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(11) EP 1 381 346 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 9/12 (2006.01) A61K 9/72 (2006.01) 18.11.2015 Bulletin 2015/47 A61K 9/08 (2006.01) A61P 11/08 (2006.01) A61K 31/167 (2006.01) (21) Application number: 02709742.7 (86) International application number: (22) Date of filing: 28.02.2002 PCT/US2002/006240

(87) International publication number: WO 2002/083079 (24.10.2002 Gazette 2002/43)

(54) PHARMACEUTICAL COMPOSITIONS CONTAINING PHARMAZEUTISCHE ZUSAMMENSETZUNG ENTHALTEND FORMOTEROL COMPOSITIONS PHARMACEUTICALES COMPRENANT FORMOTEROL

(84) Designated Contracting States: • CHAUDRY, Imtiaz, A. AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU Napa, CA 94558 (US) MC NL PT SE TR Designated Extension States: (74) Representative: Boult Wade Tennant AL LT LV MK RO SI Verulam Gardens 70 Gray’s Inn Road (30) Priority: 17.04.2001 US 284606 P London WC1X 8BT (GB) 22.06.2001 US 887281 (56) References cited: (43) Date of publication of application: EP-A- 0 370 632 WO-A-00/00181 21.01.2004 Bulletin 2004/04 WO-A-00/23037 WO-A-01/78745 WO-A-95/31964 WO-A-99/25359 (73) Proprietor: Mylan Specialty L.P. US-A- 6 040 344 US-A- 6 150 418 Napa, CA 94558 (US) Remarks: (72) Inventors: Thefile contains technical information submitted after • BANERJEE, Partha, S. the application was filed and not included in this San Ramon, CA 94583 (US) specification • PHAM, Stephen Columbus, OH 43221 (US)

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 381 346 B1

Printed by Jouve, 75001 PARIS (FR) 1 EP 1 381 346 B1 2

Description terol ((6)-4-hydroxy-α1-(((6-(4-phenylbutoxy)hexyl)ami- no)methyl)-1,3-benzenedimethanol); (R)-; FIELD OF THE INVENTION (5-(2-((1,1-dimethylethyl)amino)-1-hydrox- yethyl)-1,3-benzenediol); (2-chloro- α-(((1,1- [0001] Compositions are provided relating to treat-5 dimethyl-ethyl)amino)methyl)benzenemethanol); and ment, prevention, or amelioration of one or more symp- TA-2005 (8-hydroxy-5-((1R)-1-hydroxy-2-(N-((1R)-2-(4- toms of broncho-constrictive disorders. In particular, the methoxyphenyl)-1-methylethyl)amino)ethyl)-carbostyril compositions herein include formoterol, and/or deriva- hydrochloride). tives thereof. The compositions are propellant-free, ster- [0003] These compounds are typically formulated for ile unit dose or multidose inhalation solutions intended 10 inhalation therapy. Aqueous or liquid formulations are for administration via nebulization. preferred oversolid formulations. Powdered formulations are more difficult to administer, particularly to the young BACKGROUND OF THE INVENTION and elderly who are most often the patients in need of such therapy. Compounds, such as formoterol, which [0002] Bronchoconstrictive disorders affect millions 15 has many desirable properties, are not adequately stable worldwide. Such disorders include (including in aqueous solutions to be formulated as liquids. Hence bronchial asthma, allergic asthma and intrinsic asthma, there is a need for formulations of compounds, such as e.g., late asthma and airway hyper-responsiveness), formoterol, in a form that can be conveniently adminis- chronic bronchitis and other chronic obstructive pulmo- tered and that are stable for extended periods of time. 20 nary diseases. Compounds having 2 ß-adrenoreceptor Therefore, it is an object herein to provide liquid formu- agonist activity have been developed to treat these con- lations of ß2-adrenoreceptor agonist compounds. It is al- ditions. Such compounds include, but are not limited to, so an object herein to provide more stable formulations Albuterol (a1-(((1,1-dimethylethyl)amino)methyl)-4-hy- of others of these compounds. droxy-1,3-benzenedimethanol); (dimethyl- carbamic acid 5-(2-((1,1-dimethylethyl)amino)-1-hy-25 SUMMARY OF THE INVENTION droxyethyl)-1,3-phenylene ester); (4-methyl- benzoic acid 4-(2-((1,1-dimethylethyl)amino)-1-hydrox- [0004] A pharmaceutical composition, comprising for- yethyl)-1,2-phenylene ester); (3-bromo- moterol free base at a concentration m ofg/ml 5 to α-(((1,1-dimethylethyl)amino)-methyl)-5-isoxa- 50mg/ml, or a derivative thereof, in pharmacologically zolemethanol); Isoproterenol (4-(1-hydroxy-2-((1-me-30 suitable fluid, wherein the composition is stable during thyl-ethyl)amino)ethyl)-1,2-benzenediol); Trimetoquinol long term storage the fluid comprises water and the com- (1,2,3,4-tetrahydro-1-((3,4,5-trimethoxyphenyl)methyl)- position is suitable for direct administration to a subject 6,7-isoquinolinediol); (4-amino-3,5-dichloro- in need thereof is provided. Pharmacologically suitable α-(((1,1-diemthylethyl)amino)methyl)benzenemethan- fluids include, but are not limited to, polar fluids, including ol); (5-(1-hydroxy-2-(12-(4-hydroxyphenyl)-1- 35 protic fluids. In certain embodiments herein, the compo- methylethyl)-amino)ethyl)-1,3-benzenediol); Formoterol sitions are aqueous solutions. (2-hydroxy-5-((1RS)-1-hydroxy-2-(((1RS)-2-(p-methox- [0005] The compositions provided herein possess an yphenyl)-1-methylethyl)amino)ethyl)formanilide); estimated shelf-life of greater than 1, 2 or 3 months usage (R,R)-Formoterol; Desformoterol ((R,R) or (S,S)-3-ami- time at 25 °C and greater than or equal to 1, 2 or 3 years no-4-hydroxy-α-(((2-(4-methoxyphenyl)-1-methyle- 40 storage time at 5 °C. In certain of these embodiments, thyl)amino)methyl)benzenemethanol); using Arrhenius kinetics, >80% or >85% or >90% or (4,4’-(1,6-hexanediyl)-bis(imino(1-hydroxy-2,1-ethan- >95% estimated bronchodilating agent remains after ediyl)))bis-1,2-benzenediol); Isoetharine (4-(1-hydroxy- such storage. 2-((1-methylethyl)amino)-butyl)-1,2-benzenediol); Iso- [0006] These compositions are particularly useful for prenaline (4-(1-hydroxy-2-((1-methylethyl)-ami-45 administration via nebulization. In certain embodiments no)ethyl)-1,2-benzenediol); Metaproterenol (5-(1-hy- herein, the subject is a mammal. In other embodiments, droxy-2-((1-methyl-ethyl)amino)ethyl)-1,3-benzenedi- the subject is a human. ol); Picumeterol (4-amino-3,5-dichloro-α-(((6-(2-(2-py- [0007] The compositions provided herein are formulat- ridinyl)ethoxy)hexyl)amino)methyl)benzenemethanol); ed to remain stable over a relatively long period of time. α ( 6-(((1,1-dimethylethyl)amino)methyl)-3-hy- 50 For example, the compositions provided herein are droxy-2,6-pyridine-methanol); (((R*,S*)-(6)- stored between -15 °C and 25 °C, or between 2 °C and 8-hydroxy-5-(1-hydroxy-2-((1-methylethyl)amino)butyl)- 8 °C, and remain stable for the desired time. In one em- 2(1H)-quinolinone); ((7-(3-((2-(3,5-dihydrox- bodiment, the compositions are stored at 5 °C. yphenyl)-2-hydroxyethyl)amino)propyl)-3,7-dihydro- [0008] Formoterol has the formula: 1,3-dimethyl-1 H-purine-2,6-dione); (4-(hy-55 droxy-2-piperidinylmethyl)-1,2-benzenediol); Salbuta- mol 6 (()-α1-(((1,1-dimethylethyl)amino)methyl)-4-hy- droxy-1,3-benzenedimethanol); (R)-; Salme-

2 3 EP 1 381 346 B1 4

[0013] Use of the compositions provided herein for the preparation of a medicament for the treatment, preven- tion, or amelioration of one or more symptoms of bron- choconstrictive disorders, including, but not limited to, 5 asthma, including, but not limited to, bronchial asthma, allergic asthma and intrinsic asthma, e.g., late asthma and airway hyper-responsiveness; chronic bronchitis; and other chronic obstructive pulmonary diseases are provided. 10 Also provided are pharmaceutical compositions for use in treating, preventing or ameliorating one or more symp- toms of bronchoconstructive disorders. [0014] Articles of manufacture, containing packaging [0009] Formoterol for use in the compositions provided material, an aqueous composition comprising a compo- herein includes 2-hydroxy-5-((1RS)-1-hydroxy-15 sition provided herein formulated for single dosage ad- 2-(((1RS)-2-(p-methoxy-phenyl)-1-methylethyl)ami- ministration, which is useful for treatment, prevention or no)ethyl)formanilide; or a stereoisomer thereof; and also amelioration of one or more symptoms of diseases or includes the single enantiomers 2-hydroxy-5-((1S)-1-hy- disorders associated with undesired and/or uncontrolled droxy-2-(((1S)-2-(p-methoxyphenyl)-1-methylethyl)ami- bronchoconstriction, and a label that indicates that the no)ethyl)formanilide and 2-hydroxy-5-((1R)-1-hydroxy- 20 composition is used for treatment, prevention or amelio- 2-(((1R)-2-(p-methoxyphenyl)-1-methylethyl)-ami- ration of one or more symptoms of diseases or disorders no)ethyl)formanilide. associated with undesired and/or uncontrolled bronchoc- [0010] In certain embodiments, the compositions are onstriction, are also provided. administered via nebulization. Administration of a neb- ulized aerosol is preferred over the use of dry powders 25 DETAILED DESCRIPTION OF PREFERRED EMBOD- for inhalation in certain subject populations, including IMENTS pediatric and geriatric groups. [0011] In one embodiment, the compositions provided Definitions herein contain a pharmaceutically acceptable derivative of formoterol. In another embodiment, the compositions 30 [0015] Unless defined otherwise, all technical and sci- for use in the methods provided herein contain a phar- entific terms used herein have the same meaning as is maceutically acceptable salt of formoterol. Pharmaceu- commonly understood by one of ordinary skill in the art ticallyacceptable saltsinclude, butare not limitedto, salts to which this invention belongs. In the event that there of mineral acids, such as but not limited to hydrochlorides are a plurality of definitions for a term herein, those in and sulfates; and salts of organic acids, such as but not 35 this section prevail unless stated otherwise. limited to acetates, lactates, malates, tartrates, citrates, [0016] As used herein, formoterol refers to 2-hydroxy- ascorbates, succinates, butyrates, valerates and fuma- 5-((1RS)-1-hydroxy-2-(((1RS)-2-(p-methoxyphenyl)-1- rates. In one embodiment, the compositions provided methylethyl)amino)ethyl)formanilide; or a stereoisomer herein contain formoterol fumarate or formoterol fuma- thereof. The term formoterol also refers to the single rate dihydrate. In another embodiment, the compositions 40 enantiomers 2-hydroxy-5-((1S)-1-hydroxy-2-(((1S)-2-(p- provided herein contain formoterol tartrate. methoxyphenyl)-1-methylethyl)amino)ethyl)formanilide [0012] Also provided herein are combinations contain- and 2-hydroxy-5-((1R)-1-hydroxy-2-(((1R)-2-(p-methox- ing a composition provided herein and a nebulizer. The yphenyl)-1-methylethyl)amino)ethyl)formanilide. combinations can be packaged as kits, which optionally [0017] As used herein, formoterol fumarate refers to a contain other components, including instructions for use 45 salt of formoterol having the formula (formoterol) ·© fu- of the nebulizer. Any nebulizer is contemplated for use marate. in the kits and methods provided herein. In particular, the [0018] As used herein, formoterol free base refers to nebulizers for use herein nebulize liquid formulations, in- the neutral, anhydrous form of formoterol. Thus, a reci- cluding the compositions provided herein, containing no tation that a composition contains, e.g., 59 mg/mL of for- propellant.The nebulizer may produce the nebulized mist 50 moterol free base means that the composition contains by any method known to those of skill in the art, including, 59 mg/mL of neutral, anhydrous formoterol. Such com- but not limited to, compressed air, ultrasonic waves, or positions may be prepared using a derivative of formot- vibration. The nebulizer may further have an internal baf- erol. fle. The internal baffle, together with the housing of the [0019] As used herein, an aerosol is liquid or particu- nebulizer, selectively removes large droplets from the 55 late matter dispersed in air. Aerosols include dispersions mist by impaction and allows the droplets to return to the of liquids, including aqueous and other solutions, and reservoir. The fine aerosol droplets thus produced are solids, including powders, in air. entrained into the lung by the inhaling air/oxygen. [0020] As used herein, a nebulized solution refers to a

