Title of Invention	"PHARMACEUTICAL PREPARATION CONTAINING 2,2-DIPHENYL-PROPIONIC ESTER-METHOBROMIDE OF FORMULA 1"
Abstract	Pharmaceutical preparation for inhalation, containing as sole active substance 2,2-diphenyl-propionic acid scopine ester-methobromide of formula 1 as herein described.

Full Text

The present invention relates to pharmaceutical preparation containing 2,2-diphenyl-propionic acid scopine ester-methobromide of formula 1. The present invention relates to pharmaceutical preparations for inhalation containing as the sole active substance a compound of formula 1 (Formula Removed) wherein X - denotes an anion which is preferably selected from among the chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate, as solvent ethanol or mixtures of ethanol and water, at least one pharmacologically acceptable acid and optionally other pharmacologically acceptable excipients and/or complexing agents. The compounds of formula 1 are known from WO 02/32899. They have valuable pharmacological properties and as highly effective anticholinergics may provide therapeutic benefit in the treatment of respiratory diseases, particularly 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 formulations according to the invention have to meet high quality standards. The formulations according to the invention may be inhaled orally or nasally. To achieve an optimum distribution of the active substances in the lungs it is expedient to use a liquid 2 formulation free from propellant gases using suitable inhalers. A formulation of this kind may also be inhaled orally or nasally. Those inhalers which are capable of nebulising a small amount of a liquid formulation in the dosage needed for therapeutic purposes within a few seconds into an aerosol suitable for therapeutic inhalation are particularly suitable. Within the scope of the invention, preferred nebulisers are those in which an amount of less than 100 microlitres, preferably less than 50 microlitres, most preferably less than 20 microlitres of active substance solution can be nebulised preferably in one or two puffs to form an aerosol having an average particle size of less than 20 microns, preferably less than 10 microns, so that the inhalable part of the aerosol already corresponds to the therapeutically effective quantity. An apparatus of this kind for the propellant-free administration of a metered amount of a liquid pharmaceutical composition for inhalation is described in detail for example in International Patent Application WO 91/14468 "Atomizing Device and Methods" and also in WO 97/12687, cf. Figures 6a and 6b and the accompanying description. In a nebuliser of this kind a pharmaceutical solution is converted by means of a high pressure of up to 600 bar into an aerosol destined for the lungs, which is sprayed. Within the scope of the present specification reference is expressly made to the entire contents of the literature mentioned above. In inhalers of this kind the formulations of solutions are stored in a reservoir. It is essential that the active substance formulations used are sufficiently stable when stored and at the same time are such that they can be administered directly, if possible without any further handling, in accordance with their medical purpose. Moreover, they must not contain any ingredients which might interact with the inhaler in such a way as to damage the inhaler or the pharmaceutical quality of the solution or of the aerosol produced. To nebulise the solution a special nozzle is used as described for example in WO 94/07607 or WO 99/16530 Reference is expressly made here to both these publications. 3 The aim of the present invention is to provide a formulation of the compound of formula 1 which meets the high standards needed in order to allow optimum nebulisation of a solution using the inhalers mentioned above. The active substance formulations according to the invention must be of sufficiently high pharmaceutical quality, i.e. they should be pharmaceutically stable over a storage time of some years, preferably at least one year, more preferably two years. These propetlant-free formulations of solutions must also be capable of being nebulised under pressure using an inhaler, the composition delivered by the aerosol produced falling reproducibly within a specified range. Within the scope of the present invention, those compounds of formula 1 are preferably used wherein the anion X is selected from among the chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate. Preferably, the salts of formula 1 are used wherein X - denotes an anion selected from the group consisting of chloride, bromide, 4-toluenesulphonate and methanesulphonate. Particularly preferred, within the scope of the present invention, are the formulations which contain the compound of formula 1 wherein X ~ denotes bromide. References to the compound of formula 1 always include within the scope of the present invention all possible amorphous and crystalline modifications of this compound. References to the compound of formula 1 also include within the scope of the present invention all the possible solvates and hydrates which may be formed from this compound. Any reference to the compound 1' within the scope of the present invention is to be regarded as a reference to the pharmacologically active cation of the following formula (Figure Removed) contained in the salts 11. In the formulation according to the invention the compound 1 is present dissolved in ethanol