(19) &   

(11) EP 2 484 382 A1

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) Int Cl.: 08.08.2012 Bulletin 2012/32 A61K 45/06 (2006.01) A61K 45/00 (2006.01) A61P 11/00 (2006.01) A61K 9/00 (2006.01) (2006.01) (2006.01) (21) Application number: 12154081.9 C07D 413/14 A61K 31/4709 A61K 9/12 (2006.01) (22) Date of filing: 30.03.2006

(84) Designated Contracting States: (72) Inventors: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • Sequeira, Joel, A. HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI Ocean, NJ New Jersey 07712 (US) SK TR • Yang, Tsong-Toh Designated Extension States: Warren, NJ New Jersey 07059 (US) AL BA HR MK YU (74) Representative: Simpson, Tobias Rutger et al (30) Priority: 30.03.2005 US 666420 P Mathys & Squire LLP 08.11.2005 US 734452 P 120 Holborn 29.03.2006 US 786960 P London EC1N 2SQ (GB)

(62) Document number(s) of the earlier application(s) in Remarks: accordance with Art. 76 EPC: •This application was filed on 06-02-2012 as a 06740200.8 / 1 879 620 divisional application to the application mentioned under INID code 62. (71) Applicant: Schering Corporation •Claims filed after the date of receipt of the divisional Kenilworth, NJ 07033 (US) application (Rule 68(4) EPC).

(54) Medicament comprising a phosphodiesterase IV inhibitor in an inhalable form

(57) Disclosed are inhalablemedicaments and meth- acting beta agonist, for simultaneous or sequential ad- ods based on an in combination with a ministration in the prevention or treatment of a respira- corticosteroid, and a long acting beta agonist, for simul- tory, inflammatory or obstructive airway disease. Also taneous or sequential administration in the prevention or disclosed are inhalable medicaments and methods com- treatment of a respiratory, inflammatory or obstructive prising a phosphodiesterase IV inhibitor for administra- airway disease. In addition, disclosed are inhalable med- tion in the prevention or treatment of a respiratory, in- icaments and methods based on combinations of an an- flammatory or obstructive airway disease. ticholinergic and a corticosteroid; an anticholinergic and a long acting beta agonist; or a corticosteroid and a long EP 2 484 382 A1

Printed by Jouve, 75001 PARIS (FR) 1 EP 2 484 382 A1 2

Description (A) or (B) or (C), or each of (A) and (B) and (C), has an average particle diameter up to 10 microns. FIELD OF THE INVENTION [0006] There is also disclosed a medicament compris- ing, separately or together, (A) an anticholinergic, (B) a [0001] The present invention relates to novel inhalable 5 corticosteroid, and (C) a long acting beta agonist, for si- medicaments and methods based on an anticholinergic multaneous or sequential administration in the preven- in combination with a corticosteroid, and a long acting tion or treatment of a respiratory, inflammatory or ob- beta agonist, for simultaneous or sequential administra- structive airway disease, each of (A), (B), and (C) being tion in the prevention or treatment of a respiratory, in- in inhalable form, wherein the anticholinergic is (R)- 3-[2- flammatory or obstructive airway disease. In addition, the 10 hydroxy-2,2-(dithien-2-yl)acetoxy]-1-1 [2-(phenyl)ethyl]- present invention relates to novel inhalable medicaments 1-azoniabicyclo[2.2.2] octane or a pharmaceutically ac- and methods based on combinations of an anticholiner- ceptable salt or hydrate thereof, wherein the corticoster- gic and a corticosteroid; an anticholinergic and a long oid is Furoate or a pharmaceutically ac- acting beta agonist; or a corticosteroid and a long acting ceptable salt or hydrate thereof, and wherein the long beta agonist, for simultaneous or sequential administra- 15 acting beta agonist is Carmoterol, or a phar- tion in the prevention or treatment of a respiratory, in- maceutically acceptable salt or hydrate of any of the flammatory or obstructive airway disease. The present above, or a combination of two or more of the above. invention also relates to novel inhalable medicaments [0007] Likewise, there is disclosed a medicament com- and methods comprising a phosphodiesterase IV inhib- prising, separately or together, (A) an anticholinergic, (B) itor for administration in the prevention or treatment of a 20 a corticosteroid, and (C) a long acting beta agonist, for respiratory, inflammatory or obstructive airway disease.. simultaneous or sequential administration in the preven- tion or treatment of a respiratory, inflammatory