3 5 EP 1 381 346 B1 6 solution that is dispersed in air to form an aerosol. Thus, but not limited to zinc; and other metal salts, such as but a nebulized solution is a particular form of an aerosol. not limited to sodium hydrogen phosphate and disodium [0021] As used herein, a nebulizer is an instrument that phosphate; and also including, but not limited to, salts of is capable of generating very fine liquid droplets for in- mineral acids, such as but not limited to hydrochlorides halation into the lung. Within this instrument, the nebuliz- 5 and sulfates; and salts of organic acids, such as but not ing liquid or solution is atomized into a mist of droplets limited to acetates, lactates, malates, tartrates, citrates, with a broad size distribution by methods known to those ascorbates, succinates, butyrates, valerates and fuma- of skill in the art, including, but not limited to, compressed rates. Pharmaceutically acceptable esters include, but air, ultrasonic waves, or a vibrating orifice. Nebulizers are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, may futher contain, e.g., a baffle which, along with the 10 aralkyl, heteroaralkyl, cycloalkyl and heterocyclyl esters housing of the instrument, selectively removes large of acidic groups, including, but not limited to, carboxylic droplets from the mist by impaction. Thus, the mist in- acids, phosphoric acids, phosphinic acids, sulfonic acids, haled into the lung contains fine aerosol droplets. sulfinic acids and boronic acids. Pharmaceutically ac- [0022] As used herein, a pharmacologically suitable ceptable enol ethers include, but are not limited to, de- fluid is a solvent suitable for pharmaceutical use which 15 rivatives of formula C = C(OR) where R is hydrogen, alkyl, is not a liquified propellant gas. Exemplary pharmaco- alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, logically suitable fluids include polar fluids, including pro- cycloalkyl and heterocyclyl. Pharmaceutically accepta- tic fluids such as water. ble enol esters include, but are not limited to, derivatives [0023] As used herein, a combination refers to any as- of formula C=C(OC(O)R) where R is hydrogen, alkyl, sociation between two or among more items. 20 alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, [0024] As used herein, fluid refers to any composition cycloalkyl and heterocyclyl. Pharmaceutically accepta- that can flow. Fluids thus encompass compositions that ble solvates and hydrates are complexes of a compound are in the form of semi-solids, pastes, solutions, aqueous with one or more solvent or water molecule, in certain mixtures, gels, lotions, creams and other such composi- embodiments 1 to about 100, in other embodiments 1 to tions. 25 about 10, in further embodiments one to about 2, 3 or 4, [0025] As used herein, a mixture is a mutual incorpo- solvent or water molecules. Formoterol salts and hy- rationof two or more substances, without chemicalunion, drates are used in certain embodiments herein. the physical characteristics of each of the components [0028] As used herein, treatment means any manner being retained. in which one or more of the symptoms of a condition, [0026] As used herein, the stability of a composition 30 disorder or disease are ameliorated or otherwise bene- provided herein refers to the length of time at a given ficially altered. Treatment also encompasses any phar- temperature that is greater than 80%, 85%, 90% or 95% maceutical use of the compositions herein, such as use of the initial amount of active ingredient, e.g., formoterol, for treating cancer. is present in the composition. Thus, for example, a com- [0029] As used herein, amelioration of the symptoms position that is stable for 30 days at 25 °C would have 35 of a particular disorder by administration of a particular greater than 80%, 85%, 90% or 95% of the initial amount pharmaceutical composition refers to any lessening, of active ingredient present in the composition at 30 days whether permanent or temporary, lasting or transient that following storage at 25 °C. can be attributed to or associated with administration of [0027] As used herein, pharmaceutically acceptable the composition. derivatives of a compound include salts, esters, enol40 [0030] As used herein, a prodrug is a compound that, ethers, enol esters, acids, bases, solvates, hydrates or upon in vivo administration, is metabolized or otherwise prodrugs thereof. Such derivatives may be readily pre- converted to the biologically, pharmaceutically or thera- pared by those of skill in this art using known methods peutically active form of the compound. To produce a for such derivatization. The compounds produced may prodrug, the pharmaceutically active compound is mod- be administered to animals or humans without substan- 45 ified such that the active compound will be regenerated tial toxic effects and either are pharmaceutically active by metabolic processes. The prodrug may be designed or are prodrugs. Pharmaceutically acceptable salts in- to alter the metabolic stability or the transport character- clude, but are not limited to, amine salts, such as but not istics of a drug, to mask side effects or toxicity, to improve limited to N,N’-dibenzylethylenediamine, chloropro- the flavor of a drug or to alter other characteristics or caine, choline, ammonia, diethanolamine and other hy- 50 properties of a drug. By virtue of knowledge of pharma- droxyalkylamines, ethylenediamine, N-methylglu- codynamicprocesses and in vivo,those camine, procaine, N-benzylphenethylamine, 1-para- of skill in this art, once a pharmaceutically active com- chlorobenzyl-2-pyrrolidin-1’-ylmethylbenzimidazole, di- pound is known, can design prodrugs of the compound ethylamine and other alkylamines, and (see, e.g., Nogrady (1985) Medicinal Chemistry A Bio- tris(hydroxymethyl)aminomethane; alkali metal salts,55 chemical Approach, Oxford University Press, New York, such as but not limited to lithium, potassium and sodium; pages 388-392). alkali earth metal salts, such as but not limited to barium, [0031] It is to be understood that the compounds for calcium and magnesium; transition metal salts, such as use in the compositions and methods provided herein

4 7 EP 1 381 346 B1 8 may contain chiral centers. Such chiral centers may be 12(3):573-579; Palmqvist et al. (1997) Eur. Respir. J. of either the (R) or (S) configuration, or may be a mixture 10(11):2484-2489; Nielsen et al. (1997) Eur. Respir. J. thereof. Thus, the compounds for use in the compositions 10(9):2105-2109; Ullman et al. (1996) Allergy provided herein may be enantiomerically pure, or be ster- 51(10):745-748; Selroos et al. (1996) Clin. Immunother. eoisomeric or diastereomeric mixtures. It is to be under- 5 6:273-299; and Schreurs et al. (1996) Eur. Respir. J. stood that the chiral centers of the compounds provided 9(8):1678-1683. herein may undergo epimerization in vivo. Thus, one of [0037] Formoterol is also available as a tablet and a skill in the art will recognize that administration of a com- dry syrup in certain areas of the worlde.g., ( Atock®, pound in its (R) form is equivalent, for compounds that marcketed by Yamanouchi Pharmaceutical Co. Ltd., Ja- undergo epimerization in vivo, to administration of the 10 pan). Formoterol formulations are also available in other compound in its (S) form. areas (e.g., Europe and U.S.) for propellant-based me- [0032] As used herein, bronchoconstriction refers to a tered dose inhalers and dry powder inhalers (e.g., Tur- reduction in the caliber of a bronchus or bronchi. buhaler®, Aerolizer® and Foradil Aerolizer®). None of [0033] As used herein, undesired and/or uncontrolled these formulationsare waterbased. Sterile, stable, aque- bronchoconstriction refers to bronchoconstriction that re- 15 ous based inhalation solutions of formoterol for nebuli- sults in or from a pathological symptom or condition. zation are not available, nor have they been reported. Pathological conditions include, but are not limited to, [0038] Compositions containing formoterol in combi- asthma and chronic obstructive pulmonary disease nation with other active ingredients have been disclosed. (COPD). Pathological symptoms include, but are not lim- See, e.g., U.S. Patent Nos. 6,004,537, 5,972,919 and ited to, asthma and COPD. 20 5,674,860 (formoterol and budenoside), 5,668,110, [0034] As used herein, the statement that a composi- 5,683,983, 5,677,280 and 5,654,276 (formoterol and IL- tion is stable during "long term storage" means that the 5 inhibitors), 6,136,603 (formoterol and antisense mod- composition is suitable for administration to a subject in ulators of IL-5), 5,602,110 (formoterol and millrinone), need thereof when it has an estimated shelf-life of greater 5,525,623 (formoterol and a tryptase inhibitor), than 1, 2 or 3 months usage time at 25 °C and greater 25 5,691,336, 5,877,191, 5,929,094, 5,750,549 and than or equal to 1, 2 or 3 years storage time at 5 °C. In 5,780,467 (formoterol and a tachykinin receptor antago- certain embodiments herein, using Arrhenius kinetics, > nist); and International Patent Application Publication 80% or > 85% or > 90% or > 95% estimated bronchodi- Nos. WO 99/00134 (formoterol and rofleponide) and WO lating agent remains after such storage. 99/36095 (formoterol and a D2 receptor ago- 30 nist). A. Formoterol [0039] Other compositions containing formoterol have been disclosed in U.S. Patent Nos. 5,677,809, [0035] Formoterol (2-hydroxy-5-((1RS)-1-hydroxy- 6,126,919, 5,733,526, 6,071,971, 6,068,833, 5,795,564, 2-(((1RS)-2-(p-methoxy-phenyl)-1-methylethyl)ami- 6,040,344, 6,041,777, 5,874,481, 5,965,622 and no)ethyl)formanilide) is derived from and, as 35 6,161,536. noted above, is used as a β2-stimulator in inhalation ther- [0040] U.S. Patent No. 6,150,418 discloses a "liquid apy of respiratory diseases, particularly for the treatment active substance concentrate" containing formoterol in of bronchial asthma. It has been reported that in patients the form of its free base or in the form of one of the phar- with reversible obstructive respiratory diseases, formot- macologically acceptable salts or addition products (ad- erol has a bronchodilatory effect. This effect has a rela- 40 ducts) thereof as active substance. This "liquid active tively rapid onset (approximately 1-3 minutes) and a rel- substance concentrate" is reported to be a concentrated atively long duration (greater than 12 hours). Formoterol (i.e., greater than 10 mg/mL, preferably 75 to 500 mg/mL) inhibits the release of leukotrienes and other messenger solutionor suspensionthat is stablefor a period ofseveral substances involved with inflammation, such as hista- months possibly up to several years without any deteri- mines. In addition, formoterol may bring about a hyper- 45 oration in the pharmaceutical quality. This patent teaches glycaemic activity. that it is the high concentration that allows for the stability [0036] To date, formoterol has been formulated as a of the concentrate. The "liquid active substance concen- dry powder and administered via devices such as the trate" is not suitable for direct administration to a patient. Turbuhaler® and the Aerolizer®. See, e.g., Seberova et [0041] U.S. Patent No. 6,040,344 discloses an aque- al. (2000) Respir. Med. 94(6):607-611; Lotvall et al.50 ous aerosol formulation of formoterol tartrate for use in (1999) Can. Respir. J. 6(5):412-416; Campbell et al. a nebulizer. This patent states that the formulation dis- (1999) Respir. Med. 93(4):236-244; Nightingale et al. closed therein is not attractive for long term storage. (1999) Am. J. Respir. Crit. Care Med. 159(6):1786-1790; Lecaillon et al. (1999) Eur. J. Clin. Pharmacol.B. Compositions for use in treatment, prevention, or 55(2):131-138; Bartow et al. (1998) 55 amelioration Drugs of one or more symptoms of bronchoc- 55(2):303-322; Ekstrom et al. (1998) Respir. Med. onstrictive disorders 92(8):1040-1045; Ringdal et al. (1998) Respir. Med. 92(8):1017-1021; Totterman et al. (1998) Eur. Respir. J. [0042] Pharmaceutical compositions containing a