or in mixtures of ethanol and water. According to the invention, the formulation preferably contains only a single salt of formula 1 However, the formulation may also contain a mixture of different salts of formula 1 Formulations which contain active substances other than those of formula 1 are not a subject of this invention. The concentration of the compound of formula 1 based on the proportion of pharmacologically active cation 1'in the pharmaceutical preparation according to the invention is about 4 to 2000 mg per 100 ml, according to the invention, preferably about 8 to 1600 mg per 100 ml. Particularly preferably, 100 ml of the formulations according to the invention contain about 80 to about 1360 mg of 1' . If the compound of formula 1 used is the particularly preferred compound wherein X denotes the bromide, the proportion of 1 according to the invention is about 5 to 2500 mg per 100 ml, preferably about 10 to 2000 mg per 100 ml of pharmaceutical preparation. Most preferably, 100 ml of the formulations according to the invention contain about 100 to 1700 mg of 1 . Formulations according to the invention contain as solvent pure ethanol or mixtures of ethanol and water. If ethanol-water mixtures are used, the mass percentage of 5 ethanol present in these mixtures is preferably in the range from 5 to 99 % ethanol, more preferably in the range from 10 to 96 % ethanol. Most particularly preferably according to the invention, ethanol-water mixtures used as solvent contain between 50 and 92 %, most preferably between 69 and 91% of ethanol. Other co-solvents may be used apart from ethanol and water. Preferably, however, no other solvents are used according to the invention. The formulations according to the invention contain pharmacologically acceptable organic or inorganic acids for adjusting the pH. The pH of the formulations according to the invention is preferably between 2.5 and 6.5 and more preferably between 3.0 and 5.0, most preferably between about 3.5 and 4.5, according to the invention. Examples of preferred inorganic acids are selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and phosphoric acid. Examples of particularly suitable organic acids are selected from the group consisting of 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 sulphuric acid, of which hydrochloric acid is particularly preferred according to the invention. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred, citric acid being particularly preferred. If desired, mixtures of the abovementioned acids may also be used, particularly in the case of acids which have other properties in addition to their acidifying properties, e.g. those which act as flavourings or antioxidants, such as for example citric acid or ascorbic acid. If desired, pharmacologically acceptable bases may be used to titrate the pH precisely. Suitable bases include for example alkali metal hydroxides and alkali metal carbonates. The preferred alkali metal ion is sodium. If bases of this kind are used, care must be taken to ensure that the resulting salts, which are then contained in the finished pharmaceutical formulation, are pharmacologically compatible with the abovementioned acid. The formulations according to the invention may contain complexing agents as other ingredients. By complexing agents are meant within the scope of the present invention molecules which are capable of entering into complex bonds. Preferably, these compounds should have the effect of complexing cations, most preferably metal cations. The formulations according to the invention preferably contain editic acid (EDTA) or one of the known salts thereof, e.g. sodium EDTA or disodium EDTA dihydrate, as complexing agent. Preferably, sodium edetate is used, optionally in the form of its hydrates, more preferably in the form of its dihydrate. If complexing agents are used within the formulations according to the invention, their content is preferably in the range from 1 to 100 mg per 100 ml, more preferably in the range from 5 to 50 mg per 100 ml of the formulation according to the invention. Preferably, the formulations according to the invention contain a complexing agent in an amount of about 6 to 30 mg per 100 ml, more preferably about 7 to 20 mg per 100 ml of the formulation according to the invention. The remarks made concerning sodium edetate also apply analogously to other possible additives which are comparable to EDTA or the salts thereof, which have complexing properties and can be used instead of them, such as for example nitrilotriacetic acid and the salts thereof. Other pharmacologically acceptable excipients may also be added to the formulation according to the invention. By adjuvants and additives are meant, in this context, any pharmacologically acceptable and therapeutically useful substance which is not an active substance, but can be formulated together with the active substance in the pharmacologically suitable solvent, in order to improve the qualities of the active substance formulation Preferably, these substances have no pharmacological effects or no appreciable or at least no undesirable pharmacological effects in the context of the desired therapy The adjuvants and additives include, for example, stabilisers, antioxidants and/or preservatives which prolong the shelf life of the finished pharmaceutical formulation, as well as flavourings, vitamins and/or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride, for example. The preferred excipients