EP1957070A1

EP1957070A1 - Aerosol formulation for inhalation containing an anticholinergic agent

Info

Publication number: EP1957070A1
Application number: EP06819435A
Authority: EP
Inventors: Friedrich Schmidt
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: 2005-11-24
Filing date: 2006-11-13
Publication date: 2008-08-20
Also published as: DE102005055958A1; CA2629073A1; WO2007060105A1; US20090221626A1; JP2010509183A

Abstract

The invention relates to specific aqueous aerosol formulations that are devoid of propellant, containing one or more anticholinergic agents of formula (1), in which X represents an anion, and containing at least one pharmacologically compatible organic acid and optionally additional pharmacologically compatible adjuvants and/or complexing agents. The cation of formula (1') is contained in the preparation at a concentration of between 411 and 460.32 mg per 100 ml of medicament preparation.

Description

Aerosol formulation for inhalation containing an anticholinergic

The present invention relates to specific propellant-free, aqueous aerosol formulations containing one or more anticholinergics of formula 1

wherein

X ^"means an anion

at least one pharmacologically acceptable, organic acid and optionally further pharmacologically acceptable excipients and / or complexing agents,

where the cation of the formula V

in the preparation at a concentration of 411 to 460.32 mg per 100 ml of pharmaceutical preparation.

The compounds of the formula 1 are known from WO 02/32899. They have valuable pharmacological properties and can be used as highly effective anticholinergics in the treatment of respiratory diseases, in particular in the treatment of inflammatory and / or obstructive respiratory diseases, in particular in the treatment of asthma or COPD (chronic obstructive pulmonary disease = chronic obstructive pulmonary disease) develop a therapeutic benefit.

The present invention is concerned with inhalable liquid drug formulations of these compounds, wherein the liquid formulations of the invention must meet high quality standards. The formulations according to the invention can be inhaled orally or pernasally. In order to obtain an optimal active ingredient distribution of the active substances in the lung, the application of a liquid, dispensing with propellant gases, formulation by means of suitable inhalers offers. The inhalative administration of such a formulation can be carried out both orally and nasally. Particularly suitable are those inhalers which can nebulise a small amount of a liquid formulation in the therapeutically necessary dosage within a few seconds in a therapeutically inhalable aerosol. In the context of the present invention, preference is given to those nebulizers in which an amount of less than 100 microliters, preferably less than 50 microliters, more preferably less than 20 microliters of active solution, preferably one stroke or two strokes, results in an aerosol with an average particle size of less than 20 microns, preferably less than 10 microns, can be so nebulised that the inhalable fraction of the aerosol already corresponds to the therapeutically effective amount.

Such a device for propellant-free administration of a metered quantity of a liquid medicament for inhalation use is described, for example, in International Patent Application WO 91/14468 "Atomizing Device and Methods" and also in WO 97/12687 (there FIGS. 6a and 6b and the associated description). described in detail. In such a nebulizer, a drug solution is transferred by means of high pressure of up to 500 bar in a respirable aerosol and sprayed. In the context of the present invention description, reference is expressly made to the cited references in their entirety. In such inhalers, the solution formulations are stored in a reservoir. It is necessary that the active compound formulations used have sufficient storage stability and at the same time are such that they can be applied directly for medical purposes as possible without further manipulation. Furthermore, they must not contain components which may interact with the inhaler in such a way that the inhaler or the pharmaceutical grade of the solution or the aerosol produced could be damaged. To atomize the solution, a special nozzle is used, as described, for example, WO 94/07607 or WO 99/16530. Both are hereby incorporated by reference.

WO 04/022052 A1 likewise describes aqueous, propellant-free aerosol formulations for the anticholinergic of the formula 1. In these aqueous formulations, the anticholinergic of formula 1 is contained in combination with at least one organic or inorganic, pharmacologically acceptable acid and optionally with further pharmacologically acceptable excipients and / or complexing agents.