or ob- SUMMARY OF THE INVENTION structive airway disease, each of (A), (B), and (C) being in inhalable form, wherein the anticholinergic is Glycop- [0002] Accordingly, there is disclosed a medicament 25 yrrolate or a pharmaceutically acceptable salt or hydrate comprising, separately or together, (A) an anticholiner- thereof, wherein the corticosteroid is Mometasone Furo- gic, (B) a corticosteroid, and (C) a long acting beta ago- ate or a pharmaceutically acceptable salt or hydrate nist, for simultaneous or sequential administration in the thereof, and wherein the long acting beta agonist is Car- prevention or treatment of a respiratory, inflammatory or moterol, Indacaterol or a pharmaceutically acceptable obstructive airway disease,each of (A), (B), and(C) being 30 salt or hydrate of any of the above, or a combination of in an inhalable form. two or more of the above. [0003] In one embodiment, the medicament is a phar- [0008] In one embodiment, the anticholinergic is (R)- maceutical composition comprising an inhalable mixture 3-[2-hydroxy-2,2-(dithien-2-yl)acetoxy]-1-1 [2-(phenyl) of effective amounts of (A) and (B) and (C), optionally ethyl]-1-azoniabicyclo[2.2.2] octane, Glycopyrrolate, together with a pharmaceutically acceptable carrier.35 , , Atropine Me- Preferably, the medicament is an aerosol comprising a thyl Nitrate, Atropine Sulfate, Ipratropium, Belladonna mixture of (A) and (B) and (C) in solution or dispersion Extract, Scopolamine, Scopolamine Methobromide, in a propellant, or a combination of an aerosol containing Methscopolamine, Homatropine Methobromide, Hyo- (A) in solution or dispersion in a propellant with an aerosol scyamine, Isopriopramide, Orphenadrine, Benzalko- containing (B) in solution or dispersion in a propellant 40 nium Chloride, , GSK202405, or a with an aerosol containing (C) in solution or dispersion pharmaceutically acceptable salt or hydrate of any of the in a propellant. More preferably, (A) or (B) or (C), or (A) above, or a combination of two or more of the above. In and (B) and (C), are in dispersion in the propellant, which one preferred embodiment, the anticholinergic is (R)- is a halogen-substituted hydrocarbon. More preferably, 3-[2-hydroxy-2,2-(dithien-2-yl)acetoxy]-1-1 [2-(phenyl) (A) or (B) or (C), or each of (A) and (B) and (C), has an 45 ethyl]-1-azoniabicyclo[2.2.2] octane or a pharmaceuti- average particle diameter of up to 10 microns. cally acceptable salt or hydrate thereof. In another pre- [0004] In another embodiment, the medicament is a ferred embodiment, the anticholinergic is Glycopyrrolate nebulizable composition comprising a dispersion of (A) or a pharmaceutically acceptable salt or hydrate thereof. and (B) and (C) in an aqueous, organic or aqueous/or- [0009] In one embodiment, the corticosteroid is ganic medium or a combination of a dispersion of (A) in 50 Mometasone Furoate; Beclomethasone Dipropionate; said medium with a dispersion of (B) in said medium with ; ; Dexamethasone; ; a dispersion of (C) in said medium. ; (22R)-6.alpha.,9.alpha.-difluoro-11.be- [0005] In one embodiment, the medicament is a dry ta.,21-dihydroxy-16.alpha.,17.alpha. -propylmethylene- powder comprising finely divided (A) or (B) or (C), or finely dioxy-4-pregnen-3,20-dione, Tipredane, GSK685698, divided (A) and (B) and (C), optionally together with a 55 GSK799943 or a pharmaceutically acceptable salt or hy- pharmaceutically acceptable carrier in finely divided drate of any of the above, or a combination of two or more form. Preferably, the carrier is present and is a saccha- of the above. ride. More preferably, the carrier is lactose. Preferably, [0010] In one preferred embodiment, the anticholiner-

2 3 EP 2 484 382 A1 4 gic is (R)-3-[2-hydroxy-2,2-(dithien-2-yl)acetoxy]-1-1 thereof, wherein the long acting beta agonist is Carmot- [2-(phenyl)ethyl]-1-azoniabicyclo[2.2.2] octane or a erol, Indacaterol or a pharmaceutically acceptable salt pharmaceutically acceptable salt or hydrate thereof and or hydrate of any of the above, or a combination of two the corticosteroid is Mometasone Furoate or a pharma- or more of the above, and wherein the phosphodieste- ceutically acceptable salt or hydrate thereof. In another 5 rase IV inhibitor is a xinafoate salt of 1-[[5-(1(S)-aminoe- preferred embodiment, the anticholinergic is Glycopyr- thyl)- 2-[8- methoxy- 2-(trifluoromethyl)- 5- quinolinyl]- 4- rolate or a pharmaceutically acceptable salt or hydrate