HK1095745A - Aerosol formulation for inhalation, containing an anticholinergic agent - Google Patents

Description

Aerosol formulation for inhalation comprising anticholinergic agent

The present invention relates to pharmaceutical preparations for inhalation containing a compound of formula 1 as the only active substance

Wherein

X^-Is an anion, preferably selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate, in a solvent selected from the group consisting of ethanol or a mixture of ethanol and water, at least one pharmacologically acceptable acid and, if desired, further pharmacologically acceptable excipients and/or complexing agents.

The compounds of formula 1 are known from WO 02/32899. They have valuable pharmacological properties and can provide therapeutic benefits as potent anticholinergics in the treatment of respiratory diseases, in particular in the treatment of inflammatory and/or obstructive respiratory diseases, especially in the treatment of asthma or COPD (chronic obstructive pulmonary disease).

The present invention relates to liquid active substance formulations of these compounds, which can be administered by inhalation; the liquid formulation according to the invention must meet high quality standards. The formulation according to the invention can be inhaled orally or nasally. To obtain an optimal distribution of the active substance in the lungs, liquid formulations of propellant-free gas can be conveniently used with the aid of suitable inhalers. The inhalation of the formulation can also be carried out orally or nasally. Particularly suitable is an inhaler which is capable of aerosolizing within a few seconds a small quantity of a liquid formulation of a therapeutically desired dose into an aerosol suitable for inhalation therapy. Within the scope of the present invention, a preferred nebulizer is one in which the amount of active substance solution is less than 100 microliters, preferably less than 50 microliters, optimally less than 20 microliters, which can be nebulized, preferably in one or two sprays, to form an aerosol with an average 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 a propellant-free delivery device for metered amounts of a liquid pharmaceutical composition for inhalation is described in detail in, for example, International patent application WO91/14468, "aerosolization device and method" and WO97/12687 (see FIGS. 6a and 6b and the accompanying description). In this nebulizer, a medical solution is transferred and sprayed through a high pressure of up to 600 bar as an aerosol for lung use. The entire contents of the above documents are expressly incorporated in the scope of this specification. In such inhalers, the solution formulation is stored in a reservoir, it being important that the applied formulation of active substance is sufficiently stable in storage, while allowing direct administration according to its pharmaceutical purpose without any further treatment. Furthermore, it must not contain any ingredients that can interact with such an inhaler so as to impair the pharmaceutical properties of the inhaler or of the aerosol-generating solution.

For atomizing the solution, a special nozzle is used, as described for example in WO 94/07607 or WO 99/16530. Both publications are expressly incorporated herein by reference.

Disclosure of Invention

The object of the present invention is to provide a formulation of the compound of formula 1 which meets the high criteria required to allow optimal nebulization of solutions using the above mentioned inhalers. The active substance formulations according to the invention must have a sufficiently high pharmaceutical quality, i.e. they should be pharmaceutically stable over a period of several years of storage, preferably at least one year, more preferably two years.

These propellant-free solution formulations must also be capable of being nebulized at low pressures using an inhaler, the aerosol generated by the removal of the substance being reproducible within a specific range.

Within the scope of the present invention, preference is given to using compounds in which the anion X is^-Is a compound of formula 1 selected from: chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, and p-toluenesulfonate.

Preferably, a salt of formula 1 may be used, wherein X^-Means an anion selected from the group consisting of chloride, bromide, 4-toluene sulfate and methane sulfate.

Within the scope of the present invention, particular preference is given to compositions containing X therein^-A formulation of a compound of formula 1 which is a bromide.

The compounds of formula 1 are generally intended to include within the scope of the invention all possible amorphous and crystalline modifications of such compounds. The compound of formula 1 referred to also includes within the scope of the invention all possible solvates and hydrates that may be formed from this compound.

Compound 1' as referred to within the scope of the present invention is identified as relating to a pharmacologically active cation of the formula:

in the formulation according to the invention, compound 1 is present dissolved in ethanol or a mixture of ethanol and water.