It is an object of the present invention to provide an aqueous formulation of the compound of the formula ,_ which meets the high standards which are necessary in order to be able to optimally nebulize a solution by means of the inhalers mentioned above and which ones over the aqueous formulations according to the prior art possess improved properties. The active ingredient formulations according to the invention must also have a sufficient pharmaceutical grade, i. they should be pharmaceutically stable over a shelf life of a few years, preferably at least one year, more preferably two years.

These propellant-free solution formulations must also be able to be atomized under pressure by means of an inhaler, wherein the mass discharged in the generated aerosol is reproducibly within a defined range.

The object of the invention is achieved by an aqueous

Pharmaceutical preparation for inhalation containing one or more, preferably a compound of formula I ₁

wherein X ^{~ is} an anion, a pharmacologically acceptable organic acid and other pharmacologically acceptable excipients and / or complexing agents, wherein the cation of formula V

in the preparation in a concentration of 411 to 460.32 mg per 100 ml of pharmaceutical preparation.

Used within the scope of the present invention, preferred are those compounds of formula 1 for use, in which the anion X ^~ is selected from chloride, bromide, iodide from the group, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, Tartrate, oxalate, succinate, benzoate and p-toluenesulfonate.

Preferably, the salts of formula 1 are used, wherein X - is an anion selected from the group consisting of chloride, bromide, 4-toluenesulfonate and methanesulfonate.

According to the invention particularly preferred in the context of the present invention are those formulations which contain the compound of the formula I _1, wherein X ^~ denotes bromide.

Aqueous pharmaceutical preparation are preferred for inhalation containing one or more, preferably one compound of the formula 1_Jn the X ^"denotes bromide, a pharmacologically acceptable organic acid, and other pharmacologically acceptable excipients and / or complexing agent, wherein per 100 ml of pharmaceutical preparation 500 mg to 560 of the Bromids of formula 1 are included.

References to the compound of formula 1 in the context of the present invention always include all possible amorphous and crystalline Modifications of this connection with. References to the compound of formula 1 in the context of the present invention furthermore include all possible solvates and hydrates which can be formed by this compound.

An optionally occurring within the scope of the present invention

Reference to compound V is to be understood as referring to the pharmacologically active cation of the following formula contained in salts 1

In the formulation according to the invention, compound 1 is dissolved in water. If necessary, co-solvents can be used. According to the invention, however, a further solvent is not used.

According to the invention, the concentration of the compound of the formula Λ_ based on the proportion of pharmacologically active cation V in the pharmaceutical preparation according to the invention is preferably about 419.2 to 452.1 mg per 100 ml. More preferably, 100 ml of the formulations according to the invention contain about 427.44 to 448 mg 1 ', in particular about 434.69 mg Y_.

If, as the compound of the formula 1, the compound particularly preferred according to the invention is used in which X - represents the bromide, the proportion of I according to the invention is preferably about 510 to 550 mg of pharmaceutical preparation. Particularly preferably, 100 ml of the pharmaceutical preparation according to the invention contain 520 to 545 mg, in particular about 528.821 mg of the compounds of the formula I-.

According to the invention, the formulation preferably contains only a single salt of the formula I-. However, the formulation may also contain a mixture of different salts of formula 1. The pH of the formulation according to the invention is preferably in a range from 2.5 to 6.5, preferably in a range from 3.0 to 5.0, more preferably in the range from 3.5 to 4.5, in particular in the range from 2.5 to 6.5 Range 3.6 to 4.4.

The pH is adjusted by adding organic, pharmacologically acceptable acids. Examples of organic, pharmacologically acceptable acids are selected from the group consisting of ascorbic, citric, malic, tartaric, maleic, succinic, fumaric, acetic, formic and propionic acids. Preferred organic, pharmacologically acceptable acids are ascorbic acid, fumaric acid and citric acid, citric acid being particularly preferred according to the invention. Optionally, mixtures of said acids may also be employed, particularly in the case of acids which, in addition to their acidification properties, also possess other properties, e.g. as flavorants or antioxidants, such as citric acid or ascorbic acid.