oxazolyl] carbonyl]- 4 (R)-[(cyclopropylcarbonyl) ami- thereof and the corticosteroid is Mometasone Furoate or no]-L-proline, ethyl ester. a pharmaceutically acceptable salt or hydrate thereof. [0016] In another embodiment, the anticholinergic is [0011] In one embodiment, the long actingbeta agonist 10 (R)-3-[2-hydroxy-2,2-(dithien-2-yl)acetoxy]-1-1 [2-(phe- is Carmoterol, Indacaterol, TA- 2005, Albuterol, Terbuta- nyl)ethyl]-1-azoniabicyclo[2.2.2] octane or a pharmaceu- line, , , , , Met- tically acceptable salt or hydrate thereof, wherein the cor- aprotenerol, GSK159802, GSK642444, GSK159797, ticosteroid is Mometasone Furoate or a pharmaceutically GSK597901, GSK678077, or a pharmaceutically accept- acceptable salt or hydrate thereof, wherein the long act- able salt or hydrate of any of the above, or a combination 15 ing beta agonist is Carmoterol, Indacaterol or a pharma- of two or more of the above. In one preferred embodi- ceutically acceptable salt or hydrate of any of the above, ment, the long acting beta agonist is Carmoterol or a or a combination of two or more of the above, and wherein pharmaceutically acceptable salt or hydrate thereof. In the phosphodiesterase IV inhibitor is a xinafoate salt of another preferred embodiment, the long acting beta ag- 1-[[5-(1 (S)-aminoethyl)-2-[8-methoxy-2-(trifluorome- onist is Indacaterol or a pharmaceutically acceptable salt 20 thyl)-5-quinolinyl]-4-oxazolyl]carbonyl]-4(R)-[(cyclopro- or hydrate thereof. pylcarbonyl)amino]-L-proline, ethyl ester. [0012] In one preferred embodiment, the long acting [0017] In one embodiment, the medicament compris- beta agonist is Carmoterol or a pharmaceutically accept- ing (A), (B), (C), and (D) as defined above, is in admixture able salt or hydrate thereof and the corticosteroid is with a polyanionic beta- cyclodextrin derivative with about Mometasone Furoate or a pharmaceutically acceptable 25 one to about seven sodium sulfonate groups separated salt or hydrate thereof. In another preferred embodiment, from the lipophilic cavity of the polyanionic beta-cyclo- the long acting beta agonist is Indacaterol or a pharma- dextrin derivative by at least one butyl ether spacer group. ceutically acceptable salt or hydrate thereof and the cor- [0018] There is also disclosed a medicament compris- ticosteroid is Mometasone Furoate or a pharmaceutically ing phosphodiesterase IV inhibitor in an inhalable form. acceptable salt or hydrate thereof. 30 In one preferred embodiment, the phosphodiesterase IV [0013] In one embodiment, the medicament compris- inhibitor is Cilomilast, , Tetomilast, 1-[[5-(1 ing (A), (B), and (C) as defined above, is in admixture (S)-aminoethyl)-2-[8-methoxy-2-(trifluoromethyl)-5-qui- with a polyanionic beta- cyclodextrin derivative with about nolinyl]- 4- oxazolyl] carbonyl]- 4 (R)-[(cyclopropylcarbo- one to about seven sodium sulfonate groups separated nyl)amino]-L-proline, ethyl ester or a pharmaceutically from the lipophilic cavity of the polyanionic beta-cyclo- 35 acceptable salt or hydrate of any of the above, or a com- dextrinderivative by at least one butyl ether spacer group. binationof two or moreof the above. Preferably, the phos- [0014] In another embodiment, the medicament fur- phodiesterase IV inhibitor is 1-[[5-(1 (S)-aminoethyl)- ther comprises, (D) a phosphodiesterase IV inhibitor, 2-[8- methoxy- 2-(trifluoromethyl)- 5- quinolinyl]- 4- oxa- wherein (D) is in an inhalable form. In one preferred em- zolyl] carbonyl]- 4 (R)-[(cyclopropylcarbonyl) amino]-L- bodiment, the phosphodiesterase IV inhibitor is Cilomi- 40 proline, ethyl ester or a pharmaceutically acceptable salt last, Roflumilast, Tetomilast, 1-[[5-(1 (S)-aminoethyl)- or hydrate thereof. More preferably, the phosphodieste- 2-[8- methoxy- 2-(trifluoromethyl)- 5- quinolinyl]- 4- oxa- rase IV inhibitor is a xinafoate salt of 1-[[5-(1 (S)-aminoe- zolyl] carbonyl]- 4 (R)-[(cyclopropylcarbonyl) amino]-L- thyl)- 2-[8- methoxy- 2-(trifluoromethyl)- 5- quinolinyl]- 4- proline, ethyl ester or a pharmaceutically acceptable salt oxazolyl] carbonyl]- 4 (R)-[(cyclopropylcarbonyl) ami- or hydrate of any of the above, or a combination of two 45 no]-L-proline, ethyl ester. or more of the above. Preferably, the phosphodiesterase [0019] In one embodiment, the medicament compris- IV inhibitor is 1-[[5-(1(S)-aminoethyl)-2-[8-methoxy- ing phosphodiesterase IV inhibitor in an inhalable form 2-(trifluoromethyl)- 5- quinolinyl]- 4- oxazolyl] carbonyl]- 4 further comprises separately or together, one or more of (R)-[(cyclopropylcarbonyl)amino]-L-proline, ethyl ester the following: (A) an anticholinergic in an inhalable form, or a pharmaceutically acceptable salt or hydrate thereof. 