According to the present invention, the formulation preferably contains only one single salt of chemical formula 1. However, the formulation may also contain a mixture of different salts of formula 1. Formulations containing active substances other than the salt of formula 1 are not a subject of the present invention.

The concentration of the compound of formula 1 in the pharmaceutical preparation of the present invention is about 4 to 2000 mg per 100 ml, preferably about 8 to 1600 mg per 100 ml according to the present invention, based on the ratio of the pharmacologically active cation 1'. According to the invention, it is particularly preferred that 100 ml of the formulation contain from about 80 to about 1360 mg of 1'.

If the compound of formula 1 is used in which X is^-Bromides are particularly preferred compounds, the proportion of 1 according to the invention being from about 5 to 2500 mg per 100 ml of pharmaceutical preparation, preferably from about 10 to 2000 mg per 100 ml of pharmaceutical preparation. According to the present invention, it is most preferred that 100 ml of the formulation contains about 100 to 1700 mg of 1.

The formulation according to the invention contains as solvent pure ethanol or a mixture of ethanol and water. If ethanol-water mixtures are used, the weight percentage of ethanol present in these mixtures is preferably in the range of 5% to 99% ethanol, more preferably in the range of 10% to 96% alcohol. It is most preferred according to the invention that the ethanol-water mixture used as solvent contains 50% to 92% ethanol, most preferably 69% to 91%.

Other co-solvents besides ethanol and water may also be used. Preferably, however, no other solvent is used according to the invention.

The formulation according to the invention contains a pharmaceutically acceptable organic or inorganic acid for adjusting the pH. The pH of the formulation according to the invention is preferably between 2.5 and 6.5, more preferably between 3.0 and 5.0, most preferably between 3.5 and 4.5 according to the invention.

Examples of preferred inorganic acids are selected from hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid.

Examples of particularly suitable organic acids are selected from ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and propionic acid. Preferred mineral acids according to the invention are hydrochloric acid and sulfuric acid, hydrochloric acid being particularly preferred. Among the organic acids, ascorbic acid, fumaric acid and citric acid are preferred, and citric acid is particularly preferred. Mixtures of the above acids may also be used if desired, especially acids having properties other than their intrinsic acidity, for example acids which may be used as flavouring or antioxidant agents, such as citric acid or ascorbic acid.

Pharmacologically acceptable bases can be used to titrate the pH accurately, 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 final pharmaceutical formulation is pharmacologically compatible with the above-mentioned acid.

The formulation according to the invention may contain complexing agents as further components. By complexing agent is meant within the scope of the invention a molecule capable of entering a coordination bond. Preferably, the cation can be complexed by such compounds, in particular a metal cation. The formulation according to the invention preferably contains ethylenediaminetetraacetic acid (EDTA) or one of its known salts, for example sodium EDTA or disodium EDTA dihydrate, as complexing agent. Preferably, sodium edetate may be used, optionally in its hydrate form, more preferably in its dihydrate form. If a complexing agent is used in the formulation according to the invention, it is preferably present in an amount of from 1 to 100 mg per 100 ml of formulation according to the invention, more preferably from 5 to 50 mg per 100 ml. Preferably, the formulation according to the invention contains a complexing agent in an amount of about 6 to 30 mg per 100 ml of formulation according to the invention, more preferably about 7 to 20 mg per 100 ml.

Such as sodium edetate, other additives comparable to EDTA or its salts, having coordinating characteristics and being used instead, such as, for example, nitrilotriacetic acid and its salts, may likewise be used.