5 9 EP 1 381 346 B1 10

β2-adrenoreceptor agonist for administration via nebuli- [0049] Therefore, the decomposition of formoterol in zation are provided. The compositions are sterile filtered aqueous solution at 60 °C at a buffer concentration of 5 and filled in vials, including unit dose vials providing ster- mM and an ionic strength of 0.05 is slowest at a pH of ile unit dose formulations which are used in a nebulizer about 5.0. and suitably nebulized. Each unit dose vial is sterile and 5 [0050] The solubility of formoterol in aqueous solution is suitably nebulized without contaminating other vials or has been found herein to be dependent on pH. Thus, at the next dose. a pH of between about 5 and about 7, the aqueous sol- [0043] The unit dose vials are formed in a form-fill-seal ubility of formoterol at ambient temperature is approxi- machine or by any other suitable method known to those mately 2.2 mg/mL. At a pH of about 4, the aqueous sol- of skill in the art. The vials may be made of plastic ma- 10 ubility of formoterol at ambient temperature is approxi- terials that are suitably used in these processes. For ex- mately 3 mg/mL, while at a pH of about 3, the aqueous ample, plastic materials for preparing the unit dose vials solubility of formoterol at ambient temperature is about include, but are not limited to, low density polyethylene, 4.8 mg/mL. The solubility of formoterol in pure water, for high density polyethylene, polypropylene and polyesters. example, high performance liquid chromatography In one embodiment, the plastic material is low density 15 (HPLC) water, at ambient temperature is approximately polyethylene. 2 mg/mL.

[0044] The ß2-adrenoreceptor agonist is formoterol, or [0051] In other of the above embodiments, the com- a pharmaceutically acceptable derivative thereof. In oth- positions further contain a buffer, including, but not lim- er embodiments, the formoterol for use in the composi- ited to, citric acid/phosphate, acetate, barbital, , Britton- tions provided herein is formoterol fumarate. Formoterol 20 Robinson, cacodylate, citrate, collidine, formate, refers to 2-hydroxy-5-((1RS)-1-hydroxy-2-(((1RS)-2-(p- maleate, Mcllvaine, phosphate, Prideaux-Ward, succi- methoxyphenyl)-1-methylethyl)amino)ethyl)formani- nate, veronal acetate, MES (2-(N-morpholino)ethanesul- lide; or a stereo-isomer thereof. The term formoterol also fonic acid), ADA (N-(2-acetamido)-2-iminodiacetic acid), refers herein to the single enantiomers 2-hydroxy- ACES (N-(carbamoylmethyl)-2-aminoethanesulfonaic 5-((1S)-1-hydroxy-2-(((1S)-2-(p-methoxyphenyl)-1- 25 acid), PIPES (piperazine-N,N’-bis(2-ethanesulfonic ac- methylethyl)amino)ethyl)formanilide and 2-hydroxy- id)), MOPSO (3-(N-morpholino)-2-hydroxypropanesul- 5-((1R)-1-hydroxy-2-(((1R)-2-(p-methoxyphenyl)-1- fonic acid), BES (N,N-bis(2-hydroxyethyl)-2-ami- methylethyl)amino)ethyl)formanilide. noethanesulfonaic acid), MOPS (3-(N-morpholino)pro- [0045] The compositions contain formoterol free base panesulfonicacid), TES (N-tris(hydroxymethyl)methyl-2- at a concentration of 5 mg/mL to 50 mg/mL. 30 aminoethanesulfonic acid), HEPES (N-(2-hydroxye- [0046] The compostions containing formoterol, are for- thyl)piperazine-N’-(2-ethanesulfonic acid), DIPSO mulated with a pharmacologically suitable fluid. Pharma- (3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypro- cologically suitable fluids include, but are not limited to, panesulfonic acid), MOBS (4-(N-morpholino)butanesul- polar solvents, including, but not limited to, compounds fonic acid), TAPSO (3-(N-tris(hydroxymethyl)methyl- that contain hydroxyl groups or other polar groups. Such 35 amino)-2-hydroxypropanesulfonic acid), HEPPSO solvents include, but are not limited to, water or alcohols, (N-(2-hydroxyethyl)piperazine-N’-(2-hydroxy-pro- such as ethanol, isopropanol, and glycols including pro- panesulfonic acid), POPSO (piperazine-N,N’-bis(2-hy- pylene glycol, polyethylene glycol, polypropylene glycol, droxypropane-sulfonic acid)), EPPS (N-(2-hydroxye- glycol ether, glycerol and polyoxyethylene alcohols. thyl)-piperazine-N’-(3-propanesulfonic acid), TRICINE [0047] Polar solvents also include protic solvents, in- 40 (N-tris(hydroxy-methyl)methylglycine), GLY-GLY (gly- cluding, but not limited to, water, aqueous saline solu- cylglycine), BICINE (N,N-bis(2-hydroxyethyl)glycine), tions with one or more pharmaceutically acceptable HEPBS (N-(2-hydroxyethyl)piperazine-N’-(4-butanesul- salt(s), alcohols, glycols or a mixture thereof. For a saline fonic acid)), TAPS (N-tris(hydroxymethyl)methyl-3-ami- solution as the solvent or as a component othereof, par- no-propanesulfonicacid), AMPD (2-amino-2-methyl-1,3- ticularly suitable salts are those which display no or only 45 propanediol), and/or any other buffers known to those of negligible pharmacological activity after administration. skill in the art. In one embodiment, the buffer is citric [0048] In the embodiments herein, the compositions acid/phosphate buffer, acetate buffer, citrate buffer or have a pH of about 2.0 to about 8.0. In other embodi- phosphate buffer. In another embodiment, the buffer is ments, the compositions have a pH of about 4.0 to about a citrate buffer (citric acid/sodium citrate). The buffer con- 6.0, or about 4.5 to about 5.5. In certain of the above 50 centration has been found herein to affect the stability of embodiments, the compositions are formulated at a pH the composition. Buffer concentrations for use herein in- of about 4, 4.4 or 4.6 up to about 5.5, 5.7 or 6. In other clude from about 0 or 0.01 mM to about 150 mM, or about embodiments, the pH is about 5.0. It has been found 1 mM to about 20 mM. In one embodiment, the buffer herein that the rate constant for decomposition of an concentration is about 5 mM. In other embodiments, the aqueous solution of formoterol is dependent on pH. The 55 buffer concentration is about 1 mM to about 50 mM. In rate constant (kobs) at 60 °C at a pH of 3, 4, 5 and 7 is one embodiment, the buffer concentration is about 20 approximately 0.62, 0.11, 0.044 and 0.55 day -1, respec- mM. The kinetic-pH profile of formoterol is dependent on tively. buffer concentration. At low and approximately neutral

6 11 EP 1 381 346 B1 12 conditions, increasing the buffer concentration from 5 tions stored at higher temperatures. The effect of tem- mM to 20 mM increased the rate constant of decompo- perature on the rate constant of decomposition at pH5, sition significantly. However, no noticeable differences a buffer concentration of 5 mM, and an ionic strength of in rate constant were observed in the pH region of about 0.05, was linear according to Arrhenius kinetics,i.e. , 5 4.5 to about 5.5 with increasing buffer concentration from when Ln kobs was plotted against 1/T, where T is the 5 mM to 20 mM. The particular buffer and buffer concen- temperature in degree Kelvin. tration of a given composition for long term storage pro- [0055] The estimated shelf-life of formoterol in the vided herein may be determined empirically using stand- compositions provided herein is significantly greater than ard stability assays well known to those of skill in the art that reported for known formoterol compositions. The es- (see, e.g., the Examples). 10 timated shelf-life of formoterol in the compositions pro- [0052] The ionic strength of the compositions provided vided herein is about 6.2 years at 5 °C and about 7.5 herein also has been found herein to affect the stability months at 25 °C. The estimated formoterol concentra- of the composition. Ionic strengths of the compositions tions in the compositions provided herein as a function provided herein are from about 0 to about 0.4, or from of storage time at 5 ° C and usage time at 25 °C was about 0.05 to about 0.16. Compositions having a lower 15 determined. It is estimated that greater than 90% of the ionic strength exhibit improved stability over formulations initial formoterol present in the composition remains after having higher ionic strength. The rate constant of decom- 3 months of usage time at 25 °C and 3 years of storage position was essentially the same at ionic strength 0.05 time at 5 °C as well as after 0.5 months of usage time at to 0.1, but increased to some extent at ionic strength of 25 °C and 1 year of storage time at 5 °C. 0.2. The particular ionic strength of a given composition 20 [0056] In one embodiment, the compositions provided for long term storage provided herein may be determined herein are prepared containing formoterol fumarate at a empirically using standard stability assays well known to nominal concentration of 0.1 mg/mL at the indicated pH those of skill in the art (see, e.g., the Examples). and citric acid/phosphate buffer concentrations. The so- [0053] In embodiments where the pharamacologicaliy lutions were stored at 60 °C. In these compositions, for- suitable fluid is a saline solution, tonicity adjusting agents 25 moterol is relatively more stable at a pH from about 4 to may be added to provide the desired ionic strength. To- about 5, and is also more stable at lower buffer concen- nicity adjusting agents for use herein include those which tration. display no or only negligible pharmacological activity af- [0057] The compositions provided herein also may in- ter administration. Both inorganic and organic tonicity ad- clude excipients and additives. The particular excipient justing agents may be used in the compositions provided 30 or additive for use in the compositions for long term stor- herein. Tonicity adjusting agents include, but are not lim- age provided herein may be determined empirically using ited to, ammonium carbonate, ammonium chloride, am- methods well known to those of skill in the art (see, e.g., monium lactate, ammonium nitrate, ammonium phos- the Examples). Excipients and additives are any phar- phate, ammonium sulfate, ascorbic acid, bismuth sodium macologically suitable and therapeutically useful sub- tartrate, calcium chloride, calcium disodium edetate, cal- 35 stance which is not an active substance. Excipients and cium gluconate, calcium lactate, citric acid, dextrose, di- additives generally have no pharmacological activity, or ethanolamine, dimethylsulfoxide, edetate disodium, ede- at least no undesirable pharmacological activity. The ex- tate trisodium monohydrate, fluorescein sodium, fruc- cipients and additives include, but are not limited to, sur- tose, galactose, glycerin, lactic acid, lactose, magnesium factants, stabilizers, complexing agents, antioxidants, or chloride, magnesium sulfate, mannitol, polyethylene gly- 40 presevatives which prolong the duration of use of the col, potassium acetate, potassium chlorate, potassium finished pharmaceutical formulation, flavorings, vita- chloride, potassium iodide, potassium nitrate, potassium mins, or other additives known in the art. Complexing phosphate, potassium sulfate, propylene glycol, silver ni- agents include, but are not limited to, ethylenediamine- trate, sodium acetate, sodium bicarbonate, sodium bi- tetraacetic acid (EDTA) or a salt thereof, such as the phosphate, sodiumbisulfite, sodiumbromide, sodium ca- 45 disodium salt, citric acid, nitrilotriacetic acid and the salts codylate, sodium carbonate, sodium chloride, sodium ci- thereof. In one embodiment, the complexing agent is ED- trate, sodium iodide, sodium lactate, sodium metabi- TA. Preservatives include, but are not limited to, those sulfite, sodium nitrate, sodium nitrite, sodium phosphate, that protect the solution from contamination with patho- sodium propionate, sodium succinate, sodium sulfate, genic particles, including benzalkonium chloride or ben- sodium sulfite, sodium tartrate, sodium thiosulfate, sorb- 50 zoic acid, or benzoates such as sodium benzoate. Anti- itol, sucrose, tartaric acid, urea, urethan, uridine and zinc oxidants include, but are not limited to, vitamins, provi- sulfate. In certain embodiments, the tonicity adjusting tamins, ascorbic acid, vitamin E or salts or esters thereof. agent is sodium chloride. In these embodiments, the [0058] The compositions provided herein also may in- pharmacologically suitable fluid is aqueous saline. clude a cosolvent, which increases the solubility of addi- [0054] The storage temperature of the compositions 55 tives or the active ingredient(s). The particular cosolvent provided herein also has been found herein to affect the for use in the compositions for long term storage provided stability ofthe composition. Compositions storedat a low- hereinmay be determined empirically using methodswell er temperature exhibit improved stability over formula- known to those of skill in the art (see, e.g., the Examples).

