HK1081461A - Aerosol formulation for inhalation containing an anticholinergic agent - Google Patents

Description

Aerosol formulation for inhalation comprising an anticholinergic

Field of the invention

The invention relates to a method for producing a composite material1Propellant-free aqueous aerosol formulations for anticholinergics

Wherein X^-Represents an anion.

Prior Art

Formula (II)1The compounds are known from WO 02/32899. Formula (II)1The compounds have valuable pharmacological properties and are useful as highly potent anticholinergic agents in the treatment of respiratory disorders, in particular in the treatment of inflammatory and/or obstructive airways diseases, in particular in the treatment of asthma or COPD (chronic obstructive pulmonary disease).

Disclosure of Invention

The invention relates to liquid active substance preparations of such compounds for administration by inhalation; wherein the liquid formulation according to the invention meets high quality standards. The formulations according to the invention can be inhaled by the oral or nasal route. To achieve an optimal distribution of the active substance in the lungs, liquid preparations without propellant can be administered with the aid of suitable inhalers. Administration of such formulations by inhalation may be oral or nasal. A particularly suitable inhaler is one that can aerosolize a small quantity of a liquid formulation in a few seconds in a dose required for therapeutic inhalation. Within the scope of the present invention, a preferred nebulizer is an active substance solution of less than 100 microliters, preferably less than 50 microliters, more preferably less than 20 microliters, preferably nebulizable in one or two sprays and forming an aerosol with a mean particle size of less than 20 micrometers, preferably less than 10 micrometers, so that the respirable fraction of the aerosol already corresponds to a therapeutically effective amount.

Such devices for propellant-free administration of a metered dose of a liquid pharmaceutical formulation for inhalation are described, for example, in international patent application WO 91/14468 "atomising device and method"; and WO 97/12678, reference being made to figures 6a and 6b and the accompanying description thereof. Such nebulizers transfer the pharmaceutical preparation solution to the lungs as an aerosol and spray by means of high pressures of up to 500 bar. Within the scope of this specification, the entire contents of which are incorporated herein by reference.

In such inhalers, the solution formulation is stored in a reservoir. It is therefore necessary that the active substance preparations used are of a type which have sufficient storage stability and at the same time can be administered directly, depending on the medical purpose, without further processing. It furthermore does not contain any components that can interact with the inhaler and thus impair the inhaler, or the pharmaceutical quality of harmful solutions, or the harmful generation of aerosols.

For atomizing the solution, special nozzles as described in, for example, WO 94/07607 or WO 99/16530 are used. Both of these publications are incorporated herein by reference.

The invention aims to provide a formula1Aqueous formulations of the compounds which meet the high standards required for the use of the best nebulized solutions for the above-mentioned inhalers. The active substance formulations according to the invention must therefore have sufficient pharmaceutical quality, i.e. have a pharmaceutical stability of up to several years, preferably at least one year, more preferably two years. Such propellant-free solution formulations must be nebulized under pressure by means of an inhaler, wherein the substance removed from the aerosol produced is reproducible within specified limits.

Within the scope of the present invention, preference is given to using compounds in which the anion X is^-Is selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, and p-toluenesulfonate1A compound is provided.

Preference is given to using compounds of the formula in which X-is selected from the group consisting of chloride, bromide, 4-toluenesulfonate and methanesulfonate1A salt.

Particularly preferred formulations within the scope of the present invention are those containing X therein^-Is a bromide of formula1A compound is provided.

The formulae referred to within the scope of the invention1The compound often comprises all possible none of the compoundModified compounds in both amorphous and crystalline forms. To the formula1The compounds also include all solvates and hydrates that may be formed from the compounds.

Within the scope of the invention, any reference to a compound1′Can be considered as a salt 1 comprising a pharmacologically active cation of the formula:

in the formulations according to the invention, the compounds1Is dissolved in water. Cosolvents may also be used if desired. Preferably no other solvent is used according to the invention.

According to the invention, the preparation preferably contains only a single formula1And (3) salt. However, the formulations may also contain1Mixtures of different salts of (a). Contains formula (II)1The formulation of active substances other than these is not the subject of the present invention.