Other pharmacologically acceptable excipients may also be added to the formulation according to the invention. Adjuvants and additives in this context mean any pharmacologically acceptable and therapeutically useful substance which is not an active substance but which can be co-formulated with the active substance in a pharmacologically suitable solvent in order to improve the quality of the active substance formulation. Preferably, these substances are of no therapeutic value or are not discernible or at least not undesired pharmacological effects in the treatment desired herein. Such adjuvants and additives include, for example, stabilizers, antioxidants and/or preservatives which prolong the shelf life of the final pharmaceutical formulation, as well as flavoring agents, vitamins and/or additives well known in the art. The additive also comprises a pharmacologically acceptable salt, such as, for example, sodium chloride.

For example, preferred excipients include antioxidants such as ascorbic acid (but not used to correct pH), vitamin a, vitamin E, tocopherol, and similar vitamins or provitamins present in the human body.

Preservatives may be added to protect the formulation from contamination by pathogenic bacteria. Suitable preservatives are those known in the art, especially benzalkonium chloride or benzoic acid or a benzoate salt (such as sodium benzoate), the concentrations of which are known in the art. Preferably, benzalkonium chloride is added to the formulation of the present invention. The amount of benzalkonium chloride is between 1 mg and 50 mg per 100 ml of formulation, preferably about 7 to 15 mg per 100 ml, more preferably about 9 to 12 mg per 100 ml. However, formulations which do not contain any preservatives are particularly preferred according to the invention.

Preferred formulations contain only benzalkonium chloride, sodium edetate and the acid required to correct the pH, in addition to ethanol or an ethanol/water mixture as solvent and the compound of formula 1.

The pharmaceutical formulation of the present invention containing the compound of chemical formula 1 is preferably used in one of the above-mentioned inhalers to produce an aerosol without propellant according to the present invention. In this regard, we will once again make explicit reference to the above-mentioned patent documents, the contents of which are incorporated in the present description by reference.

As mentioned at the outset, a further improved embodiment of the preferred inhaler is disclosed in WO97/12687 (see especially FIGS. 6a and 6b and their associated description pages). This sprayer (Respimat)^®) Can be conveniently used to produce an inhalable aerosol according to the inventionAnd (3) preparing. Due to its cylindrical shape and light size, the device can be carried by the patient at any time. The nebulizer ejects a defined volume of the pharmaceutical formulation through a small nozzle under high pressure to produce an inhalable aerosol.

The preferred atomizer consists essentially of an upper chamber part, a pump chamber, a nozzle, a tensioning mechanism, a spring chamber, a spring and a reservoir, characterized in that

A pump chamber which is fixed to the upper chamber part and which carries at one end a nozzle body with a nozzle or an array of nozzles,

-a barrel piston with a valve body,

a driven flange in which the cavity cylinder is fixed and which is located in the upper chamber part,

-a tensioning mechanism located in the upper chamber portion,

a spring chamber, in which a spring is located, which is rotatably fixed to the upper chamber part by means of a rotary bearing,

-a lower chamber portion fitted over the axial spring chamber.

The barrel piston with valve body corresponds to one of the devices disclosed in WO 97/12687. Which partly projects into the cylinder of the pump chamber and is arranged axially displaceable in the cylinder. Reference is made in particular to figures 1 to 4, and in particular to figure 3, of the above-mentioned international application and to the relevant description thereof. At the time of the release of the spring, the cylindrical piston with the valve body exerts a pressure of 5 to 60Mpa (about 50 to 600 bar), preferably 10 to 60Mpa (about 100 to 600 bar), on the fluid (metered active substance solution) at its high-pressure end. A volume of 10 to 50. mu.l is preferred per actuation, a volume of 10 to 20. mu.l is more preferred, and a volume of 10 to 15. mu.l is particularly preferred.

The valve body is preferably arranged at the end of the cylindrical piston facing the nozzle body.

The nozzles in the nozzle body are preferably microstructured, i.e. produced by micro-engineering. Microstructured nozzle bodies are disclosed for example in WO 99/16530; the contents of this specification, and in particular figure 1 and its associated description, are incorporated herein by reference.