include antioxidants such as ascorbic acid, for example, provided that it has not already been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins or provitamins occurring in the human body. Preservatives can be added to protect the formulation from contamination with pathogenic bacteria. Suitable preservatives are those known from the prior art, particularly benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art. Preferably, benzalkonium chloride is added to the formulation according to the 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 of the formulation according to the invention. However, according to the invention, formulations which do not contain any preservatives are particularly preferred. Preferred formulations contain only benzalkonium chloride, sodium edetate and the acid needed to adjust the pH in addition to the ethanol or ethanol/water mixtures as solvent and the compounds of formula 1 The pharmaceutical formulations according to the invention containing compounds of formula 1 are preferably used in an inhaler of the kind described hereinbefore in order to produce the propellant-free aerosols according to the invention. At this point we should once again expressly mention the patent documents described hereinbefore, the contents of which are hereby incorporated by reference. As described at the beginning, a further developed embodiment of the preferred inhaler is disclosed in WO 97/12687 (cf. in particular Figures 6a and 6b and the associated passages of description). This nebuliser (Respimat®) can advantageously be used to produce the inhalable aerosols according to the invention. Because of its cylindrical shape and handy size, this device can be carried anywhere by the patient. The nebuliser sprays a defined volume of the pharmaceutical formulation out through small nozzles at high pressures, so as to produce inhalable aerosols. The preferred atomiser essentially consists of an upper housing part, a pump housing, a nozzle, a locking clamp, a spring housing, a spring and a storage container, characterised by - a pump housing fixed in the upper housing part and carrying at one end a nozzle body with the nozzle or nozzle arrangement, a hollow piston with valve body, - a power take-off flange in which the hollow body is fixed and which is located in the upper housing part, - a locking clamping mechanism located in the upper housing part, - a spring housing with the spring located therein, which is rotatably mounted on the upper housing part by means of a rotary bearing, - a lower housing part which is fitted onto the spring housing in the axial direction The hollow piston with valve body corresponds to a device disclosed in WO 97/12687. It projects partially into the cylinder of the pump housing and is disposed to be axially movable in the cylinder. Reference is made particularly to Figures 1-4 -especially Figure 3 - and the associated passages of description in the abovementioned International Patent Application. At the moment of release of the spring the hollow piston with valve body exerts, at its high pressure end, 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 amount of active substance solution. Volumes of 10 to 50 microlitres are preferred, volumes of 10 to 20 microlitres are more preferable, whilst a volume of 10 to 15 microlitres per actuation is particularly preferred. The valve body is preferably mounted at the end of the hollow piston which faces the nozzle body The nozzle in the nozzle body is preferably microstructured, i.e. produced by micro-engineering. Microstructured nozzle bodies are disclosed for example in WO- 99/16530; reference is hereby made to the contents of this specification, especially Figure 1 and the associated description. The nozzle body consists for example of two sheets of glass and/or silicon securely fixed together, at least one of which has one or more microstructured channels which connect the nozzle inlet end to the nozzle outlet end. At the nozzle outlet end there is at least one round or non-round opening 2 to 10 microns deep and 5 to 15 microns wide, the depth preferably being 4.5 to 6.5 microns and the length being 7 to 9 microns. If there is a plurality of nozzle openings, preferably two, the directions of spraying of the nozzles in the nozzle body may run parallel to each other or may be inclined relative to one another in the direction of the nozzle opening. In the case of a nozzle body having at least two nozzle openings at the outlet end, the directions of spraying may be inclined relative to one another at an angle of 20 degrees to 160 degrees, preferably at an angle of 60 to 150 degrees, most preferably 80 to 100°. The nozzle openings are preferably arranged at a spacing of 10 to 200 microns, more preferably at a spacing of 10 to 100 microns, still more preferably 30 to 70 microns. A spacing of 50 microns is most preferred. The directions of spraying therefore meet in the region of the nozzle openings. As already mentioned, the liquid pharmaceutical preparation hits the nozzle body at an entry pressure of up to 600 bar, preferably 200 to 300 bar and is atomised through the nozzle openings into an inhalable aerosol. The preferred particle sizes of the aerosol are up to 20 microns, preferably 3 to 10 microns. The locking clamping mechanism contains a spring, preferably a cylindrical helical compression spring, as a store for the mechanical energy. The spring acts on the power take-off flange as a spring member the movement of