7 13 EP 1 381 346 B1 14

Cosolvents for use herein include, but are not limited to, D. Formulation of pharmaceutical compositions hydroxylated solvents or other polar solvents, such as alcohols such as isopropyl alcohol, glycols such as pro- [0064] The compositions provided herien are prepared pylene glycol, polyethylene glycol, polypropylene glycol, by procedures well known to those of skill in the art. For glycol ether, glycerol, and polyoxyethylene alcohols. 5 example, a formoterol fumarate solution may be pre- pared by the procedure of EXAMPLE 1. Briefly, a buffer C. Preparation of compounds for use in the compo- solution having a pH and ionic strength of interest herein sitions is prepared. In one embodiment, the buffer is a mixture of citric acid and sodium citrate, with sodium chloride [0059] The preparation of the compounds used in the 10 added to achieve the desired ionic strength. Formoterol compositions provided herein is described below. Any fumarate dihydrate is added to the buffer solution with such compound or similar compound may be synthe- agitation to produce a solution of the desired formoterol sized according to a method discussed in general below concentration. Exemplary formoterol concentrations are or by only minor modification of the methods by selecting 0.17 g formoterol fumarate dihydrate/2 L and 0.34 g for- appropriate starting materials. 15 moterol fumarate dihydrate/2 L buffer. [0060] Formoterol may be prepared according to the method disclosed in U.S. Patent No. 3,994,974. Briefly, E. Evaluation of the activity of the compositions 4-benzyloxy-3-nitro-α-bromoacetophenone is reacted with N-benzyl-N-(1-methyl-2-p-methoxyphenyle-[0065] Standard physiological, pharmacological and thyl)amine to form the α-aminoacetophenone. This com- 20 biochemical procedures are available for testing the com- pound was subjected to the following series of reactions: positions provided herein to identify those that possess (i) reduction of the ketone with sodium borohydride; (ii) bronchodilatory activity. reduction of the nitro group with aqueous hydrochloric [0066] In vitro and in vivo assays that may be used to acid and iron powder; (iii) amine formylation with acetic evaluate bronchodilatory activity are well known to those anhydride and formic acid; and (iv) catalytic reduction 25 of skill in the art. See also,e.g. , U.S. Patent Nos. over 10% palladium on carbon to afford formoterol free 3,994,974, and 6,068,833; German Patent No. base. Crystallization of the fumarate salt from ethanol 2,305,092; Kaumann et al. (1985) Naunyn-Schmied provides (formoterol) ·© fumarate. Arch. Pharmacol. 331:27-39; Lemoine et al. (1985) [0061] The individual enantiomers of formoterol, 2-hy- Naunyn-Schmied Arch. Pharmacol. 331:40-51; Tomioka droxy-5-((1S)-1-hydroxy-2-(((1S)-2-(p-methoxyphenyl)- 30 et al. (1981) Arch. Int. Pharmacodyn. 250:279-292; Del- 1-methylethyl)amino)ethyl)-formanilide and 2-hydroxy- lamary et al. (2000) Pharm. Res. 17(2):168-174: Rico- 5-((1R)-1-hydroxy-2-(((1R)-2-(p-methoxy-phenyl)-1- Mendez et al. (1999) Rev. Alerg. Mex. 46(5):130-135; methylethyl)amino)ethyl)formanilide, may be prepared Seberova et al. (2000) Respir. Med. 94(6):607-611; by the method disclosed in U.S. Patent No. 6,040,344. Lotvall et al (1999) Can. Respir. J. 6(5):412-416; Camp- Briefly, reaction of optically pure 4-benzyloxy-3-formami- 35 bell et al (1999) Respir. Med. 93(4):236-244; Nightingale dostyrene oxide with an optically pure 4-methoxy- α-me- et al (1999) Am. J. Respir. Crit. Care Med. 159(6): thyl-N-(phenylmethyl)benzeneethanamine, followed by 1786-1790; Lecaillon et al (1999) Eur. J. Clin. Pharmacol. debenzylation, affords the desired enantiomer of formot- 55(2): 131-138;Bartow et al (1998) Drugs55(2):303-322; erol. Debenzylation may be accomplished by reduction Ekstrom et al (1998) Respir. Med. 92(8): 1040-1045; with hydrogen gas in the presence of a noble metal cat- 40 Ringdal et al (1998) Respir. Med. 92(8): 1017-1021 ; Tot- alyst, such as palladium on carbon. terman et al (1998) Eur. Respir. J. 12(3):573-579; [0062] The required optically pure 4-benzyloxy-3-for- Palmqvist et al (1997) Eur. Respir. J. 10(11):2484-2489; mamidostyrene oxide may be prepared from 4-benzy- Nielsen et al (1997) Eur. Respir. J. 10(9):2105-2109; Ul- loxy-3-nitro-α-bromoacetophenone by (i) reduction with lman et al (1996) Allergy 51(10):745-748; Selroos et al vorane in the presence of an optically pure aminoindanol, 45 (1996) Clin. Immunother. 6:273-299; and Schreurs et al (ii) hydrogenation over platinum oxide catalyst, (iii) (1996) Eur. Respir. J. 9(8): 1678-1683. formylation with formic acid and acetic anhydride, and (iv) epoxide formation in the presence of potassium car- F. Methods of treatment of bronchoconstrictive dis- bonate. orders [0063] The required optically pure 4-methoxy-α-me- 50 thyl-N-(phenylmethyl)-benzeneethanamine may be pre- [0067] The compositions provided herein are used for pared from 4-methoxyphenylacetone by (i) reductive am- the preparation of a medicament for treating, preventing, ination with benzylamine in the presence of hydrogen or ameliorating one or more symptoms of a bronchocon- and a platinum catalyst, and (ii) crystallization of the de- strictive disorders in a subject. The subject is, in certain sired optically pure amine from the resulting racemic mix- 55 embodiments, a mammal. The mammal is, in certain em- ture as its mandelic acid salt. bodiments, a human. [0068] A composition provided herein may be suitable for oral administration. The composition may be suitable

8 15 EP 1 381 346 B1 16 for direct administration to a subject in need of such treat- 6-methyl-4H-dibenzo[de,g]quinoline-10,11-diol); Bro- ment via nebulization without dilution or other modifica- mocriptine ((5’α)-2-bromo-12’-hydroxy-2’-(1-methyle- tion of the composition prior to administration. thyl)-5’-(2-methylpropyl)ergotaman-3’,6’,18-trione); Ca- [0069] The medicament in another embodiment, fur- bergoline ((8β)-N-(3-(dimethylamino)propyl)-N-((ethyl- ther includes one or more of (a), (b), (c) or (d) as follows: 5 amino)carbonyl)-6-(2-propenyl)-8-carboxam-

(a) a ß2-adrenoreceptor agonist; (b) a dopamine (D2) ide); (N’-((8α)-9,10-didehydro-6-methylergolin- receptor agonist; (c) a prophylactic therapeutic, such as 8-yl)-N,N-diethylurea); β ((8)-8-((methylth- a steroid; or (d) an agent; administered io)methyl)-6-propylergoline); Levodopa (3-hydroxy-L- simultaneously with, prior to or subsequent to the com- tryrosine); Pramipexole ((s)-4,5,6,7-tetrahydro-N6-pro- position provided herein. 10 pyl-2,6-benzothiazolediamine); Quinpirole hydrochlro-