50 (B) a corticosteroid in an inhalable form, (C) a long acting More preferably, the phosphodiesterase IV inhibitor is a beta agonist in an inhalable form, for simultaneous or xinafoate salt of 1-[[5-(1 (S)-aminoethyl)-2-[8-methoxy- sequential administration in the prevention or treatment 2-(trifluoromethyl)- 5- quinolinyl]- 4- oxazolyl] carbonyl]- 4 of a respiratory, inflammatory or obstructive airway dis- (R)-[(cyclopropylcarbonyl)amino]-L-proline, ethyl ester. ease. [0015] In one embodiment, the anticholinergic is Gly- 55 [0020] There is also disclosed a pharmaceutical kit copyrrolate or a pharmaceutically acceptable salt or hy- comprising (A), (B), and (C) as defined above, in separate drate thereof, wherein the corticosteroid is Mometasone unit dosage forms, said forms being suitable for admin- Furoate or a pharmaceutically acceptable salt or hydrate istration of (A) and (B) and (C) in effective amounts, to-

3 5 EP 2 484 382 A1 6 gether with one or more inhalation devices for adminis- [0026] The pharmaceutical compositions and medica- tration of (A) and (B) and (C), and instructions for admin- ments may be administered prophylactically as a pre- istering (A) and (B) and (C). ventative or during the course of a medical condition as [0021] There is also disclosed a pharmaceutical kit a treatment or cure. comprising (A), (B), (C) and (D) as defined above, in sep- 5 arate unit dosage forms, said forms being suitable for DETAILED DESCRIPTION OF THE INVENTION administration of (A) and (B) and (C) and (D) in effective amounts, together with one or more inhalation devices [0027] Most preferably, in accordance with the present for administration of (A) and (B) and (C) and (D), and invention, the medicament is or contains a material ca- instructions for administering (A) and (B) and (C) and (D). 10 pable of being administered in an inhalable dry powder [0022] In addition, there is disclosed a medicament form to the respiratory system, including the lungs. For comprising, separately or together, (A) an anticholinergic example, a medicament in accordance with the present and (B) a corticosteroid, for simultaneous or sequential invention could be administered so that it is absorbed administration in the prevention or treatment of a respi- into the blood stream through the lungs. More preferably, ratory, inflammatory or obstructive airway disease, each 15 however, the medicament is a powdered drug in dry pow- of (A) and (B) being in an inhalable form. In one embod- der form which is effective to treat some condition of the iment, the anticholinergic is (R)-3-[2-hydroxy-2,2-(dith- lungs or respiratory system directly and/or topically. ien-2-yl)acetoxy]-1-1 [2-(phenyl)ethyl]-1-azoniabicyclo [0028] Particularly preferred corticosteroids in accord- [2.2.2] octane, Glycopyrrolate or a pharmaceutically ac- ance with the present invention include, without limita- ceptable salt or hydrate of any of the above, or a combi- 20 tion, Mometasone Furoate; Beclomethasone Dipropion- nation of two or more of the above, and the corticosteroid ate; Budesonide; Fluticasone; Dexamethasone; Flu- is Mometasone Furoate or a pharmaceutically accepta- nisolide; Triamcinolone; (22R)-6.alpha.,9.alpha.-dif- ble salt or hydrate thereof. luoro-11.beta.,21-dihydroxy-16.alpha.,17.alpha.- pro- [0023] In addition, there is disclosed a medicament pylmethylenedioxy-4-pregnen-3,20-dione, Tipredane, comprising, separately or together, (A) an anticholinergic 25 GSK685698, GSK799943, or a pharmaceutically accept- and (C) a long acting beta agonist, for simultaneous or able salt or hydrate of any of the above, or a combination sequential administration in the prevention or treatment of two or more of the above. of a respiratory, inflammatory or obstructive airway dis- [0029] The corticosteroid preferably for use in the ease, each of (A) and (C) being in an inhalable form. In present invention is preferably Mometasone Furoate, the one embodiment, the anticholinergic is (R)- 3-[2-hydroxy- 30 active agent of Nasonex® and Asmanex®. These prod- 2,2-(dithien-2-yl)acetoxy]-1-1 [2-(phenyl)ethyl]-1-azoni- ucts are available from Schering-Plough Corporation, abicyclo[2.2.2] octane or a pharmaceutically acceptable