which is determined by the position of a locking member. The travel of the power take-off flange is precisely limited by an upper stop and a lower stop. The spring is preferably tensioned via a stepping-up gear, e.g. a helical sliding gear, by an external torque which is generated when the upper housing part is turned relative to the spring housing in the lower housing part. In this case, the upper housing part and the power take-off flange contain a single- or multi-speed spline gear. The locking member with the engaging locking surfaces is arranged in an annular configuration around the power take-off flange. It consists for example of a ring of plastics or metal which is inherently radially elastically deformable. The ring is arranged in a plane perpendicular to the axis of the atomiser. After the tensioning of the spring, the locking surfaces of the locking member slide into the path of the power take-off flange and prevent the spring from being released. The locking member is actuated by means of a button. The actuating button is connected or coupled to the locking member. In order to actuate the locking clamping mechanism the actuating button is moved parallel to the annular plane, preferably into the atomiser, and the deformable ring is thereby deformed in the annular plane. Details of the construction of the locking clamping mechanism are described in WO 97/20590, The lower housing part is pushed axially over the spring housing and covers the bearing, the drive for the spindle and the storage container for the fluid. When the atomiser is operated, the upper part of the housing is rotated relative to the lower part, the lower part taking the spring housing with it. The spring meanwhile is compressed and biased by means of the helical sliding gear, and the clamping mechanism engages automatically. The angle of rotation is preferably a whole-number fraction of 360 degrees, e.g. 180 degrees. At the same time as the spring is tensioned, the power take-off component in the upper housing part is moved along by a given amount, the hollow piston is pulled back inside the cylinder in the pump housing, as a result of which some of the fluid from the storage container is sucked into the high pressure chamber in front of the nozzle. If desired, a plurality of replaceable storage containers containing the fluid to be atomised can be inserted in the atomiser one after another and then used. The storage container contains the aerosol preparation according to the invention. The atomising process is initiated by gently pressing the actuating button. The clamping mechanism then opens the way for the power take-off component. The biased spring pushes the piston into the cylinder in the pump housing. The fluid emerges from the nozzle of the atomiser in the form of a spray. Further details of the construction are disclosed in PCT applications WO 97/12683 and WO 97/20590, to which reference is hereby made. The components of the atomiser (nebuliser) are made of a material suitable for their function. The housing of the atomiser and - if the function allows - other parts as well are preferably made of plastics, e.g. by injection moulding. For medical applications, physiologically acceptable materials are used. Figures 6a/b of WO 97/12687 show the Respimat® nebuliser with which the aqueous aerosol preparations according to the invention can advantageously be inhaled. Figure 6a shows a longitudinal section through the atomiser with the spring under tension, Figure 6b shows a longitudinal section through the atomiser with the spring released. The upper housing part (51) contains the pump housing (52), on the end of which is mounted the holder (53) for the atomiser nozzle. In the holder is the nozzle body (54) and a filter (55). The hollow piston (57) fixed in the power take-off flange (56) of the locking clamping mechanism projects partly into the cylinder of the pump housing. At its end the hollow piston carries the valve body (58). The hollow piston is sealed off by the gasket (59). Inside the upper housing part is the stop (60) on which the power take-off flange rests when the spring is relaxed. Located on the power take-off flange is the stop (61) on which the power take-off flange rests when the spring is under tension. After the tensioning of the spring, the locking member (62) slides between the stop (61) and a support (63) in the upper housing part. The actuating button (64) is connected to the locking member. The upper housing part ends in the mouthpiece (65) and is closed off by the removable protective cap (66). The spring housing (67) with compression spring (68) is rotatably mounted on the upper housing part by means of the snap-fit lugs (69) and rotary bearings. The lower housing part (70) is pushed over the spring housing. Inside the spring housing is the replaceable storage container (71) for the fluid (72) which is to be atomised. The storage container is closed off by the stopper (73), through which the hollow piston projects into the storage container and dips its end into the fluid (supply of active substance solution). The spindle (74) for the mechanical counter is mounted on the outside of the spring housing. The drive pinion (75) is located at the end of the spindle facing the upper housing part. On the spindle is the slider (76). The nebuliser described above is suitable for nebulising the aerosol preparations 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 the nebuliser described above in which