[0070] ß2-Adrenoreceptor agonists for use in combi- die (trans-(-)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl- nation with the compositions provided herein include, but 1 H-pyrazolo[3,4-g]quinoline hydrochloride); Ropinirole are not limited to, Albuterol ( α1-(((1,1-dimethylethyl)ami- (4-(2-(dipropylamino)ethyl)-1,3-dihydro-2H-indol-2- no)methyl)-4-hydroxy-1,3-benzenedimethanol); Bam- one); and (5,6,7,8-tetrahydro-6-(2-propenyl)- 15 buterol (dimethylcarbamic acid 5-(2-((1,1-dimethyle- 4H-thiazolo[4,5-d]azepin-2-amine). Other dopamine D2 thyl)amino)-1-hydroxyethyl)-1,3-phenylene ester); Bitol- receptor agonists for use herein are disclosed in Inter- terol(4-methylbenzoic acid4-(2-((1,1-dimethylethyl)ami- national Patent Application Publication No. WO no)-1-hydroxyethyl)-1,2-phenylene ester); Broxa-terol 99/36095. (3-bromo-α-(((1,1-dimethylethyl)amino)methyl)-5-isox- [0072] Prophylactic therapeutics for use in combina- azolemethanol); Isoproterenol (4-(1-hydroxy-2-((1-20 tion therapy herein include steroidal anti-inflammatory methylethyl)amino)ethyl)-1,2-benzenediol); Trimetoqui- agents, including, but not limited to, beclomethasone di- nol (1,2,3,4-tetrahydro-1-((3,4,5-trimethoxyphenyl)-me- propionate (BDP), beclomethasone monopropionate thyl)-6,7-isoquinolinediol); Clenbuterol (4-amino-3,5- (BMP), , acetonide, dexameth- dichloro-α-(((1,1-diemthylethyl)amino)methyl)benzen- asone, tipredane, ciclesonid, rofleponide, , emethanol); Fenoterol (5-(1-hydroxy-2-((2-(4-hydroxy- 25 mometasone furoate (Asmanex ® Twisthaler™, Shering- phenyl)-1-methylethyl)amino)ethyl)-1,3-benzenediol); Plough Corporation, Kenilworth, NJ), RPR 106541, fluti- Formoterol (2-hydroxy-5-((1RS)-1-hydroxy-2-(((1RS)- casone or propionate and or by 2-(p-methoxyphenyl)-1-methylethyl)amino)ethyl)form- way of sodium cromoglycate or sodium. anilide); (R,R)-Formoterol; Desformoterol ((R,R) or [0073] Anticholinergic agents for use herein include, (S,S)-3-amino-4-hydroxy-α-(((2-(4-methoxyphenyl)-1- 30 but are not limited to, , oxitropium methyl-ethyl)amino)methyl)benzenemethanol); Hexo- bromide, atropine methyl nitrate, atropine sulfate, iprat- prenaline (4,4’-(1,6-hexane-diyl)-bis(imino(1-hydroxy- ropium, belladonna extract, scopolamine, scopolamine 2,1-ethanediyl)))bis-1,2-benzenediol); Isoetharine (4-(1- methobromide, homatropine methobromide, hyo- hydroxy-2-((1-methylethyl)amino)butyl)-1,2-benzenedi- scyamine, isopriopramide, orphenadrine, benzalkonium ol); (4-(1-hydroxy-2-((1-methylethyl)ami- 35 chloride, and glycopyrronium bro- no)ethyl)-1,2-benzenediol); Metaproterenol (5-(1-hy- mide. In certain embodiments, the compositions contain droxy-2-((1-methylethyl)amino)ethyl)-1,3-benzenediol); an anticholinergic agent, such as ipratropium bromide or Picumeterol (4-amino-3,5-dichloro-α-(((6-(2-(2-pyridi- tiotropium bromide, at a concentration of about 5 mg/mL nyl)ethoxy)hexyl)-amino)methyl)benzenemethanol); to about 5 mg/mL, or about 50 mg/mL to about 200 mg/mL. Pirbuterol (α6-(((1,1-dimethylethyl)-amino)methyl)-3-hy- 40 In other embodiments, the compositions for use in the droxy-2,6-pyridinemethanol); Procaterol (((R*,S*)-( 6)-8- methods herein contain an anticholinergic agent, includ- hydroxy-5-(1-hydroxy-2-((1-methylethyl)amino)butyl)- ing ipratropium bromide and tiotropium bromide, at a con- 2(1H)-quinolinone); Reproterol ((7-(3-((2-(3,5-dihydrox- centration of about 83 mg/mL or about 167 mg/mL. yphenyl)-2-hydroxyethyl)amino)-propyl)-3,7-dihydro- [0074] Other active ingredients for use herein in com- 1,3-dimethyl-1H-purine-2,6-dione); Rimiterol (4-(hy-45 bination therapy, include, but are not limited to, IL-5 in- droxy-2-piperidinylmethyl)-1,2-benzenediol); Salbuta- hibitors such as those disclosed in U.S. Patent Nos. mol 6 (()-α1-(((1,1-dimethylethyl)amino)methyl)-4-hy- 5,668,110, 5,683,983, 5,677,280 and 5,654,276; anti- droxy-1,3-benzenedimethanol); (R)-Salbutamol; Salme- sense modulators of IL-5 such as those disclosed in U.S. terol ((6)-4-hydroxy-α1-(((6-(4-phenylbu- Patent No. 6,136,603; milrinone (1,6-dihydro-2-methyl- toxy)hexyl)-amino)methyl)-1,3-benzenedimethanol); 50 6-oxo-[3,4’-bipyridine]-5-carbonitrile); milrinone lactate; (R)-Salmeterol; Terbutaline (5-(2-((1,1-dimethyle- tryptase inhibitors such as those disclosed in U.S. Patent thyl)amino)-1-hydroxyethyl)-1,3-benzenediol); Tu- No. 5,525,623; tachykinin receptor antagonists such as lobuterol (2-chloro-α-(((1,1-dimethylethyl)amino)me- those disclosed in U.S. Patent Nos. 5,691,336, thyl)benzenemethanol); and TA-2005 (8-hydroxy- 5,877,191, 5,929,094, 5,750,549 and 5,780,467; leuko- 5-((1R)-1-hydroxy-2-(N-((1R)-2-(4-methoxyphenyl)-1- 55 triene receptor antagonists such as sodium methylethyl)amino)ethyl)carbostyril hydrochloride). (Singular®, R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinoli- [0071] Dopamine (D2) receptor agonists include, but nyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phe- are not limited to, ((r)-5,6,6a,7-tetrahydro- nyl]-propyl]thio]methyl]cyclopropaneacetic acid, mono-

9 17 EP 1 381 346 B1 18 sodium salt), 5-lypoxygenase inhibitors such as NEB, Micro Mist, and PulmoMate. Exemplary ultrasonic (Zyflo®, Abbott Laboratories, Abbott Park, IL), and anti- nebulizers for use herein include MicroAir, UltraAir, Sie- IgE antibodies such as Xolair ® (recombinant humanized mens Ultra Nebulizer 145, CompAir, Pulmosonic, Scout, anti-IgE monoclonal antibody (CGP 51901; IGE 025A; 5003 Ultrasonic Neb, 5110 Ultrasonic Neb, 5004 Desk rhuMAb-E25), Genentech, Inc., South San Francisco, 5 Ultrasonic Nebulizer, Mystique Ultrasonic, Luminscope’s CA). Ultrasonic Nebulizer, Medisana Ultrasonic Nebulizer, [0075] The bronchoconstrictive disorder to be treated, Microstat Ultrasonic Nebulizer, and MABISMist Hand prevented, or whose one or more symptoms are to be Held Ultrasonic Nebulizer. Other nebulizers for use here- ameliorated is associated with asthma, including, but not in include 5000 Electromagnetic Neb, 5001 Electromag- limited to, bronchial asthma, allergic asthma and intrinsic 10 netic Neb 5002 Rotary Piston Neb, Lumineb I Piston Neb- asthma, e.g., late asthma and airway hyper-responsive- ulizer 5500, Aeroneb™ Portable Nebulizer System, Aer- ness; and, particularly in embodiments where an anti- odose™ Inhaler, and AeroEclipse Breath Actuated Neb- cholinergic agent is used, other chronic obstructive pul- ulizer. monary diseases (COPDs), including, but not limited to, chronic bronchitis, emphysema, and associated cor pul- 15 H. Articles of manufacture monale (heart disease secondary to disease of the lungs and respiratory system) with pulmonary hypertension, [0078] The compositions provided herein may be right ventricular hypertrophy and right heart failure. packaged as articles of manufacture containing packag- COPD is frequently associated with cigarette smoking, ing material, an aqueous composition comprising a com- infections,environmental pollution and occupational dust 20 position provided herein formulated for single dosage ad- exposure. ministration, which is useful for treatment, prevention or amelioration of one or more symptoms of diseases or G. Nebulizers disorders associated with undesired and/or uncontrolled bronchoconstriction, and a label that indicates that the [0076] The compositions provided herein are intended 25 composition is used for treatment, prevention or amelio- for administration to a subject in need of such treatment ration of one or more symptoms of diseases or disorders via nebulization. Nebulizers that nebulize liquid formula- associated with undesired and/or uncontrolled bronchoc- tions containing no propellant are suitable for use with onstriction. the compositions provided herein. Nebulizers are avail- [0079] The articles of manufacture provided herein able from, e.g., Pari GmbH (Starnberg, Germany), DeV- 30 contain packaging materials. Packaging materials for ilbiss Healthcare (Heston, Middlesex, UK), Healthdyne, use in packaging pharmaceutical products are well Vital Signs, Baxter, Allied Health Care, Invacare, Hud- known to those of skill in the art. See, e.g., U.S. Patent son, Omron, Bremed, AirSep, Luminscope, Medisana, Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of Siemens, Aerogen, Mountain Medical, Aerosol Medical pharmaceutical packaging materials include, but are not Ltd. (Colchester, Essex, UK), AFP Medical (Rugby, War- 35 limited to, blister packs, bottles, tubes, inhalers, pumps, wickshire, UK), Bard Ltd. (Sunderland, UK), Carri-Med bags, vials, containers, syringes, bottles, and any pack- Ltd. (Dorking, UK), Plaem Nuiva (Brescia, Italy), Henleys aging material suitable for a selected formulation and in- Medical Supplies (London, UK), Intersurgical (Berkshire, tended mode of administration and treatment. UK), Lifecare Hospital Supplies (Leies, UK), Medic-Aid [0080] In one embodiment herein, the compositions Ltd. (West Sussex, UK), Medix Ltd. (Essex, UK), Sinclair 40 are packaged with a nebulizer for direct administration Medical Ltd. (Surrey, UK), and many others. of the composition to a subject in need thereof. [0077] Nebulizers for use herein include, but are not [0081] The following examples are included for illus- limited to, jet nebulizers (optionally sold with compres- trative purposes only and are not intended to limit the sors), ultrosonic nebulizers, and others. Exemplary jet scope of the invention. nebulizers for use herein include Pari LC plus/ProNeb, 45 Pari LC plus/ProNeb Turbo, Pari LC plus/Dura Neb 1000 EXAMPLE 1 & 2000, Pari LC plus/Walkhaler, Pari LC plus/Pari Mas- ter, Pari LC star, Omron CompAir XL Portable Nebulizer Preparation of Formoterol Inhalation Solution For- System (NE-C18 and JetAir Disposable nebulizer), Om- mulation ron CompAir Elite Compressor Nebulizer System (NE- 50 C21 and Elite Air Reusable Nebilizer), Pari LC Plus or [0082] To a 5 L stainless steel vessel were added 0.68 Pari LC Star nebulizer with Proneb Ultra compressor, g citric acid USP, 1.99 g sodium citrate USP, and 17.5 g Pulmo-aide, Pulmo-aide LT, Pulmo-aide traveler, In- sodium chloride USP. Purified water USP (2 L) was add- vacare Passport, Inspiration Healthdyne 626, Pulmo- ed to the stainless steel vessel and the contents were Neb Traverler, DeVilbiss 646, Whisper Jet, Acorn II,55 mixed with an overhead stirrer at a speed of 240 rpm for Misty-Neb, Allied aerosol, Schuco Home Care, Lexan 10 minutes. Formoterol fumarate dihydrate (0.17 g for Plasic Pocet Neb, SideStream Hand Held Neb, Mobil low dosage strength formulation, 0.34 g for high dosage Mist, Up-Draft, Up-Draft II, T Up-Draft, ISO-NEB, AVA- strength formulation) was added and the solution was