Kenilworth, New Jersey. It is an anti-inflammatory corti- salt or hydrate thereof, and the long acting beta agonist costeroid having the chemical name, 9, 21-Dichloro-11 is Carmoterol, Indacaterol or a pharmaceutically accept- (beta), 17-dihydroxy-16(alpha)-methylpregna-1,4-di- able salt or hydrate of any of the above, or a combination 35 ene-3,20-dione 17-(2 Furoate). This active agent may be of two or more of the above. In another embodiment, the present in an amount of about 25 to about 1000 Pg per anticholinergic is Glycopyrrolate or a pharmaceutically actuation of an MDI or DPI. Doses of 25 Pg, 50 Pg, 75 acceptable salt or hydrate thereof, and the long acting Pg, 100 Pg, 125 Pg, 150 Pg, 175 Pg, 200 Pg, 250 Pg, beta agonist is Carmoterol, Indacaterol or a pharmaceu- 300 Pg, 400 Pg and/or 500 Pg are preferred. tically acceptable salt or hydrate of any of the above, or 40 [0030] Other inhalable corticosteroids for use in the a combination of two or more of the above. present invention include GSK685698 (also known as [0024] In addition, there is disclosed a medicament GW686698X, and under the trademark Avamys® or comprising, separately or together, (B) a corticosteroid Allernmist®) and GSK799943 available from Glaxo- and (C) a long acting beta agonist, for simultaneous or SmithKline. sequential administration in the prevention or treatment 45 [0031] A preferred anticholinergic is known as LAS of a respiratory, inflammatory or obstructive airway dis- 34273 (chemically identified as 3-[2-hydroxy- (R)- ease, each of (B) and (C) being in an inhalable form. In 2,2-(dithien-2-yl)acetoxy]-1-1 [2-(phenyl)ethyl]-1-azoni- one embodiment, the corticosteroid is Mometasone abicyclo[2.2.2]octane) available from Almirall Prodesfar- Furoate or a pharmaceutically acceptable salt or hydrate ma SA. It may be prepared in accordance with the pro- thereof, and the long acting beta agonist is Carmoterol, 50 cedures set forth in WO 01/04118 and U.S. Patent No. Indacaterol or a pharmaceutically acceptable salt or hy- 6,750,226, both of which are incorporated by reference. drate of any of the above, or a combination of two or more It is a new long acting anticholinergic with once a day of the above. efficacy. This active agent may be present in an amount [0025] In one embodiment, the medicament is a phar- of about 10 to about 1000 Pg per day, preferably in an maceutical composition comprising an inhalable mixture 55 amount of about 100 to about 500 Pg per day. of effective amounts of (A) and (B); (A) and (C); or (B) [0032] Glycopyrrolate, also known as glycopyrronium and C), optionally together with a pharmaceutically ac- bromide is an anticholinergic drug that decreases trache- ceptable carrier. obronchial and pharyngeal secretions. It does not easily

4 7 EP 2 484 382 A1 8 cross the blood-brain barrier, like atropine and scopo- for use in the present invention is Met- lamine, and thus it has less CNS side effects. This active aproterenol, which is the subject of U.S. Pat. No. agent may be present in an amount of about 25P g to 3,341,594 and is commercially available under the trade about 1000 Pg per actuation of an MDI or DPI. names of Alotec, Alupent, Metaprel or Novasmasol. 5 [0033] The long acting beta agonist can be one of a [0040] Another long acting selective beta 2 - number of different pharmaceutically active agents. By bronchodilator for use in the present invention is Terbu- long acting it is meant that the drug will have an effect taline, which is described in U.S. Pat. No. 3,938,838 and on the bronchi that lasts around 6 hours or more, up to is available commercially as Brethine from Novartis. The about 12 hours in some instances and up to about 24 preparation of fenoterol is described in U.S. Pat. No. hours in other instances. This active agent may be10 4,341,593. It is sold under several trade names, including present in an amount of about 10 to about 1000 Pg per Airum, Berotec, Dosberotec and Partusisten. Albuterol day. (also known as ) is sold under the trademark [0034] Long acting beta agonists for use in the present Proventil® by Schering Corporation. Salmeterol is sold invention include without limitation, Carmoterol, Indacter- under the trademark Serevent®, available from Glaxo- ol, TA-2005, Albuterol, , Salmeterol, Bitolter- 15 SmithKline. ol, Formoterol, Fenoterol, Metaprotenerol, GSK159802, [0041] Other active agents for use in another embod- GSK642444, GSK159797, GSK597901, GSK678077, or