Based on pharmacologically active cations in the pharmaceutical preparations of the invention1′Is of the formula1The compound concentration is about 4 to 2000 mg per 100 ml and preferably about 8 to 1600 mg per 100 ml. Particularly preferred 100 ml formulations of the present invention contain from about 80 to about 1360 mg1′。

If the invention is used1Compounds As particularly preferred compounds are those in which X-represents a bromide, according to the invention1In an amount of about 5 to 2500 mg per 100 ml of the pharmaceutical preparation, preferably about 10 to 2000 mg per 100 ml. Most preferably 100 ml of the formulation of the present invention contains about 100 to 1700 mg of the formula1A compound is provided.

The pH of the preparations according to the invention is preferably from 2.5 to 6.5, more preferably from 3.0 to 5.0, particularly preferably from about 3.5 to 4.5.

The pH can be adjusted by the addition of a pharmacologically acceptable acid. Pharmacologically acceptable inorganic acids or organic acids may be used. Preferred inorganic acids are, for example, those selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid. Particularly suitable organic acids are, for example, those selected from ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and propionic acid. Preferred inorganic acids are hydrochloric acid and sulfuric acid, with hydrochloric acid being particularly preferred according to the invention. Among the organic acids, ascorbic acid, fumaric acid and citric acid are preferable, and citric acid is more preferable. If desired, it is also possible to use mixtures of the abovementioned acids, in particular acids which have other properties in addition to the acidifying properties, for example as flavoring or antioxidant agents, for example acids of citric acid or ascorbic acid.

Pharmacologically acceptable bases can be used to accurately titrate the pH if desired. Suitable bases include, for example, alkali metal hydroxides and alkali metal carbonates. The preferred alkali metal ion is sodium. If such a base is used. Care must be taken to ensure that the resulting salt contained in the finished pharmaceutical formulation is pharmacologically compatible with the above-mentioned acids.

The preparations according to the invention may also contain complexing agents as further constituents. Complexing agents in the context of the present invention mean molecules which can be brought into a complex state. Preferably, the complexation is performed by a cation, most preferably a metal cation, of such a compound. The formulation according to the invention is preferably edetic acid (EDTA) or its known salts, such as sodium EDTA or disodium EDTA, as complexing agent. Sodium acetate is preferably used, optionally in the form of its hydrate, more preferably in the form of the dihydrate. The complexing agent used in the context of the preparation according to the invention is preferably present in an amount of from 5 to 20 mg per 100 ml of the preparation according to the invention, more preferably from 7 to 15 mg per 100 ml. The preparations according to the invention preferably contain an amount of complexing agent of about 9 to 12 mg per 100 ml of the preparation according to the invention, more preferably about 10 mg per 100 ml.

Similar to EDTA sodium salt, it can also be used in comparable additives to EDTA or its salts, which have complexing properties, which can be used instead of DETA sodium salt, such as nitrilotriacetic acid and its salts.

Other pharmacologically acceptable adjuvants may also be added to the formulations of the present invention. The terms adjuvant and additive are used herein to denote any pharmacologically acceptable and therapeutically useful substance which is not an active substance per se but which can be formulated with the active substance in a pharmacologically suitable solvent to improve the quality of the active substance preparation. Preferably these substances show no pharmacological effect or are not discernible or at least do not contain any undesired pharmacological effect in the treatment. Examples of adjuvants and additives are stabilizers, antioxidants and/or preservatives which prolong the shelf life of the finished pharmaceutical preparations, and also flavoring agents, vitamins and/or other additives known in the art. Examples of additives also include pharmacologically acceptable salts such as sodium chloride.

Preferred adjuvants include antioxidants such as ascorbic acid, vitamin a, vitamin E, tocopherol, and vitamins or vitamin precursors similar to those found in the human body, which have not been used to adjust pH.

Preservatives may be added to protect the formulation from contamination by pathogenic bacteria. As preservatives, there are known from the prior art, in particular benzalkonium chloride or benzoic acid or benzoates, for example sodium benzoate, in the concentrations known from the prior art. Benzalkonium chloride is preferably added to the formulations of the present invention. The benzalkonium chloride is used in an amount of 1 mg to 50 mg per 100 ml of the inventive formulation, preferably about 7 to 15 mg per 100 ml, more preferably about 9 to 12 mg per 100 ml.