a replaceable storage container is used containing the pharmaceutical formulation according to the invention inside a gas- and fluid-tight container as described in WO 99/43571. Some details of the construction of this container will now be described; the reference numerals quoted in the following description correspond to those disclosed in WO 99/43571. The description that follows incorporates the disclosure of WO 99/43571 by reference. Accordingly, for administering the formulations according to the invention, it is particularly preferable to use a gas- and fluid-tight container as a replaceable cartridge for a medical fluid in a propellant-free atomiser, which, as disclosed in WO 99/43571, comprises a dispensing outlet in the form of a hollow piston, the container comprising: - a foil bag (11, 21, 31) sealed at both ends, at least one end being closed off by a weld seam (13, 23, 32) which runs substantially at right angles to the axis of the bag, and the foil bag is deformable by external pressure at a differential pressure between the interior of the container and its surroundings of less than 300 hPa (300 mbar), - an inherently rigid flange (15, 25, 34) which is firmly attached to the foil bag and is constructed as a removable connecting member for fitting the container onto a dispensing outlet (67), - a guide channel (42, 54) in the flange, - while in the guide channel is formed a sealing point (56, 64, 74) and/or a press fit (55, 66, 77) which surrounds the dispensing outlet - and a removal point for the fluid in the region of the guide channel into which the hollow piston projects during use so as to dip into the medical fluid. If the formulation according to the invention is nebulised using the method described above (Respimat®) the quantity delivered should correspond to a defined quantity with a tolerance of not more than 25%, preferably 20% of this amount in at least 97%, preferably at least 98% of all operations of the inhaler (spray actuations). Preferably, between 5 and 30 mg of formulation, most preferably between 5 and 20 mg of formulation are delivered as a defined mass on each actuation. However, the formulation according to the invention may also be nebulised by means of inhalers other than those described above, e.g. jet stream inhalers or ultrasound nebulisers. The present invention also relates to an inhalation kit consisting of one of the pharmaceutical preparations according to the invention described above and an inhaler suitable for nebulising this pharmaceutical preparation. The present invention preferably relates to an inhalation kit consisting of one of the pharmaceutical preparations according to the invention described above and the Respimat'* inhaler described above. The examples of formulations given below serve as illustrations without restricting the subject matter of the present invention to the compositions shown by way of example. I. Examples of formulations 100 ml of pharmaceutical preparation contain: (Table Removed) The formulations according to the invention are prepared analogously to methods known in the art, for example by dissolving the ingredients of the formulation in the solvent ethanol or ethanol/water. We Claim: 1. Pharmaceutical preparation for inhalation, containing as sole active substance 2,2-diphenyl-propionic acid scopine ester-methobromide of formula 1 (Formula Removed) wherein X- denotes an anion which is preferably selected from among the chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate, characterized therein that the preparation contains as the solvent ethanol or mixtures of ethanol and water, at least one pharmacologically acceptable acid of the kind such as herein described and optionally other pharmacologically acceptable excipients and/or complexing agents. 2. Pharmaceutical preparations as claimed in claim 1, containing at least one compound of formula 1 wherein X - is selected from among chloride, bromide, 4-toluenesulphonate and methanesulphonate. 3. Pharmaceutical preparations as claimed in claim 1 or 2 which contain mixtures of ethanol and water as solvent, the proportion by mass of ethanol in these mixtures being in the range from 5 to 99 %. 4. Pharmaceutical preparations as claimed in one of claims 1 to 3 which contain mixtures of ethanol and water as solvent, the proportion by mass of ethanol in these mixtures being in the range from 10 to 96 %. 5. Pharmaceutical preparations as claimed in one of claims 1 to 4, wherein the pharmacologically acceptable acid is selected from the inorganic acids hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and phosphoric acid or from the organic acids ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and propionic acid. 6. Pharmaceutical preparations as claimed in one of claims 1 to 5, wherein a pH of 2.5 to 6.5. 7. Pharmaceutical preparation as claimed in one of claims 1 to 6, wherein the content of 1' is about 4 to 2000 mg per 100 ml of solution. 8. Pharmaceutical preparation as claimed in one of claims 1 to 7, wherein they contain a complexing agent as an additional ingredient. 9. Pharmaceutical preparation as claimed in one of claims 1 to 8, wherein the content of complexing agent is 1 to 100 mg per 100 ml of solution. 10. Pharmaceutical preparation as claimed in one of claims 1 to 9, wherein they contain benzalkonium chloride as excipient. 11. Pharmaceutical preparation as claimed in claim 10, wherein the content of benzalkonium chloride is 1 to 50 mg per 100 ml of solution.