iment of the present invention include phosphodieste- any one of those described in the following patents which rase IV inhibitors. One such active agent is SB 207499 are incorporated by reference in their entirety: 6,949,568, (c-4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-r-L- 6,919,482, 6,916,961, 6,713,651, 6,683,115, 6,670,376, 20 cyclohexane carboxylic acid), available under the trade- 6,653,323, 6,593,497, 6,576,793 and 6,541,669, all of name Ariflo®. Ariflo, also known a Cilomilast, is an oral which are assigned to Theravance Inc., of California, or selective phosphodiesterase (PDE) IV inhibitor under de- a pharmaceutically acceptable salt or hydrate of any of velopment by GlaxoSmithKline Pharmaceuticals for the above, or a combination of two or more of the above. treatment of COPD. [0035] Carmoterol, also known as Karmoterolis and 25 [0042] In another embodiment of the present inven- Carmoterolum, is identified chemically as hydroxy- 8- tion, the compositions of the present invention may fur- 5-[(1R)-1-hydroxy-2-(4-methoxyphenyl)-1-methylethyl] ther include the phosphodiesterase IV inhibitor Roflum- amino)+ethyl]quinolin-2(1 H)-one. It is a new long acting ilast. Roflumilast is being developed by Altana Pharma beta agonist available from Chiesi Farmaceutici, Parma, as a potential treatment of and COPD. It is await- Italy. 30 ing regulatory approval in Europe and phase III clinical [0036] Formoterol (also known as eformoterol) e.g., as trials are ongoing in the US. Like Cilomilast, this active the fumarate or tartrate, a highly selective long-lasting agent is also well tolerated, and does not appear to be Beta- having bronchospasmolytic ef- associated with the nausea and vomiting that have posed fect, is effective in the treatment of reversible obstructive a problem with older PDE-IV inhibitors. In a multicentre lung ailments of various genesis, particularly asthmatic 35 randomised study, the tolerability profile observed in 516 conditions. patients with COPD was equivalent to that seen in pla- [0037] TA-2005, another long acting beta agonist, is cebo recipients after 26 weeks of dosing. Altana said that chemically identified as 2(1H)-Quinolinone, 8-hydroxy- Roflumilast may also have a role in the treatment of pso- 5-[1- hydroxy- 2-[[2-(4-(methoxyphenyl)- 1- methylethyl] riasis and allergic rhinitis. amino]ethyl] -monohydrochloride, [R-(R*,R*)]-- also 40 [0043] In another embodiment of the present inven- identified by Chemical Abstract Service Registry Number tion, the compositions of the present invention may fur- 137888-11-0 and disclosed in U.S. Pat. No. 4,579,854, ther include Tetomilast. Tetomilast (also known as OPC- the text of which is hereby incorporated by reference. Its 6535) is a phosphodiesterase-4 inhibitor currently in chemical name is  ()-2-hydroxy-5-[(1RS)-1-hydroxy- phase II development with Otsuka in the U.S. as a treat- 2-[[(1 RS)-2-(4-methoxyphenyl)-1-methylethyl]- amino] 45 ment for COPD. Preclinical studies have demonstrated ethyl]formanilide Fumarate dihydrate. This active agent the efficacy of Tetomilast in the inhibition of airway in- may be present in an amount of about 3 to about 50 Pg flammation in COPD, and in a guinea- pig model of COPD per actuation of the MDI or DPI. It is available under the induced by cigarette smoke exposure, Tetomilast result- trade name of Foradil®. ed in improvements in specific airway resistance and 50 [0038] Another long acting selective beta 2 -adrenergic neutrophilia (O’Mahoney, IDrugs, 8(6):502-507 (2005). bronchodilator for use in the present invention is Inda- [0044] According to one embodiment, all the active caterol (also known as QAB149), reportedly useful for agents of the medicaments would be administered at the the treatment of asthma and chronic obstructive pulmo- same time, or very close in time. Alternatively, one active nary disorder which is being developed by Novartis Cor- agent could be taken in the morning and one later in the poration, East Hanover, New Jersey. This active agent 55 day. Or in another scenario, one active agent could be may be present in an amount of about 10P g to about taken twice daily and the other once daily, either at the 1000 Pg per day. same time as one of the twice-a-day dosing occurred, or [0039] Another long acting selective beta 2 -adrenergic separately. Preferably all of the active agents would be

