 microns and 25 microns is present, (iii) drying of the spray thus obtained with the aid of a drying gas

Application of the following parameters: - An inlet temperature of the drying gas from 3O ⁰ C to 35O ⁰ C, preferably from 4O ⁰ C to 25O ⁰ C and particularly preferably from 45 ⁰ C to 15O ⁰ C and

- A starting temperature of the drying gas from 3O ⁰ C to 12O ⁰ C and (iv) separating the dried solid particles from the drying gas stream in a conventional manner. includes.

7. A process for the preparation of microparticles in the form of embedding particles according to claim 3, containing one or more active ingredients, by the active substance (s) in an organic solvent which is indefinitely water

5 is miscible, the active substance or solubility in this

Solvents greater than 0.01 g per 100 mL, comprising the steps of (i) preparing a solution by dissolving the active compound and the polymer in an organic solvent,

(Ii) spraying the solution thus obtained in a conventional manner, so that a lo mist with a droplet size with the characteristic X ₅₀ between 7 microns and

25 μm is present

(iii) drying the spray mist thus obtained by means of a drying gas, while applying the following parameters: an inlet temperature of the drying gas of 3O ⁰ C to 35O ⁰ C,

15 preferably from 4O ⁰ C to 25O ⁰ C and most preferably from 45 ⁰ C to

15O ⁰ C and a starting temperature of the drying gas from 3O ⁰ C to 12O ⁰ C and (iv) separating the dried solid particles from the drying gas stream in a conventional manner. 20

8. A process for the preparation of microparticles in the form of embedding particles according to claim 4, comprising one or more active substances which have a solubility in an organic solvent, preferably dichloromethane of more than 0.01 g per 100 ml, comprising the steps

25 (i) preparing a solution containing the active substance (s) and the polymer,

(Ii) spraying the solution thus obtained in the usual way, so that a

(Iii) drying of the spray thus obtained with the aid of a drying gas under 30 application of the following parameters: an inlet temperature of the drying gas of 3O ⁰ C to 35O ⁰ C, preferably from 4O ⁰ C to 25O ⁰ C and particularly preferably from 45 ⁰ C to 15O ⁰ C and a starting temperature of the drying gas from 3O ⁰ C to 12O ⁰ C and 35 (iv) separating the dried solid particles from the drying gas stream in a conventional manner.

9. Inhalable powder obtainable by one of the methods according to one of claims 6 to 8.

10. Medicament characterized in that it contains an inhalable powder according to one of claims 1 to 5 or 9.