Optionally, pharmacologically acceptable bases can be used to accurately titrate out the pH. Suitable bases are, for example, alkali metal hydroxides and alkali metal carbonates. Preferred alkali ion is sodium. If such bases are used, care should be taken that the resulting salts, which are then included in the finished drug formulation, are pharmacologically acceptable with the above acid.

Preferably, the formulations according to the invention contain as organic, pharmacologically acceptable acid citric acid in a concentration of 2 to 5 mg per 100 ml solution, in particular in a concentration of 3 mg per 100 ml solution.

The formulations according to the invention may contain complexing agents as further constituents. In the context of the present invention, complexing agents are understood as meaning molecules which are capable of being formed

To enter into complex bonds. Cations, more preferably metallic cations, are preferably to be complexed by these compounds. The formulations according to the invention contain as complexing agents preferably editic acid (EDTA) or a known salt thereof, for example sodium EDTA or disodium EDTA. Preference is given to using sodium edetate, if appropriate in the form of its hydrates, particularly preferably in the form of its dihydrate. If complexing agents are used in the formulations according to the invention, their content is preferably in a range of 5 to 20 mg per 100 ml, more preferably in a range of 7 to 15 mg per 100 ml of inventive formulation. The formulations according to the invention particularly preferably contain a complexing agent, preferably sodium edetate or one of its hydrates, in an amount of about 9 to 12 mg per 100 ml, in particular about 10 mg per 100 ml of the formulation according to the invention.

Analogous as already stated for sodium edetate, also applies to possible, comparable with EDTA or its salts additives that have complexing properties and can be used instead, such as nitrilotriacetic acid and its salts.

The formulation according to the invention may be added further pharmacologically acceptable excipients. In this context, auxiliaries and additives are understood as meaning any pharmacologically acceptable and therapeutically useful substance which is not an active substance but which can be formulated together with the active substance in the pharmacologically suitable solvent in order to improve the qualitative properties of the active ingredient formulation. These substances preferably do not develop any appreciable or at least no undesirable pharmacological effect in the context of the intended therapy. The auxiliaries and additives include e.g. Stabilizers, antioxidants and / or preservatives that extend the useful life of the finished drug formulation as well as flavorings, vitamins and / or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride.

Preferred excipients include antioxidants, such as ascorbic acid, if not already used for pH adjustment, vitamin A, vitamin E, tocopherols, and similar vitamins or provitamins found in the human organism.

Preservatives may be used to protect the formulation from contamination with pathogenic germs. Suitable preservatives are those known in the art, in particular benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art. Preferably, the formulation of the invention benzalkonium chloride is added. The amount of benzalkonium chloride is between 1 mg and 50 mg per 100 ml formulation, preferably about 7 to 15 mg per 100 ml, more preferably about 9 to 12 mg per 100 ml of the formulation according to the invention, in particular 10 mg per 100 ml of the formulation according to the invention.

Preferred formulations contain, in addition to the solvent water and the compound of formula 1, only benzalkonium chloride, sodium edetate and the acid necessary for adjusting the pH.

The medicament formulations according to the invention with the compound of the formula 1 are preferably used in an inhaler of the type described above in order to produce therefrom the propellant-free aerosols according to the invention. For this reason, reference should again be made expressly to the patent documents described at the outset, to which reference is hereby incorporated by reference.

As described above, a further developed embodiment of the preferred inhaler is disclosed in WO 97/12687 (see there in particular FIGS. 6a and 6b and the relevant parts of the description). This nebuliser (Respimat ^®) can advantageously be used to produce the inhalable aerosols according to the invention. Due to its cylindrical shape and a handy size of less than 9 to 15 cm in length and 2 to 4 cm in width, this device can always be carried by the patient. The nebulizer sprays a defined volume of the drug formulation using high pressures through small nozzles to produce inhalable aerosols.