For example, the nozzle body is composed of two firmly interconnected glass and/or silicon wafers, at least one of which has one or more microstructured channels connecting the nozzle inlet end and the nozzle outlet end. At the outlet end of the nozzle there is at least one circular or non-circular opening 2 to 10 microns deep and 5 to 15 microns wide, preferably 4.5 to 6.5 microns deep and 7 to 9 microns long.

If there are a plurality of nozzle openings (preferably two), the injection directions of the nozzles in the nozzle body may proceed parallel to each other or may be inclined relative to each other in the nozzle opening direction. In the case of a nozzle body having at least two nozzle openings at its outlet end, the injection directions may be inclined at an angle of 20 to 160 degrees, preferably 60 to 150 degrees, and most preferably 80 to 100 degrees, with respect to each other.

The nozzle openings are preferably arranged at a pitch of 10 to 200 microns, preferably at a pitch of 10 to 100 microns, more preferably at a pitch of 30 to 70 microns. A 50 micron pitch is optimal.

The spray directions therefore merge in the nozzle opening area.

As mentioned above, the liquid pharmaceutical preparation impinges on the nozzle body at an entry pressure of up to 600 bar, preferably 200 to 300 bar, and is then atomized through the nozzle opening into an inhalable aerosol. The preferred particle size of the aerosol is 20 microns, preferably 3 to 10 microns.

The tensioning mechanism comprises a spring, preferably a cylindrical helical compression spring, as a reservoir of mechanical energy. The spring acts as a spring member against the driven flange, the movement of which is determined by the position of the blocking member. The movement of the driven flange is accurately limited by the upper stopper and the lower stopper. The spring is preferably tensioned in an energy linkage (e.g., a helical sliding gear drive) by external torque (which is generated when the upper chamber portion rotates relative to the spring cavity of the lower chamber portion). In this case, the upper chamber portion and the driven flange comprise a single or multi-speed spline gear.

The blocking member with the engaging locking surface is mounted in a ring around the driven flange. For example, it is formed by a ring made of plastic or metal, which is elastically deformable in a radial manner. The ring is mounted on a plane perpendicular to the atomizer axis. After the spring is tensioned, the locking surface of the blocking member slides into the driven flange channel and prevents the spring from unwinding. The blocking member is activated by a button. The activation button is connected or coupled to the obstruction member. To activate the shut-off member, the activation button is moved parallel to the annular plane, preferably into the atomizer, so that the deformable ring is deformed in the annular plane. The structure of the shut-off member is described in detail in WO 97/20590.

The lower chamber portion is pushed axially through the spring chamber and covers the bearing, shaft drive and liquid reservoir.

When the atomizer is activated, the upper chamber part is rotated relative to the lower chamber part, which carries the spring chamber. While the spring is compressed and tensioned by the helical slip gearbox, the brake member then automatically engages. The angle of rotation is preferably an integer part of 360 degrees, for example 180 degrees. Whilst when the spring is tensioned, the driven member in the upper chamber portion moves by a given amount, the barrel piston is drawn back into the cylinder in the pump chamber, with the result that some of the liquid in the reservoir is drawn into the high pressure chamber in front of the nozzle.

If desired, a plurality of alternative reservoirs containing the nebulizable liquid can be moved one after the other into the nebulizer and then used. The reservoir contains an aerosol formulation of the present invention.

The aerosolization process is initiated by lightly pressing the activation button. The brake member then opens the passage of the driven member. The tensioned spring pushes the piston into the cylinder in the pump chamber. The liquid is sprayed from the nozzle of the atomizer in the form of a spray.

Further details of this structure are described in PCT applications WO 97/12683 and WO97/20590, which are incorporated herein by reference.

The atomizer (nebulizer) member is made of a material suitable for its function. The atomizer chamber and-if the function allows-the other parts are preferably made of plastic, for example by injection molding. For medical applications, physiologically acceptable materials are used.

FIGS. 6a/b of WO97/12687 show Respimat^®A nebulizer, which can conveniently inhale the aqueous aerosol formulation according to the present invention.