Preferred formulations are those other than water as the solvent and those of formula1The compounds contained, in addition, only benzalkonium chloride, sodium EDTA and the acid required for adjusting the pH.

According to the invention, comprising formula1Pharmaceutical formulations of the compounds preferably use the above-described inhalers, whereby propellant-free aerosols according to the invention are produced. It is hereby expressly noted once again that the above-mentioned patent documents are incorporated herein by reference.

As mentioned at the outset, further developed embodiments of preferred inhalers are disclosed in WO97/12687 (see especially figures 6a and 6b and their related descriptions). Such a nebulizer (Respimat) may advantageously be used to produce the inhalable aerosol of the invention. Due to its cylindrical shape and lightness, less than 9 to 15 cm in length and 2 to 4 cm in width, the inhaler device can be carried around by the patient. Nebulizers eject a fixed volume of a pharmaceutical formulation at high pressure through a small nozzle, thereby producing an inhalable aerosol.

Preferably, the atomizer comprises a housing, a pump chamber, a nozzle, a locking mechanism, a spring housing, a spring, and a reservoir. It is characterized in that

A pump chamber which is fixed to the upper housing part and which is provided at one end with a nozzle body containing a nozzle or nozzle row,

-a hollow piston having a valve body,

a driven flange in which the hollow body is fixed and which is located in the upper housing part,

a locking mechanism is located in the upper housing part,

a spring housing with a spring therein, which is rotatably mounted to the upper housing part by means of a rotary bearing,

a lower housing part which engages in the spring housing in the axial direction.

The hollow piston with the valve body corresponds to the device disclosed in WO 97/12687. Which projects partly into the cylinder of the pump housing and is arranged inside the cylinder so as to be axially displaceable. Reference is made to figures 1 to 4, and in particular figure 3, of the aforementioned international patent and the associated description thereof. When the spring relaxes, the hollow piston with the valve body exerts a pressure of 5 to 60Mpa (approximately 50 to 600 bar), preferably 10 to 60Mpa (approximately 100 to 600 bar), on the fluid at its high-pressure end, thus metering out the active substance solution. Each actuation is preferably from 10 to 50. mu.l, more preferably from 10 to 20. mu.l, particularly preferably from 10 to 15. mu.l.

The valve body is preferably mounted at the end of the hollow piston which moves against the nozzle body.

The nozzles in the nozzle body are preferably microstructured, i.e. manufactured by means of microtechnology. Finely structured nozzle bodies are disclosed, for example, in WO 99/16530; the content of this specification is incorporated herein by reference, in particular the disclosure of fig. 1 and its associated description.

The nozzle body is formed by two glass and/or silicon sheets firmly fixed together, at least one of which has one or more channels with a fine structure, which connect the nozzle inlet end to the nozzle outlet end. At the exit end of the nozzle, there is at least one circular or non-circular opening having a depth of 2 to 10 microns, a width of 5 to 15 microns, a depth of preferably 4.5 to 6.5 microns, and a length of 7 to 9 microns.

In the case of a plurality of nozzle openings, preferably two openings, the spray directions in the nozzle body can be parallel to one another or can be inclined to one another in the direction of the nozzle openings. When the outlet end is a nozzle body with at least two nozzle openings, the spray directions can be inclined to one another by 20 to 160 degrees, preferably 60 to 150 degrees and most preferably 80 to 100 degrees.

The nozzle openings are preferably arranged at a spacing of 10 to 200 microns, more preferably 10 to 100 microns, particularly preferably 30 to 70 microns. With 50 micron spacing being most preferred.

The spray directions thus converge in the region of the nozzle opening.

As already mentioned above, the liquid drug formulation is applied to the nozzle body at an inlet pressure of up to 600 bar, preferably 200 to 300 bar, and is atomized through the nozzle opening into an inhalable aerosol. Preferred aerosol formulations have a particle size of up to 20 microns and preferably from 3 to 10 microns.