Essentially, the preferred atomizer of an upper housing part, a pump housing, a nozzle, a locking mechanism, a spring housing, a spring and a reservoir, characterized by

a pump housing which is fastened in the housing upper part and which carries at its one end a nozzle body with the nozzle or nozzle arrangement, a hollow piston with valve body,

an output flange in which the hollow piston is fastened and which is located in the upper part of the housing,

a blocking clamping mechanism, which is located in the upper housing part, a spring housing with the spring therein, which is rotatably mounted on the upper housing part by means of a rotary bearing,

- A lower housing part, which is attached to the spring housing in the axial direction. The hollow piston with valve body corresponds to a disclosed in WO 97/12687 devices. It partially protrudes into the cylinder of the pump housing and is arranged axially displaceably in the cylinder. In particular, reference is made to FIGS. 1-4, in particular FIG. 3, and the associated parts of the description of the abovementioned International Patent Application. The hollow piston with

Valve body exerts on its high pressure side at the time of release of the spring a pressure of 5 to 60 MPa (about 50 to 600 bar), preferably 10 to 60 MPa (about 100 to 600 bar) on the fluid, the measured drug solution from. Volumes of from 10 to 50 microliters are preferred, with volumes of from 10 to 20 microliters being particularly preferred, very particularly preferably a volume of from 10 to 15 microliters per actuation (stroke).

The valve body is preferably attached to the end of the hollow piston, which faces the nozzle body.

The nozzle in the nozzle body is preferably microstructured, i. produced by microtechnology. Microstructured nozzle bodies are disclosed, for example, in WO-99/16530; This document is hereby incorporated by reference, in particular to the figure 1 and its description disclosed therein. The nozzle body consists e.g. of two fixed plates of glass and / or silicon, at least one plate of which has one or more microstructured channels connecting the nozzle inlet side to the nozzle outlet side. At the nozzle outlet side, at least one round or non-round aperture is 2 to 10 microns deep and 5 to 15 microns wide, with the depth preferably being 4.5 to 6.5 microns and the length being 7 to 9 microns.

In the case of a plurality of nozzle openings, preferably two, the jet directions of the nozzles in the nozzle body can be parallel to one another or they are inclined towards one another in the direction of the nozzle opening. In a nozzle body having at least two nozzle openings on the outlet side, the jet directions may be inclined at an angle of 20 degrees to 160 degrees to each other, preferably an angle of 60 to 150 degrees, particularly preferably 80 to 100 °. The nozzle orifices are preferably located at a distance of 10 to 200 microns, more preferably at a distance of 10 to 100 microns, more preferably 30 to 70 microns. Most preferred are 50 microns.

The jet directions accordingly meet in the vicinity of the nozzle openings. The liquid pharmaceutical preparation meets as already mentioned with an inlet pressure of up to 600 bar, preferably 200 to 300 bar to the nozzle body and is atomized via the nozzle openings in an inhalable aerosol. The preferred particle sizes of the aerosol are up to 20 microns, preferably 3 to 10 microns.

The locking mechanism includes a spring, preferably a cylindrical helical compression spring, as a memory for the mechanical energy. The spring acts on the output flange as a jump piece whose movement is determined by the position of a locking member. The path of the output flange is precisely limited by an upper and a lower stop. The spring is preferably transmitted via a force translating gear, e.g. a Schraubschubgetriebe, stretched by an external torque that is generated when turning the upper housing part against the spring housing in the lower housing part. In this case, the upper housing part and the output flange contain a single or multi-start wedge gear.

The locking member with engaging locking surfaces is arranged annularly around the output flange. There is e.g. from a radially elastically deformable ring made of plastic or metal. The ring is arranged in a plane perpendicular to the atomizer axis. After tensioning the spring, the push

Locking surfaces of the locking member in the way of the output flange and prevent the relaxation of the spring. The Sprerrglied is triggered by a button. The release button is connected or coupled to the locking member. To trigger the locking mechanism, the shutter button is parallel to the ring plane, and preferably in the atomizer, moved; while the deformable ring is deformed in the ring plane. Constructive details of the locking mechanism are described in WO 97/20590.

The lower housing part is pushed in the axial direction over the spring housing and covers the storage, the drive of the spindle and the reservoir for the fluid.