10 19 EP 1 381 346 B1 20 stirred at 240 rpm for 90 minutes. present after 1 month usage time at 25 °C and 1 year storage time at 5°C. EXAMPLE 2 4. The pharmaceutical composition of any of claims Preparation of Formoterol Unit Dose Formulations 5 1-3, wherein the pharmacologically suitable fluid comprises a polar solvent. [0083] Following the procedure of EXAMPLE 1, the fol- lowing formoterol unit dose formulations were prepared. 5. The pharmaceutical composition of claim 4, wherein the polar solvent is a protic solvent. Low Strength (0.0085%) 10 6. The pharmaceutical composition of any of claims [0084] A low strength formoterol unit dose formulation 1-5, further comprising a tonicity adjusting agent. was prepared using the following reagents in the amounts indicated: formoterol fumarate dihydrate (0.170 7. The pharmaceutical composition of claim 6, wherein mg), citric acid monohydrate, USP (0.68 mg), sodium 15 the tonicity adjusting agent is ammonium carbonate, citrate dihydrate, USP (1.99 mg), sodium chloride, USP ammonium chloride, ammonium lactate, ammonium (17.5 mg), and purified water, USP (qs to 2 mL). nitrate, ammonium phosphate, ammonium sulfate, ascorbic acid, bismuth sodium tartrate, calcium chlo- High Strength (0.0170%) ride, calcium disodium edetate, calcium gluconate, 20 calcium lactate, citric acid, dextrose, dieth- [0085] A high strength formoterol unit dose formulation anolamine, dimethylsulfoxide, edetate disodium, was prepared using the following reagents in the edetate trisodium monohydrate, fluorescein sodium, amounts indicated: formoterol fumarate dihydrate (0.340 fructose, galactose, glycerin, lactic acid, lactose, mg), citric acid monohydrate, USP (0.68 mg), sodium magnesium chloride, magnesium sulfate, mannitol, citrate dihydrate, USP (1.99 mg), sodium chloride, USP 25 polyethylene glycol, potassium acetate, potassium (17.5 mg), and purified water, USP (qs to 2 mL). chlorate, potassium chloride, potassium iodide, po- tassium nitrate, potassium phosphate, potassium EXAMPLE 3 sulfate, propylene glycol, silver nitrate, sodium ace- tate, sodium bicarbonate, sodium biphosphate, so- Procedure for stability testing of formoterol solu- 30 dium bisulfate, sodium bromide, sodium cacodylate, tions sodium carbonate, sodium chloride, sodium citrate, sodium iodide, sodium lactate, sodium metabisulfite. [0086] Stability samples of the solutions prepared in sodium nitrate, sodium nitrite, sodium phosphate, EXAMPLES 1 and 2 were placed in scint illation vials with sodium propionate, sodium succinate, sodium sul- teflon-lined caps and stored in stability ovens at acceler- 35 fate, sodium sulfite, sodium tartrate, sodium thiosul- ated temperatures. At selected time points, aliquots of fate, sorbitol, sucrose, tartaric acid, urea, urethan, the samples were removed from the scintillation vials. uridine or zinc sulfate. The formoterol concentrations of the samples were an- alyzed by high performance liquid chromatography. 8. The pharmaceutical composition of claim 6 or 7, 40 wherein the tonicity adjusting agent is sodium chlo- ride. Claims 9. The pharmaceutical composition of any of claims 1. A pharmaceutical composition, comprising formot- 1-3, wherein the pharmacologically suitable fluid erol free base at a concentration of 5m g/ml to 50 45 comprises a buffer. mg/ml, or a derivative thereof, in a pharmacologically suitable fluid, wherein the composition is stable dur- 10. The pharmaceutical composition of any of claims ing long term storage, the fluid comprises water, and 4-8, further comprising a buffer. the composition is suitable for direct administration to a subject in need thereof. 50 11. The pharmaceutical composition of claim 9 or 10, wherein the buffer is citric acid/phosphate, acetate, 2. The pharmaceutical composition of claim 1, wherein barbital, Britton-Robinson, cacodylate, citrate, colli- the composition has an estimated shelf-life of greater dine, formate, maleate, Mcllvaine, phosphate, Pri- than 1 month usage time at 25 °C and greater than deaux-Ward,succinate, veronal acetate, MES(2-(N- or equal to 1 year storage time at 5°C. 55 morpholino)ethanesulfonic acid), ADA (N-(2-aceta- mido)-2-iminodiacetic acid), ACES (N-(carbamoyl- 3. The pharmaceutical composition of claim 1 or 2, methyl)-2-aminoethanesulfonaic acid), PIPES (pip- wherein greater than 80% of the initial formoterol is erazine-N,N’-bis(2- ethanesulfonic acid)), MOPSO

11 21 EP 1 381 346 B1 22

(3-(N-morpholino)-2-hydroxypropanesulfonic acid), follows: (a) β2-adrenoreceptor agonist; (b) a BES (N,N-bis(2-hydroxyethyl)- 2-aminoethanesul- dopamine (D2) receptor agonist; (c) an IL-5 inhibitor; fonaic acid), MOPS (3-(N-morpholino)propanesul- (d) an antisense modulator of IL-5; (e) a tryptase fonic acid), TES (N-tris(hydroxymethyl)methyl 1-2- inhibitor; (f) a tachykinin receptor antagonist; (g) mil- aminoethanesulfonic acid), HEPES (N-(2- hydrox- 5 rinone or milrinone lactate; (h) a leukotriene receptor yethyl)piperazine-N’-(2-ethanesulfonic acid), DIP- antagonist; (i) a 5-lypoxygenase inhibitor; or (j) an SO (3-(N,N-bis(2-hydroxyethyl)amino)- 2-hydroxy- anti-IgE antibody. propanesulfonic acid), MOBS (4-(N-morpholino)bu- tanesulfonic acid), TAPSO (3-(N-tris(hydroxyme- 23. The pharmaceutical composition of claim 10 or 11, thyl)methylamino)-2-hydroxy-propanesulfonic ac- 10 wherein the buffer comprises citric acid/phosphate id), HEPPSO (N-(2-hydroxyethyl)piperazine-N’-(2- buffer, acetate buffer, citrate buffer or phosphate hydroxypropanesulfonic acid), POPSO (piperazine- buffer. N,N’-bis(2-hydroxypropanesulfonic acid)), EPPS (N-(2-hydroxyethyl)piperazine-N’-(3-propane-sul- 24. The pharmaceutical composition of any of claims fonic acid), TRICINE (N-tris (hydroxymethyl)methyl- 15 10-13, wherein the buffer concentration is from 1 mM glycine), GLY-GLY (glycylglycine), BICINE (N,N- to 50 mM. bis(2-hydroxyethyl)glycine), HEPBS (N-(2-hydrox- yethyl)piperazine-N’-(4-butanesulfonic acid)), TAPS 25. The pharmaceutical composition of claim 24, where- (N-tris(hydroxy-methyl)methyl-3-aminopropanesul- in the buffer concentration is 20 mM. fonic acid), or AMPD (2-amino-2- methyl- 1,3-pro- 20 panediol) buffer. 26. The pharmaceutical composition of any of claims 1-25, further comprising an anticholinergic agent. 12. The pharmaceutical composition of claim 10 or 11, wherein the buffer is citrate buffer. 27. The pharmaceutical composition of claim 26, where- 25 in the anticholinergic agent is ipratropium bromide, 13. The pharmaceutical composition of any of claims , atropine methyl nitrate, tiotro- 10-12, wherein the buffer concentration is from 0.01 pium bromide or . mM to 150 mM. 28. The pharmaceutical composition of claim 26 or 27, 14. The pharmaceutical composition of any of claims 30 wherein the anticholinergic agent is ipratropium bro- 10-13, wherein the buffer concentration is from 1 mM mide. to 20 mM. 29. The pharmaceutical composition of claim 27 or 28, 15. The pharmaceutical composition of any of claims wherein the ipratropium bromide is present at a con- 10-14, wherein the buffer concentration is 5 mM. 35 centration of 5 mg/ml to 5 mg/ml.

16. The pharmaceutical composition of any of claims 30. The pharmaceutical composition of claim 26 or 27, 1-15, wherein the ionic strength of the composition wherein the anticholinergic agent is tiotropium bro- is 0 to 0.4. mide. 40 17. The pharmaceutical composition of any of claims 31. The pharmaceutical composition of claim 27 or 30, 1-16, wherein the ionic strength of the composition wherein the tiotropium bromide is present at a con- is 0.05 to 0.16. centration of 5 mg/ml to 5 mg/ml.

18. The pharmaceutical composition of any of claims 45 32. The pharmaceutical composition of any of claims 1-17, wherein the pH of the composition is 2.0 to 8.0. 1-31 that has been nebulized.

19. The pharmaceutical composition of any of claims 33. A kit comprising: 1-18, wherein the pH of the composition is 4.0 to 6.0. 50 (a) the pharmaceutical composition of any one 20. The pharmaceutical composition of any of claims of claims 1 to 31 formulated for single dose ad- 1-19, wherein the pH of the composition is 4.5 to 5.5. ministration: and (b) a nebuluizer. 21. The pharmaceutical composition of any of claims 1-20, wherein the pH of the composition is 5.0. 55 34. A kit, comprising:

22. The pharmaceutical composition of any of claims (a) a composition of any of claims 1-31; and 1-21, further comprising one or more of (a) to (j) as (b) a nebulizer.

12 23 EP 1 381 346 B1 24

35. A combination, comprising: spruch 1, worin die Zusammensetzung eine ge- schätzte Haltbarkeit von mehr als 1 Monat Ge- (a) the pharmaceutical composition of any of brauchszeit bei 25 °C und mehr als oder gleich ein claims 1-31 formulated for single dosage admin- Jahr Aufbewahrungszeit bei 5 °C hat. istration; and 5 (b) a vial. 3. Pharmazeutische Zusammensetzung nach An- spruch 1 oder 2, worin mehr als 80 % des anfängli- 36. Anarticle ofmanufacture, comprising packaging ma- chen Formoterol nach 1 Monat Gebrauchszeit bei terial, an aqueous composition comprising the com- 25 °C und 1 Jahr Aufbewahrungszeit bei 5 °C vor- position of any of claims 1-32 formulated for single 10 liegt. dosage administration, which is useful for treatment, prevention or amelioration of one or more symptoms 4. Pharmazeutische Zusammensetzung nach einem of diseases or disorders associated with undesired der Ansprüche 1 - 3, worin das pharmakologisch ge- and/or uncontrolled bronchoconstriction, and a label eignete Fluid ein polares Lösungsmittel umfasst. that indictates that the composition is used for treat- 15 ment, prevention or amelioration of one or more 5. Pharmazeutische Zusammensetzung nach An- symptoms of diseases or disorders associated with spruch 4, worin das polare Lösungsmittel ein proti- undesired and/or uncontrolled bronchoconstriction. sches Lösungsmittel ist.

37. The pharmaceutical composition of any of claims 20 6. Pharmazeutische Zusammensetzung nach einem 1-31, when used for the treatment, prevention, or der Ansprüche 1 - 5, weiterhin umfassend ein Mittel amelioration of one or more symptoms of bronchoc- zur Tonizitätseinstellung. onstrictive disorders. 7. Pharmazeutische Zusammensetzung nach An- 38. Use of the pharmaceutical composition of any of25 spruch 6, worin das Mittel zur Tonizitätseinstellung claims 1-31 for the preparation of a medicament for Ammoniumcarbonat, Ammoniumchlorid, Ammoni- the treatment, prevention, or amelioration of one or umlactat, Ammoniumnitrat, Ammoniumphosphat, more symptoms of bronchoconstrictive disorders. Ammoniumsulfat, Ascorbinsäure, Bismutnatrium- tartrat, Calciumchlorid, Calciumdinatriumedetat, 39. The pharmaceutical composition of any of claims 30 Calciumgluconat, Calciumlactat, Zitronensäure, 1-31 for use in treating, preventing, or ameliorating Dextrose, Diethanolamin, Dimethylsulfoxid, Dinatri- one or more symptoms of bronchoconstrictive dis- umedetat, Trinatriumedetat-Monohydrat, Fluores- orders. zein-Natrium, Fructose, Galactose, Glycerin, Milch- säure, Lactose, Magnesiumchlorid, Magnesiumsul- 40. The use according to claim 38, wherein said medi- 35 fat, Mannitol, Polyethylenglykol, Kaliumacetat, Kali- cament further comprises one or more of: (a) umchlorat, Kaliumchlorid, Kaliumiodid, Kaliumnitrat,

β2-adrenoreceptor agonist; (b) a dopamine (D2) re- Kaliumphosphat, Kaliumsulfat, Propylenglykol, Sil- ceptor agonist; (c) an IL-5 inhibitor; (d) an antisense bernitrat, Natriumacetat, Natriumbicarbonat, Natri- modulator of IL-5; (e) a tryptase inhibitor; (f) a tach- umbiphosphat, Natriumbisulfat, Natriumbromid, Na- ykinin receptor antagonist; (g) milrinone or milrinone 40 triumcacodylat, Natriumcarbonat, Natriumchlorid, lactate; (h) a leukotriene receptor antagonist; (i) a 5- Natriumcitrat, Natriumiodid, Natriumlactat, Natrium- lypoxygenase inhibitor; or (j) an anti-IgE antibody; metabisulfit, Natriumnitrat, Natriumnitrit, Natrium- administered simultaneously with, prior to or subse- phosphat, Natriumpropionat, Natriumsuccinat, Nat- quent to said pharmaceutical composition. riumsulfat, Natriumsulfit, Natriumtartrat, Natriumthi- 45 osulfat, Sorbitol, Sucrose, Weinsäure, Harnstoff, Urethan, Uridin oder Zinksulfat ist. Patentansprüche 8. Pharmazeutische Zusammensetzung nach An- 1. Pharmazeutische Zusammensetzung, umfassend spruch 6 oder 7, worin das Mittel zur Tonizitätsein- Formoterol als freie Base in einer Konzentration von 50 stellung Natriumchlorid ist. 5 mg/ml bis 50 mg/ml, oder ein Derivat davon, in ei- nem pharmakologisch geeigneten Fluid, worin die 9. Pharmazeutische Zusammensetzung nach einem Zusammensetzung während Langzeitlagerung sta- der Ansprüche 1 - 3, worin das pharmkologisch ge- bil ist, das Fluid Wasser umfasst und die Zusammen- eignete Fluid einen Puffer umfasst. setzung geeignet ist für direkte Verabreichung an 55 einen Probanden, der sie benötigt. 10. Pharmazeutische Zusammensetzung nach einem der Ansprüche 4 - 8, weiterhin umfassend einen Puf- 2. Pharmazeutische Zusammensetzung nach An- fer.