5 9 EP 2 484 382 A1 10 taken together at the same time. be administered via nebulization. The suspension formu- [0045] In one embodiment of the invention, the inhal- lations of the invention may be delivered to a patient using able form of the medicament is a dry powder, i.e. (A) any of the usual nebulizer devices. Typical commercial and/or (B) and/or (C) are present in a dry powder com- nebulizer devices produce dispersions of droplets in gas prising finely divided (A) and (B) and (C) optionally to- 5 streams by one of two methods. Jet nebulizers use a gether with a finely divided pharmaceutically acceptable compressed air supply to draw up a fluid by venturi action carrier, which is preferably present and may be one or and introduce it into a flowing gas stream, after which the more materials known as pharmaceutically acceptable fluid is caused to impact one or more stationary baffles carriers, preferably chosen from materials known as car- to remove excessively large droplets. Ultrasonic nebuliz- riers in dry powder inhalation compositions, for example 10 ers use an electrically driven transducer to subject a fluid saccharides, including monosaccharides, disaccha- to high-frequency oscillations, producing a cloud of drop- rides, polysaccharides and sugar alcohols such as ara- lets which can be entrained in a moving gas stream; these binose, glucose, fructose, ribose, mannose, sucrose, tre- devices are less preferred for delivering suspensions. halose, lactose, maltose, starches, dextran or mannitol. There are hand-held nebulizers which atomize the fluid An especially preferred carrier is lactose. The dry powder 15 with a squeeze bulb air supply, but the more widely used may be in capsules of gelatin or plastic, or in blisters, for equipment incorporates an electrically powered com- use in a dry powder inhalation device, preferably in dos- pressor or connects to a cylinder of compressed gas. age units of (A) and/or (B) and/or (C) together with the Although the various devices which are commercially carrier in amounts to bring the total weight of powder per available vary considerably in their delivery efficiency for capsule to from 5 mg to 50 mg. Alternatively, the dry20 a given medicament, they all are useful for the treatment powder may be contained as a reservoir in a multi- dose of the present invention; it is necessary for the prescriber dry powder inhalation device. The amount of active agent to specify an exact amount of medicament formulation (s) in a multi-dose dry powder inhalation device would which is to be charged to each particular device, since be such that two actuations per day would deliver the their respective outputs of respirable droplets are far from requisite amount of active agent(s) per day. 25 identical. [0046] In one embodiment, the medicaments of the [0051] Suspension formulations suitable for nebuliza- present invention are prepared according to the methods tion must, of course, contain solid particles of a respirable of producing an agglomerate of drug and solid binder size (e.g., preferably averaging less than about 5. Pm in described in U.S. Patent No. 6,503,537, incorporated the largest dimension and more preferably averaging herein by reference in its entirety. 30 less than about 2 Pm, and must maintain their suspended [0047] In one embodiment, the medicaments of the particle size distribution during storage. In addition, the present invention are delivered using an inhaler as de- particle-containing droplets formed during nebulization scribed in U.S. Patent No. 6,240,918, 5,687,710, or of the formulations must have appropriate sizes for dep- 5,829,434, incorporated herein by reference in their en- osition in the desired area of the respiratory system. tirety. 35 [0052] Since the formulations of the invention are to [0048] In another embodiment, the medicaments of be inhaled, it is necessary that they be free of pathogenic the present invention are suspended in a liquefied pro- organisms. Thus, they may be prepared and handled un- pellant as described in EP Patent Publication No. 1 420 der sterile conditions, or may be sterilized before or after 759, incorporated herein by reference in its entirety. packaging. In addition, or in lieu of sterilization, a pre- [0049] In formulations of the present invention which 40 servative may be incorporated to minimize the possibility are suitable for treating lower respiratory system disor- of microbial contamination. In addition, all active agents ders such as