When actuating the atomizer, the upper housing part is rotated against the lower housing part, wherein the lower housing part entrains the spring housing. The spring is compressed and tensioned via the screw slide, and the lock engages automatically. The angle of rotation is preferably an integer fraction of 360 degrees, for example 180 degrees. Simultaneously with the tensioning of the spring, the driven part is displaced in the upper housing part by a predetermined distance, the hollow piston is within the cylinder in the pump housing withdrawn, whereby a subset of the fluid from the reservoir is sucked into the high-pressure chamber in front of the nozzle.

If necessary, a plurality of interchangeable reservoirs containing the fluid to be atomized can be inserted and used successively in the atomizer. The storage container contains the aqueous aerosol preparation according to the invention.

The sputtering process is initiated by lightly pressing the shutter button. The blocking mechanism clears the way for the stripping section. The tensioned spring pushes the piston into the cylinder of the pump housing. The fluid exits the nozzle of the atomizer in atomized form.

Further design details are disclosed in PCT applications WO 97/12683 and WO 97/20590, the contents of which are hereby incorporated by reference.

The components of the atomizer (nebulizer) are made of a functionally suitable material. The housing of the atomizer and, as far as the function permits, other parts are preferably made of plastic, e.g. by injection molding. Physiologically harmless materials are used for medical purposes.

FIGS. 6 a / b of WO 97/12687 describe the nebuliser (Respimat®) with which the aqueous aerosol preparations according to the invention can advantageously be inhaled.

FIG. 6 a shows a longitudinal section through the atomizer with the spring tensioned, FIG. 6 b shows a longitudinal section through the atomizer with the spring relaxed.

The upper housing part (51) contains the pump housing (52), at the end of which the holder (53) for the atomizer nozzle is mounted. In the holder is the nozzle body (54) and a filter (55). The hollow piston (57) fastened in the output flange (56) of the locking mechanism projects partially into the cylinder of the pump housing. At its end, the hollow piston carries the valve body (58). The hollow piston is sealed by means of the seal (59). Within the upper housing part is the stop (60) on which the output flange rests with a relaxed spring. At the output flange is the stop (61) on which the output flange rests when the spring is tensioned. After tensioning the spring, the locking member (62) slides between the stop (61) and a support (63) in the upper housing part. The release button (64) is connected to the locking member in connection. The upper housing part ends in the mouthpiece (65) and is closed with the attachable protective cap (66).

The spring housing (67) with compression spring (68) is rotatably supported by means of the snap lugs (69) and pivot bearing on the upper housing part. About the spring housing, the lower housing part (70) is pushed. Within the spring housing is the replaceable reservoir (71) for the fluid (72) to be atomized. The reservoir is closed with the stopper (73) through which the hollow piston protrudes into the reservoir and with its end immersed in the fluid (stock of drug solution).

In the lateral surface of the spring housing, the spindle (74) for the mechanical counter is mounted. At the end of the spindle, which faces the upper housing part, there is the drive pinion (75). The rider (76) sits on the spindle.

The nebulizer described above is suitable for nebulizing the aerosol preparations according to the invention to form an aerosol suitable for inhalation.

If the formulation according to the invention nebulised using the method described above (Respimat ^®), the mass expelled, in at least 97%, preferably at least 98% of all actuations of the inhaler (puffs) a defined quantity with a tolerance of not more than 25%, preferably from 20 % of this amount. Preferably, between 5 and 30 mg of formulation per stroke are applied as a defined mass, more preferably between 5 and 20 mg.

The formulation according to the invention can also be nebulized by means of inhalers other than those described above, for example jet stream inhalers.

If the pharmaceutical preparation of the formula 1 according to the invention, wherein X ^"denotes bromide, is atomized by means of the Respimats ^®, as are per stroke (= per actuation of the inhaler), preferably 47.28 to 52.95 ug ug of the compound of formula 1 administered. Depending on the desired therapeutic effect, up to 4, preferably up to 3, particularly preferably 1 or 2 actuations of the inhaler (= strokes) can be carried out per application of the solutions according to the invention. The present invention further relates to an inhalation kit consisting of one of the above-described pharmaceutical preparations according to the invention and an inhaler suitable for fogging this pharmaceutical preparation. The present invention preferably relates to an inhalation kit consisting of one of the pharmaceutical preparations according to the invention the inhaler described above and the Respimat ^® described above.