The locking mechanism contains a spring, preferably a cylindrical helical compression spring, as a reservoir of mechanical energy. The spring acts on a driven flange as a spring element, the movement of which is determined by the position of the locking element. The stroke of the driven flange is precisely limited by the upper and lower stops. The spring is preferably pressed by means of an external torque through a force transmission gear, for example a helical thrust gear, which is produced when the upper housing part is rotated relative to the spring housing in the lower housing part. In this case, the upper housing portion and the driven flange contain one or more V-gears.

Locking elements having engaging locking surfaces are arranged on the driven flange circumferential ring. Which is formed, for example, by a radially elastically deformable plastic or metal ring. The rings are arranged in a plane perpendicular to the direction of the atomizer axis. After the spring is compressed, the locking surface of the locking member slides into the path of the driven flange and prevents the spring from loosening. The locking member is activated by a button. The activation button is coupled or coupled to the locking member. To activate the locking mechanism, the actuating button is moved parallel to the annular plane, preferably into the atomizer, deforming the deformable ring in the annular plane. Details regarding the locking mechanism are described in WO 97/20590.

The lower housing portion is urged axially over the spring housing and covers the bearing structure, spindle drive and fluid reservoir.

When the atomizer is operated, the upper part of the housing rotates relative to the lower part, which rotates together with the spring housing. The spring is compressed and compressed by the spiral propelling gear, and the clamping mechanism can be automatically combined. The rotation angle is preferably an integer fraction of 360 degrees, for example 180 degrees. When the spring is compressed, the follower element of the upper housing part moves by a given amount, the hollow piston is drawn back into the cylinder of the pump housing, as a result of which a partial fluid of the storage container is drawn into the high-pressure chamber in front of the nozzle.

If desired, a plurality of replaceable reservoirs containing the fluid to be atomized can be inserted into the atomizer and then used. The storage container contains the aqueous aerosol formulation of the present invention.

The atomization process is initiated by a light pressure on the activation button. The locking member then opens the path of the driven flange. The compressed spring pushes the piston into the cylinder of the pump housing. The fluid is output in a spray from an atomizer nozzle.

Further structural details are disclosed in PCT applications WO 97/12683 and WO 97/20590, which are incorporated herein by reference.

The atomizer building elements are made of a material suitable for their function. The atomizer housing and, if the function permits, further components are preferably made of plastic, for example by injection molding. For medical use, physiologically acceptable materials are used.

FIGS. 6a/b of WO97/12687 show atomizers (Respimat)^*) The aqueous aerosol formulation of the present invention can be advantageously inhaled using the nebulizer.

Fig. 6a shows a longitudinal section through the atomizer with the spring under compression, and fig. 6b shows a longitudinal section through the atomizer with the spring relaxed.

The upper housing part (51) contains a pump housing (52) at the end of which is mounted a holder (53) for the atomiser nozzle. The holder is provided with a nozzle body (54) and a filter (55). A hollow piston (57) is secured to a follower flange (56) of the locking mechanism, the hollow piston (57) projecting partially into the cylinder of the pump housing. At its end, the hollow piston carries a valve body (58). The hollow piston is sealed by means of a sealing gasket (59). The upper housing has a stop (60) therein, and the follower flange rests against the stop (60) when the spring is released. A stop (61) is provided on the driven flange, and the driven flange is abutted against the stop (61) when the spring is compressed. After the spring is pressed, the locking piece (62) can slide between the braking piece (61) and the supporting body (63) of the upper shell part. An activation button (64) is coupled to the locking member. The upper housing portion terminates in an outlet member (65) and is sealed with a protective cover (66) that covers it.

A spring housing (67) having a compression spring (68) is rotatably mounted to the upper housing portion by a positioning pin (69) and a rotary bearing. The lower housing portion (70) is pushed onto the spring housing. Inside the spring housing there is a replaceable reservoir (71) for the fluid (72) to be atomized. The reservoir may be closed by a plug (73) through which a hollow piston projects into the interior of the reservoir and is immersed at its end in a fluid (active solution supply).

The spindle (74) of the mechanical counter is mounted outside the spring housing. A drive pinion (75) is located at the end of the spindle facing the upper housing part. Above the spindle there is a slide (76).