Fig. 6a shows a longitudinal section of the atomizer when passing with a tensioned spring, and fig. 6b shows a longitudinal section of the atomizer when passing with a relaxed spring.

The upper chamber portion (51) contains a pump chamber (52) fitted at its end with a holder (53) for the atomiser nozzle. In the holder are a nozzle body (54) and a filter (55). A cylindrical piston (57) which fixes the blocking member in the driven flange (56) projects partially into the cylinder of the pump chamber. At its end, the barrel piston carries a valve body (58). The cylindrical piston is sealed by a gasket (59). The interior of the upper chamber portion has a stopper (60) on which the follower flange is retained when the spring is relaxed. A stop (61) is located above the driven flange, on which the driven flange is retained when the spring is tensioned. After the spring is tensioned, the blocking member (62) slides between a stop (61) and a support (63) in the upper chamber portion. An activation button (64) is connected to the obstruction member. The upper chamber portion terminates at a mouthpiece (65) and is closed by a removable protective cap (66).

A spring chamber (67) having a compression spring (68) is rotatably fitted to the upper chamber portion through a snap piece (69) and a rotary bearing. The lower chamber portion (70) can be pushed through the spring chamber. Inside the spring chamber there is an alternative reservoir (71) for the liquid (72) to be atomized. The reservoir is closed by a stopper (73), through which a cylindrical piston can project into the reservoir and its end is immersed in the liquid (providing the active substance solution).

The shaft (74) of the mechanical counter is fitted outside the spring chamber. A drive pinion (75) is located at the end of the shaft facing the upper chamber portion. On the shaft is a slider (76).

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

In another preferred embodiment, the pharmaceutical formulation according to the invention is administered using a nebulizer as described above, wherein an alternative storage container is used containing the pharmaceutical formulation according to the invention, which contains a gas-and liquid-tight container as described in WO 99/43571. Some details of the construction of the container will now be described; the reference numerals referred to in the following description correspond to those disclosed in WO 99/43571. The disclosure of WO99/43571 is incorporated by reference into the following description.

Therefore, for administering the formulation of the invention, it is particularly preferred to use a gas-and liquid-tight container as an alternative container for medicinal liquids in a propellant-free nebulizer, which is disclosed in WO99/43571 and comprises a take-off fitting in the form of a cylindrical piston, the container comprising:

-a foil pouch (11, 21, 31) sealed at both ends, wherein at least one end is closed with a welded seam (13, 23, 32) running essentially at right angles to the pouch axis and which is deformed by an external pressure in the interior of the container with a pressure difference between its periphery of less than 300hPa (300 mbar),

-a form-stable flange (15, 25, 34) firmly attached to the foil pouch and constituting a detachable connection for inserting the container onto the take-up nipple (67),

-a guide duct (42, 54) in the flange.

-simultaneously forming a sealing point (56, 64, 74) in the guiding duct and/or a press-fit (55, 66, 77) around the take-off connection,

and a liquid removal point for the region of the guide channel, into which the cartridge piston is inserted in use for immersion in the medical liquid.

If the above technique is applied (Respimat)^®) The dose of the invention is aerosolized and the amount delivered in all operations of the inhaler (spray actuation) corresponds to at least 97%, preferably at least 98%, of the defined amount, with the allowable tolerance range not exceeding the defined amount of 25%, preferably 20%, of this amount. Preferably, 5 to 30 mg of the dose, most preferably 5 to 20 mg of the dose, is delivered as a defined amount per actuation.

However, the formulations according to the invention may also be aerosolized by means of an inhaler other than the inhalers described above, for example an air-jet inhaler or an ultrasonic nebulizer.

The invention also relates to an inhalation kit consisting of a pharmaceutical preparation according to the invention as described above and an inhaler suitable for nebulizing such a pharmaceutical preparation. The invention preferably relates to an inhalation kit consisting of a pharmaceutical preparation according to the invention as described above and a Respimat as described above^®An inhaler.