The formulation examples set forth below serve to further illustrate without limiting the subject matter of the present invention to the compositions exemplified.

I. Formulation example

100 ml of a particularly preferred pharmaceutical preparation contains in purified water or in water for injections with a density of 1, 00 g / cm ³ at a temperature of 15 ⁰ C to 31 ⁰ C following ingredients:

In one possible embodiment, a dose to be administered comprises two actuations of the inhaler, i. two strokes. Consequently, in the case of the abovementioned particularly preferred pharmaceutical preparations, a total of about 94.55 to 105.90 μg, in particular 100 μg, of the compound of formula 1 are administered per patient dose. The solutions are preferably used in 4.5 ml cartridges in the Respimat.

Claims

claims

1) Aqueous medicament preparation for inhalation containing a compound of the formula

wherein

X ^'is an anion, at least one pharmacologically acceptable, organic acid and optionally further pharmacologically acceptable excipients and / or

complexing

characterized in that the cation of formula V

2) An aqueous drug composition according to claim 1, wherein the anion X ^"is selected from the group consisting of chloride, bromide, iodide, sulfate,

Phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate. 3) An aqueous pharmaceutical preparation according to claim 2, comprising at least one compound of formula 1 wherein X ^{~ is} selected from the group consisting of chloride, bromide, 4-toluenesulfonate and methanesulfonate.

4) An aqueous pharmaceutical preparation according to claim 3, containing at least one compound of formula I ₁ wherein X is ^~ bromide.

5) Aqueous pharmaceutical preparation according to claim 4, characterized in that the compound of formula 1_, wherein X is ^~ bromide, present in the preparation in a concentration of 510 to 550 mg per 100 ml of pharmaceutical preparation.

6) Aqueous pharmaceutical preparation according to claim 4, characterized in that the compound of formula 1, wherein X is ^~ bromide, present in the preparation in a concentration of 520 to 545 mg per 100 ml of pharmaceutical preparation.

7) An aqueous pharmaceutical preparation according to any one of claims 1 to 6, wherein the pharmacologically acceptable, organic acid is selected from ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid,

Succinic acid, fumaric acid, acetic acid, formic acid and propionic acid.

8) An aqueous pharmaceutical preparation according to claim 7, wherein the pharmacologically acceptable, organic acid is citric acid or ascorbic acid.

9) Aqueous pharmaceutical preparation according to claim 8, characterized in that citric acid in the concentration of 2 to 5 mg per 100 ml preparation is used as the pharmacologically acceptable acid.

10) Aqueous pharmaceutical preparation according to one of claims 1 to 9, characterized by a pH of 3.0 to 5.0.

11) Aqueous pharmaceutical preparation according to one of claims 1 to 10, characterized by a pH of 3.6 to 4.4.

12) Aqueous pharmaceutical preparation according to one of claims 1 to 11, characterized in that they contain benzalkonium chloride as an excipient. 13) Aqueous pharmaceutical preparation according to claim 12, characterized in that the content of benzalkonium chloride is 7 to 15 mg per 100 ml of preparation.

14) Aqueous pharmaceutical preparation according to one of claims 1 to 13, characterized in that they contain as further constituent a complexing agent.

15) Aqueous pharmaceutical preparation according to claim 14, characterized in that is used as a complexing agent editic acid (EDTA) or one of its salts or hydrates.

16) Aqueous pharmaceutical preparation according to claim 15, characterized in that is used as a complexing agent disodium edetate or one of its hydrates in the concentration of 7 to 15 mg per 100 ml of preparation.

17) Use of an aqueous pharmaceutical preparation according to any one of claims 1 to 16 for the manufacture of a medicament for the treatment of respiratory diseases.

Use according to claim 17, wherein 94.55 μg to 105.9 μg of a compound of the formula I in which X-bromide is used are applied.