Documents:

1473-DELNP-2006-Abstract-(29-07-2008).pdf

1473-delnp-2006-abstract.pdf

1473-DELNP-2006-Claims-(29-07-2008).pdf

1473-delnp-2006-claims.pdf

1473-delnp-2006-correspondence-others 1.pdf

1473-DELNP-2006-Correspondence-Others-(18-08-2008).pdf

1473-DELNP-2006-Correspondence-Others-(29-07-2008).pdf

1473-DELNP-2006-Correspondence-Others-(30-01-2009).pdf

1473-delnp-2006-correspondence-others.pdf

1473-delnp-2006-description (complete)-29-07-2008.pdf

1473-delnp-2006-description (complete).pdf

1473-DELNP-2006-Form-1-(29-07-2008).pdf

1473-delnp-2006-form-1.pdf

1473-delnp-2006-form-18.pdf

1473-DELNP-2006-Form-2-(29-07-2008).pdf

1473-delnp-2006-form-2.pdf

1473-DELNP-2006-Form-3-(18-08-2008).pdf

1473-delnp-2006-form-3.pdf

1473-delnp-2006-form-5.pdf

1473-DELNP-2006-GPA-(29-07-2008).pdf

1473-delnp-2006-gpa.pdf

1473-DELNP-2006-Others-Document-(29-07-2008).pdf

1473-delnp-2006-pct-210.pdf

1473-DELNP-2006-PCT-237-(29-07-2008).pdf

1473-delnp-2006-pct-237.pdf

1473-delnp-2006-pct-304.pdf

1473-delnp-2006-pct-306.pdf

1473-delnp-2006-pct-308.pdf

1473-delnp-2006-pct-338.pdf

1473-DELNP-2006-PCT-373-(29-07-2008).pdf

1473-delnp-2006-pct-373.pdf

1473-DELNP-2006-Petition-137-(18-08-2008).pdf

1473-DELNP-2006-Petition-138-(30-01-2009).pdf

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