The above described nebuliser is suitable for the nebulisation of an aerosol formulation according to the invention to form an aerosol suitable for inhalation.

If the formulations of the invention use the above-described technique (Respimat)^*) Nebulization, the weight of the discharge at the start of the inhaler (per ejection) corresponds to at least 97% and preferably 98% of the defined amount, the breadth of which does not exceed 25% and preferably 20% of this amount. Preferably, the specific amount discharged per spray is 5 to 30 mg, preferably 5 to 20 mg of the formulation.

The formulations according to the invention may be aerosolized using other inhalers than those described above, for example, a jet-steam inhaler.

The invention also relates to an inhalation kit consisting of one of the above-described pharmaceutical preparations according to the invention and an inhaler suitable for the pharmaceutical preparation. The invention preferably relates to a pharmaceutical composition consisting of one of the abovementioned pharmaceutical preparations according to the invention and the abovementioned Respimat^*Inhaler and inhaler assembly.

Detailed description of the preferred embodiments

The formulation examples listed below are intended to be further illustrative and do not limit the subject matter of the invention to the examples shown.

I. Formulation examples

100 ml of the pharmaceutical preparation is contained in pure water or water for injection (the density is 1.00 g/cc, the temperature is 15 ℃ to 31 ℃):

examples	1( 1′-bromide) (mg)	Benzalkonium chloride (mg)	Disodium EDTA dihydrateCompound (mg)	Citric acid (mg)
					1	2000	10	10	3
2	1000	9	9	3
					3	1500	12	12	5
4	500	10	12	2
					5	150	7	12	3
6	250	15	7	2
					7	750	12	15	4
8	150	-	12	3
					9	250	-	7	4
10	750	-	15	3
					11	100	5	10	3

Claims (14)

1. An aqueous pharmaceutical formulation for inhalation comprising a compound of formula 1 as the sole active substance

Wherein

X^-Is selected from chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoic acidSalts, and the anion of p-toluenesulfonate.

At least one pharmacologically acceptable salt, and optionally other pharmacologically acceptable auxiliaries and/or complexing agents.

2. The aqueous pharmaceutical formulation of claim 1, comprising at least one compound of formula 1, wherein X^-An anion selected from the group consisting of chloride, bromide, 4-toluenesulfonate and methanesulfonate.

3. The aqueous pharmaceutical formulation of claim 1 or 2, wherein the pharmacologically acceptable acid is selected from the group consisting of inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid; or selected from organic acids such as ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and propionic acid.

4. Aqueous pharmaceutical formulation according to one of claims 1 to 3, characterized by a pH of 2.5 to 6.5.

5. Aqueous pharmaceutical formulation according to one of claims 1 to 4, characterized in that it contains benzalkonium chloride as an auxiliary.

6. The aqueous pharmaceutical formulation according to claim 5, characterized in that the benzalkonium chloride is present in an amount of 1 to 50 mg per 100 ml of solution.

7. Aqueous pharmaceutical formulation according to one of claims 1 to 6, characterized in that the content of 1' is about 4 to 2000 mg per 100 ml of solution.

8. Aqueous pharmaceutical formulation according to one of claims 1 to 7, characterized in that it contains a complexing agent as a further ingredient.

9. Aqueous pharmaceutical formulation according to one of claims 1 to 8, characterized in that the complexing agent is present in an amount of 5 to 20 mg per 100 ml of solution.

10. Use of an aqueous pharmaceutical formulation according to one of claims 1 to 9 for the preparation of a medicament for the treatment of a respiratory disorder.

11. A method of inhalation administration of an aqueous pharmaceutical formulation according to one of claims 1 to 9, by inhalation via the oral or nasal route.

12. Use of an aqueous pharmaceutical formulation according to one of claims 1 to 9 for aerosolization in an inhaler as described in WO 91/14468 or an inhaler as described in figures 6a and 6b of WO 97/12687.

13. An inhalation kit comprising a pharmaceutical formulation according to any one of claims 1 to 9 and an inhaler adapted to aerosolize the pharmaceutical formulation.

14. The inhalation kit of claim 13, wherein the inhaler is Respimat^*。