The examples of formulations shown below are intended as illustrations and do not limit the subject matter of the invention to the compositions shown by the examples.

1. Examples of formulations

A100 ml pharmaceutical preparation contains:

examples of the invention	1 (1' -Bromide) (mg)	Benzalkonium chloride (mg)	Disodium ethylenediaminetetraacetate dihydrate (mg)	Citric acid (mg)	The volume is adjusted to 100 ml (% by mass/mass) with an ethanol/water mixture
						1	2000	10	10	3	50/50
2	1000	5	-	3	70/30
						3	1500	-	10	5	70/30
4	500	-	20	2	70/30
						5	150	-	10	3	90/10
6	250	-	10	2	90/10
						7	750	-	-	4	90/10
8	150	-	-	3	90/10
						9	250	-	-	4	95/5
10	500	-	-	3	95/5
						11	100	5	-	3	95/5

The formulations of the invention are prepared in a manner similar to that well known in the art, for example by dissolving the components of the formulation in ethanol or an ethanol/water solvent.

Claims (16)

1. A pharmaceutical preparation for inhalation comprising a compound of formula 1 as the only active substance

Wherein

X^-Is an anion, preferably selected from chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, wineLitholate, oxalate, succinate, benzoate and p-toluenesulfonate in the presence of ethanol or a mixture of ethanol and water, at least one pharmacologically acceptable acid and, if desired, other pharmacologically acceptable excipients and/or complexing agents.

2. The pharmaceutical preparation of claim 1, which contains at least one compound of formula 1, wherein X^-Selected from the group consisting of chloride, bromide, 4-toluene sulfate and methane sulfate.

3. Pharmaceutical preparation according to claim 1 or 2, containing as solvent a mixture of ethanol and water, the proportion of ethanol in these mixtures ranging from 5% to 99%.

4. Pharmaceutical preparation according to one of claims 1 to 3, containing mixtures of ethanol and water as solvents, the proportion of ethanol in these mixtures being in the range from 10% to 96%.

5. The pharmaceutical preparation according to one of claims 1 to 4, wherein the pharmacologically acceptable acid is selected from the group consisting of hydrochloric, hydrobromic, nitric, sulfuric and phosphoric acid of inorganic acids, or ascorbic, citric, malic, tartaric, maleic, succinic, fumaric, acetic, formic and propionic acid of organic acids.

6. Pharmaceutical preparation according to one of claims 1 to 5, characterized in that the pH is from 2.5 to 6.5.

7. Pharmaceutical preparation according to one of claims 1 to 6, characterized in that the amount of 1' per 100 ml of solution is from about 4 to 2000 mg.

8. Pharmaceutical preparation according to one of claims 1 to 7, characterized in that it contains a complexing agent as a further component.

9. Pharmaceutical preparation according to one of claims 1 to 8, characterized in that the complexing agent is present in an amount of about 1 to 100 mg per 100 ml of solution.

10. Pharmaceutical preparation according to one of claims 1 to 9, characterized in that it contains benzalkonium chloride as auxiliary.

11. Pharmaceutical preparation according to claim 10, characterized in that the content of benzalkonium chloride per 100 ml of solution is between 1 and 50 mg.

12. Use of a pharmaceutical preparation according to one of claims 1 to 11 for the preparation of a pharmaceutical composition for the treatment of respiratory diseases.

13. A method of inhalation using a pharmaceutical preparation according to any one of claims 1 to 12 by the oral or nasal route.

14. Use of a pharmaceutical preparation according to one of claims 1 to 13 for aerosolization in an inhaler according to WO91/14468 or the inhaler described in figures 6a and 6b of WO 97/12687.

15. An inhalation kit consisting of a pharmaceutical preparation according to one of claims 1 to 14 and an inhaler suitable for aerosolizing such a pharmaceutical preparation.

16. The inhalation kit of claim 15, wherein the inhaler is Respimat^®。