13 25 EP 1 381 346 B1 26

11. Pharmazeutische Zusammensetzung nach An- 19. Pharmazeutische Zusammensetzung nach einem spruch 9 oder 10, worin der Puffer Zitronensäu- der Ansprüche 1 - 18, worin der pH-Wert der Zusam- re/Phosphat-, Acetat-, Barbital-, Britton-Robinson-, mensetzung 4,0 bis 6,0 ist. Cacodylat-, Citrat-, Collidin-, Formiat-, Maleat-, Mcll- vaine-, Phosphat-, Prideaux-Ward-, Succinat-, Ve- 5 20. Pharmazeutische Zusammensetzung nach einem ronalacetat, MES (2-(N-Morpholino)ethansulfon- der Ansprüche 1 - 19, worin der pH-Wert der Zusam- säure)-, ADA (N-(2-Acetamido)-2-iminoessigsäu- mensetzung 4,5 bis 5,5 ist. re)-, ACES (N-(Carbamoylmethyl)-2-aminoethan- sulfonsäure)-, PIPES (Piperazin-N,N’-bis(2-ethan- 21. Pharmazeutische Zusammensetzung nach einem sulfonsäure))-, MOPSO (3-(N-Morpholino)-2-hydro- 10 der Ansprüche 1 - 20, worin der pH-Wert der Zusam- xypropansulfonsäure)-, BES (N,N’-Bis(2-hydroxye- mensetzung 5,0 ist. thyl)-2-aminoethansulfonsäure)-, MOPS (3-(N-Mor- pholino)propansulfonsäure)-, TES 22. (N-Pharmazeutische Zusammensetzung nach einem Tris(hydroxymethyl)methyl-1,2-aminoethansulfon- der Ansprüche 1 - 21, weiterhin umfassend eines 15 säure)-, HEPES (N-(2-Hydroxyethyl)piperazin- oder mehrere aus (a) bis (j), wie folgend: (a) ß2-Ad- N’-(2-ethansulfonsäure)-, DIPSO (3-(N,N-bis-(2-Hy- renorezeptoragonist; (b) ein Dopamin (D2)-Rezep- droxyethyl)amino)-2-hydroxy-propansulfonsäure)-, toragonist; (c) ein IL-5-Inhibitor; (d) ein Anti-sense- MOBS (4-(N-Morpholino)butansulfonsäure)-, TAP- Modulator von IL-5; (e) ein Tryptase-Inhibitor; (f) ein SO (3-(N-Tris(hydroxymethyl)methylamino)-2-hy- Tachykinin-Rezeptorantagonist; (g) Milrinon oder droxypropansulfonsäure)-, HEPPSO (N-(2-Hydro- 20 Milrinon-Lactat; (h) ein Leukotrien-Rezeptorantago- xyethyl)piperazin-N’-(2-hydroxypropansulfonsäu- nist; (i) ein 5-Lipoxygenaseinhibitor; oder (j) ein anti- re)-, POPSO (Piperazin-N,N’-bis(2-hydroxypropan- IgE-Antikörper. sulfonsäure))-, EPPS (N-(2-Hydroxyethyl)piperazin- N’-(3-propan-sulfonsäure), TRICINE (N-Tris(hydro- 23. Pharmazeutische Zusammensetzung nach An- xymethyl)methylglycin)-, GLY-GLY (Glycilglycin)-, 25 spruch 10 oder 11, worin der Puffer Zitronensäu- BICINE (N,N-Bis(2-hydroxyethyl)glycin)-, HEPBS re/Phosphat-Puffer, Acetat-Puffer, Citrat-Puffer (N-(2-Hydroxyethyl)piperazin-N’-(4-butansulfon- oder Phosphat-Puffer umfasst. säure))-, TAPS (N-Tris(Hydroxy-methyl)methyl-3- aminopropansulfonsäure)- oder AMPD (2-Amino-2- 24. Pharmazeutische Zusammensetzung nach einem methyl-1,3-propandiol)-Puffer. 30 der Ansprüche 10-13, worin die Pufferkonzentration von 1 mM bis 50 mM ist. 12. Pharmazeutische Zusammensetzung nach An- spruch 10 oder 11, worin der Puffer Citrat-Puffer ist. 25. Pharmazeutische Zusammensetzung nach An- spruch 24, worin die Pufferkonzentration 20 mM ist. 13. Pharmazeutische Zusammensetzung nach einem 35 der Ansprüche 10-12, worin die Pufferkonzentration 26. Pharmazeutische Zusammensetzung nach einem von 0,01 mM bis 150 mM ist. der Ansprüche 1 - 25, weiterhin umfassend ein an- ticholinerges Mittel. 14. Pharmazeutische Zusammensetzung nach einem der Ansprüche 10-13, worin die Pufferkonzentration 40 27. Pharmazeutische Zusammensetzung nach An- von 1 mM bis 20 mM ist. spruch 26, worin das anitcholinerge Mittel Ipratropi- umbromid, Oxitropimbromid,Atropinmethylnitrat, Ti- 15. Pharmazeutische Zusammensetzung nach einem otropiumbromid oder Glycopyrroniumbromid ist. der Ansprüche 10-14, worin die Pufferkonzentration 5 mM ist. 45 28. Pharmazeutische Zusammensetzung nach An- spruch 26 oder 27, worin das anticholinerge Mittel 16. Pharmazeutische Zusammensetzung nach einem Ipratropiumbromid ist. der Ansprüche 1 - 15, worin die Ionenstärke der Zu- sammensetzung 0 bis 0,4 ist. 29. Pharmazeutische Zusammensetzung nach An- 50 spruch 27 oder 28, worin das Ipratropiumbromid in 17. Pharmazeutische Zusammensetzung nach einem einer Konzentration von 5 mg/ml bis 5 mg/ml vorliegt. der Ansprüche 1 - 16, worin die Ionenstärke der Zu- sammensetzung 0,05 bis 0,16 ist. 30. Pharmazeutische Zusammensetzung nach An- spruch 26 oder 27, worin das anticholinerge Mittel 18. Pharmazeutische Zusammensetzung nach einem 55 Tiotropiumbromid ist. der Ansprüche 1 - 17, worin der pH-Wert der Zusam- mensetzung 2,0 bis 8,0 ist. 31. Pharmazeutische Zusammensetzung nach An- spruch 27 oder 30, worin das Tiotropiumbromid in

14 27 EP 1 381 346 B1 28

einer Konzentration von 5 mg/ml bis 5 mg/ml vorliegt. 40. Verwendung nach Anspruch 38, worin das Medika- ment weiterhin eines oder mehrere umfasst aus: (a) 32. Pharmazeutische Zusammensetzung nach einem ß2-Adrenorezeptoragonist; (b) ein Dopamin der Ansprüche 1 - 31, welche vernebelt wurde. (D2)-Rezeptoragonist; (c) ein IL-5-Inhibitor; (d) ein 5 Anti-sense-Modulator von IL-5; (e) ein Tryptase-In- 33. Kit, umfassend: hibitor; (f) ein Tachykinin-Rezeptorantagonist; (g) Milrinon oder Milrinon-Lactat; (h) ein Leukotrien-Re- (a) die pharmazeutische Zusammensetzung zeptorantagonist; (i) ein 5-Lipoxygenaseinhibitor; nach einem der Ansprüche 1 bis 31, formuliert oder (j) ein anti-IgE-Antikörper; gleichzeitig verab- für Einzeldosisverabreichung; und 10 reicht mit oder vor der pharmazeutischen Zusam- (b) einen Vernebler. mensetzung oder nachfolgend auf die pharmazeu- tische Zusammensetzung. 34. Kit, umfassend:

(a) eine Zusammensetzung nach einem der An- 15 Revendications sprüche 1 - 31; und (b) einen Vernebler. 1. Composition pharmaceutique, comprenant du for- motérol sousforme de base libre à une concentration 35. Kombination, umfassend: de 5 mg/ml à 50 mg/ml, ou un de ses dérivés, dans 20 un fluide pharmacologiquement acceptable, ladite (a) eine pharmazeutische Zusammensetzung composition étant stable au cours d’un stockage de nach einem der Ansprüche 1 - 31, formuliert für longue durée, le fluide comprenant de l’eau, et la eine Einzeldosisverabreichung; und composition étant apte à l’administration directe à (b) eine Ampulle. un sujet en ayant besoin. 25 36. Produktionsgegenstand, umfassend Verpackungs- 2. Composition pharmaceutique suivant la revendica- material, eine wässrige Zusammensetzung, umfas- tion 1, ladite composition ayant une durée de con- send die Zusammensetzung nach einem der An- servation estimée supérieure à un temps d’utilisation sprüche 1 - 32, formuliert für Einzeldosisverabrei- d’un mois à 25°C et supérieure ou égale à un temps chung, die geeignet ist zur Behandlung, Verhinde- 30 de stockage d’un an à 5°C. rung oder Abschwächung eines oder mehrerer Sym- ptome von Krankheiten oder Störungen, die verbun- 3. Composition pharmaceutique suivant la revendica- den sind mit unerwünschter und/oder unkontrollier- tion 1 ou 2, dans laquelle une proportion supérieure ter Bronchokonstriktion, und eine Kennzeichnung, à 80 % du formotérol initial est présente après un daie anzeigt, dass die Zusammensetzung für Be- 35 temps d’utilisation d’un mois à 25°C et un temps de handlung, Verhinderung oder Abschwächung eines stockage d’un an à 5°C. oder mehrerer Symptome von Krankheiten oder Stö- rungen, die verbunden sind mit unerwünschter und 4. Composition pharmaceutique suivant l’une quelcon- oder unkontrollierter Bronchokonstriktion, verwen- que des revendications 1 à 3, dans laquelle le fluide det wird. 40 pharmacologiquement convenable comprend un solvant polaire. 37. Pharmazeutische Zusammensetzung nach einem der Ansprüche 1 - 31 bei Verwendung zur Behand- 5. Composition pharmaceutique suivant la revendica- lung, Verhinderung oder Abschwächung eines oder tion 4, dans laquelle le solvant polaire est un solvant mehrerer Symptome bronchokonstriktiver Störun- 45 protique. gen. 6. Composition pharmaceutique suivant l’une quelcon- 38. Verwendung der pharmazeutischen Zusammenset- que des revendications 1 à 5, comprenant en outre zung nach einem der Ansprüche 1 - 31 zur Herstel- un agent d’ajustement de tonicité. lung eines Medikaments zur Behandlung, Verhinde- 50 rung oder Abschwächung eines oder mehrerer Sym- 7. Composition pharmaceutique suivant la revendica- ptome bronchokonstriktiver Störungen. tion 6, dans laquelle l’agent d’ajustement de tonicité est le carbonate d’ammonium, le chlorure d’ammo- 39. Pharmazeutische Zusammensetzung nach einem nium, le lactate d’ammonium, le nitrate d’ammo- der Ansprüche 1 - 31 zur Verwendung bei der Be- 55 nium, le phosphate d’ammonium, le sulfate d’ammo- handlung, Verhinderung oder Abschwächung eines nium, l’acide ascorbique, le tartrate sodique de bis- oder mehrerer Symptome bronchokonstriktiver Stö- muth, le chlorure de calcium, l’édétate disodique de rungen. calcium, le gluconate de calcium, le lactate de cal-

15 29 EP 1 381 346 B1 30

cium, l’acide citrique, le dextrose, la diéthanolamine, lamino)-2-hydroxy-propane-sulfonique), au le diméthylsulfoxyde, l’édétate disodique, l’édétate HEPPSO (acide N-(2-hydroxyéthyl)-pipérazine- trisodique monohydraté, la fluorescéine sodique, le N’-(2-hydroxypropane-sulfonique), au POPSO (aci- fructose, le galactose, le glycérol, l’acide lactique, le de pipérazine-N,N’-bis-(2-hydroxypropanesulfoni- lactose, le chlorure de magnésium, le sulfate de ma- 5 que)), au EPPS (acide N-(2-hydroxyéthyl)pipérazi- gnésium,le mannitol,le polyéthylèneglycol, l’acétate ne-N’-(3-propane-sulfonique)), à la TRICINE (N- de potassium, le chlorate de potassium, le chlorure tris-(hydroxyméthyl)-méthyl-glycine), à GLY-GLY de potassium, l’iodure de potassium, le nitrate de (glycylglycine), à la BICINE (N,N-bis-(2-hydroxy- potassium, le phosphate de potassium, le sulfate de éthyl)-glycine), au HEPBS (acide N-(2-hydroxyé- potassium, le propylèneglycol, le nitrate d’argent, 10 thyl)-pipérazine-N’-(4-butane-sulfonique)), au l’acétate de sodium, le bicarbonate de sodium, le TAPS (acide N-tris-(hydroxyméthyl)-méthyl-3-ami- biphosphate de sodium, le bisulfate de sodium, le nopropane-sulfonique) ou au AMPD (2-amino-2- bromure de sodium, la cacodylate de sodium, le car- méthyl-1,3-propanediol). bonate de sodium, le chlorure de sodium, le citrate de sodium, l’iodure de sodium, le lactate de sodium, 15 12. Composition pharmaceutique suivant la revendica- le métabisulfite de sodium, le nitrate de sodium, le tion 10 ou 11, dans laquelle le tampon est un tampon nitrite de sodium, le phosphate de sodium, le pro- au citrate. pionate de sodium, le succinate de sodium, le sulfate de sodium, le sulfite de sodium, le tartrate de sodium, 13. Composition pharmaceutique suivant l’une quelcon- le thiosulfate de sodium, le sorbitol, le saccharose, 20 que des revendications 10 à 12, dans laquelle la con- l’acide tartrique, l’urée, l’uréthane, l’uridine ou le sul- centration en tampon va de 0,01 mM à 150 mM. fate de zinc. 14. Composition pharmaceutique suivant l’une quelcon- 8. Composition pharmaceutique suivant la revendica- que des revendications 10 à 13, dans laquelle la con- tion 6 ou 7, dans laquelle l’agent d’ajustement de 25 centration en tampon va de 1 mM à 20 mM. tonicité est le chlorure de sodium. 15. Composition pharmaceutique suivant l’une quelcon- 9. Composition pharmaceutique suivant l’une quelcon- que des revendications 10 à 14, dans laquelle la con- que des revendications 1 à 3, dans laquelle le fluide centration en tampon est égale à 5 mM. pharmacologiquement convenable comprend un30 tampon. 16. Composition pharmaceutique suivant l’une quelcon- que des revendications 1 à 15, dans laquelle la force 10. Composition pharmaceutique suivant l’une quelcon- ionique de la composition va de 0 à 0,4. que des revendications 4 à 8, comprenant en outre un tampon. 35 17. Composition pharmaceutique suivant l’une quelcon- que des revendications 1 à 16, dans laquelle la force 11. Composition pharmaceutique suivant la revendica- ionique de la composition va de 0,05 à 0,16. tion 9 ou 10, dans laquelle le tampon est un tampon à l’acide citrique/phosphate, à l’acétate, au barbital, 18. Composition pharmaceutique suivant l’une quelcon- de Britton-Robinson, au cacodylate, au citrate, à la 40 que des revendications 1 à 17, dans laquelle le pH collidine, au formiate, au maléate, de Mcllvaine, au de la composition va de 2,0 à 8,0. phosphate, de Prideaux-Ward, au succinate, à l’acé- tate de véronal, au MES (acide 2-(N-morpholino)- 19. Composition pharmaceutique suivant l’une quelcon- éthane-sulfonique), au ADA (acide N-(2-acétami- que des revendications 1 à 18, dans laquelle le pH do)-2-iminodiacétique), au ACES (acide (N-(carba- 45 de la composition va de 4,0 à 6,0. moylméthyl)-2-amino-éthane-sulfonique), au PI- PES (acide pipérazine-N,N’-bis-(2-éthane-sulfoni- 20. Composition pharmaceutique suivant l’une quelcon- que), au MOPSO (acide (3-(N-morpholino)-2-hy- que des revendications 1 à 19, dans laquelle le pH droxypropane-sulfonique), au BES (acide N,N- de la composition va de 4,5 à 5,5. bis-(2-hydroxyéthyl)-2-amino-éthane-sulfonique), 50 au MOPS (acide 3-(N-morpholino)-propane-sulfoni- 21. Composition pharmaceutique suivant l’une quelcon- que), au TES (acide N-tris-(hydroxyméthyl)-méthyl- que des revendications 1 à 20, dans laquelle le pH 1-2-aminoéthane-sulfonique), au HEPES (acide de la composition est égal à 5,0. N-(2-hydroxyéthyl)-pipérazine-N’-(2-éthane-sulfo- nique), au DIPSO (acide 3-(N,N-bis-(2-hydroxyé- 55 22. Composition pharmaceutique suivant l’une quelcon- thyl)-amino)-2-hydroxy-propane-sulfonique), au que des revendications 1 à 21, comprenant en outre MOBS (acide 4-(N-morpholino)-butane-sulfonique), un ou plusieurs des agents (a) à (j) suivants : (a) un au TAPSO (acide 3-(N-tris-(hydroxyméthyl)-méthy- agoniste des adrénorécepteurs β2 ; (b) un agoniste

16 31 EP 1 381 346 B1 32

des récepteurs de dopamine (D2) ; (c) un inhibiteur (b) un nébuliseur. de IL-5 ; (d) un modulateur anti-sens de IL-5 ; (e) un inhibiteur de tryptase ; (f) un antagoniste des récep- 34. Kit, comprenant : teurs de tachykinine ; (g) la milrinone ou le lactate de milrinone ; (h) un antagoniste des récepteurs de 5 (a) une composition de l’une quelconque des leucotriènes ; (i) un inhibiteur de 5-lipoxygénase ; ou revendications 1 à 31 ; et (j) un anticorps anti-IgE. (b) un nébuliseur.

23. Composition pharmaceutique suivant la revendica- 35. Association comprenant : tion 10 ou 11, dans laquelle le tampon comprend un 10 tampon à l’acide citrique/phosphate, un tampon à (a) la composition pharmaceutique de l’une l’acétate, un tampon au citrate ou un tampon au quelconque des revendications 1 à 31, formulée phosphate. pour l’administration d’une dose unique ; et (b) un flacon. 24. composition pharmaceutique suivant l’une quelcon- 15 que des revendications 10 à 13, dans laquelle la con- 36. Article manufacturé, comprenant un matériau d’em- centration en tampon va de 1 mM à 50 mM. ballage, une composition aqueuse comprenant la composition del’une quelconquedes revendications 25. Composition pharmaceutique suivant la revendica- 1 à 32 formulée pour l’administration d’une dose uni- tion 24, dans laquelle la concentration en tampon 20 que, qui est utile pour le traitement, la prévention ou est égale à 20 mM. l’amélioration d’un ou plusieurs symptômes de ma- ladies ou de troubles associés à une bronchocons- 26. Composition pharmaceutique suivant l’une quelcon- triction indésirable et/ou incontrôlée, et une étiquette que des revendications 1 à 25, comprenant en outre qui indique que la composition est utilisée pour le un agent anti-cholinergique. 25 traitement, la prévention ou l’amélioration d’un ou plusieurs symptômes de maladies ou de troubles as- 27. Composition pharmaceutique suivant la revendica- sociés à une bronchoconstriction indésirable et/ou tion 26, dans laquelle l’agent anti-cholinergique est incontrôlée. le bromure d’ipratropium, le bromure d’oxitropium, le méthylnitrate d’atropine, le bromure de tiotropium 30 37. Composition pharmaceutique de l’une quelconque ou le bromure de glycopyrronium. des revendications 1 à 31, lorsqu’elle est utilisée pour le traitement, la prévention ou l’amélioration 28. Composition pharmaceutique suivant la revendica- d’un ou plusieurs symptômes de troubles broncho- tion 26 ou 27, dans laquelle l’agent anti-cholinergi- constrictifs. que est le bromure d’ipratropium. 35 38. Utilisation de la composition pharmaceutique de 29. Composition pharmaceutique suivant la revendica- l’une quelconque des revendications 1 à 31 pour la tion 27 ou 28, dans laquelle le bromure d’ipratropium préparation d’un médicament pour le traitement, la est présent à une concentration de m 5g/ml à 5 prévention ou l’amélioration d’un ou plusieurs symp- mg/ml. 40 tômes de troubles bronchoconstrictifs.

30. Composition pharmaceutique suivant la revendica- 39. Composition pharmaceutique de l’une quelconque tion 26 ou 27, dans laquelle l’agent anti-cholinergi- des revendications 1 à 31, pour l’utilisation dans le que est le bromure de tiotropium. traitement, la prévention ou l’amélioration d’un ou 45 plusieurs symptômes de troubles bronchoconstric- 31. Composition pharmaceutique suivant la revendica- tifs. tion 27 ou 30, dans laquelle le bromure de tiotropium est présent à une concentration de m 5g/ml à 5 40. Utilisation suivant la revendication 38, dans laquelle mg/ml. ledit médicament comprend en outre : (a) un agoniste 50 des adrénorécepteurs β2 ; (b) un agoniste des récep- 32. Composition pharmaceutique suivant l’une quelcon- teurs de dopamine D 2 ; (c) un inhibiteur de IL-5 ; (d) un que des revendications 1 à 31, qui a été nébulisée. modulateur anti-sens du IL-5 ; (e) un inhibiteur de tryptase ; (f) un agoniste des récepteurs de 33. Kit comprenant : tachykinine ; (g) la milrinone ou le lactase de milrinone ; 55 (h) un antagoniste des récepteurs de leucotriènes ; (i) (a) la composition pharmaceutique de l’une un inhibiteur de 5-lypoxygénase ; ou (j) un anticorps quelconque des revendications 1 à 31 formulée anti-IgE ; administrés simultanément avec, avant ou pour l’administration d’une dose unique ; et après ladite composition pharmaceutique.

17 EP 1 381 346 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

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