asthma, at least a substantial portion of the of the formulations must be chosen for inhalation safety, active agent is present as suspended particles having as the treated tissues are quite sensitive to irritants; it is respirable sizes, e.g., about 0.5 to about 10 micrometers commonly known that many of the common preserva- in their largest dimension. In formulations which are suit- 45 tives have a considerable potential for causing irritation. able for treating upper respiratory system disorders such [0053] Water for use in the formulations should meet as rhinitis, somewhat larger active agent particles may or exceed the applicable regulatory requirements for use be permissible, but the foregoing size range remains pre- in inhaled drugs. Specifications established by the United ferred. Where the active agent forms a suspension, the States Pharmacopoeia for "Sterile Water for Injection" or particle size should be relatively uniform, with substan- 50 "Sterile Water for Inhalation" are examples of water suit- tially all the particles preferably ranging between about able for use to prepare formulations of the invention. 0.1-25 microns, preferably 0.5-10 microns, more prefer- [0054] Surfactants are frequently categorized by their ably 1-5 microns. Particles larger than 25 microns may chemical nature, i.e., as cationic, anionic or nonionic. be held up in the oropharyngeal cavity, while particles Cationic surfactants, such as cetyl pyridinium chloride, smaller than about 0.5 micron preferably are not utilized, 55 and anionic surfactants, such as docusate sodium, do since they would be more likely to be exhaled and, there- not appear to provide proper dispersions of particles in fore, not reach the lungs of the patient. the nebulizable formulations. [0050] In another embodiment, the medicament may [0055] Many nonionic surfactants are suitable for

6 11 EP 2 484 382 A1 12 maintaining the particulate suspensions of the invention. mulation, since the efficiency of the nebulization process These include surfactants identified as "polysorbates" in is particularly sensitive to viscosity. Many nonionic sur- the CTFA International Cosmetic Ingredient Dictionary; factants are useful for preparing inhalation and/or inject- such surfactants are mixtures of fatty acid esters (pre- able drug formulations, and any of these should be suit- dominately monoesters) of sorbitol and sorbitol anhy- 5 able for use in the present invention. drides, condensed with ethylene oxide. Although these [0061] The formulations further include a soluble salt. surfactants vary widely in their hydrophilic-lipophilic bal- This salt performs at least two functions: it minimizes the ance ("HLB") numbers, they all appear to function well effects of the inhaled formulation on the normal cell fluid in the invention. balanceof airway cells andalso stabilizesthe suspension [0056] Commercially available polysorbates which are 10 of medicament. For the first function, it is preferred to use useful in the invention include those listed in the following sufficient salt concentrations to render the formulation table, which shows the CTFA designation (Polysorbate isotonic; sodium chloride and potassium chloride are pre- number), identity of the fatty acid used to produce the ferred for this purpose. It has been found that adequate material and the number of moles of ethylene oxide re- suspension stability is produced by isotonic concentra- acted with each mole of ester. Compositions identified 15 tions (i.e., about 0.9 weight percent) of sodium chloride, with an asterisk are predominately triesters. although concentrations about 0.2 to about 2 weight per- cent are useful. Any physiologically compatible alkali Polysorbate Acid Moles EtO metal or alkaline earth metal soluble salt can be used in 20 Lauric 20 the present invention. 21 Lauric 4 20 [0062] Optionally, the formulations will contain a pH 40 Palmitic 20 buffer, to maintain the formulation pH between about 3 60 Stearic 20 and about 7. It has been found that stability of the drug (as measured by the absence of degradation reaction 61 Stearic 4 products) in suspension is improved by maintaining pH 65* Stearic 20 25 conditions below about 6. For reasons of tissue compat- 80 Oleic 20 ibility, excessively acidic products are not desired, so the 81 Oleic 5 pH should not be made to be below about 3. Some ex- 85* Oleic 20 perimentation may be needed to qualify specific buffers for use in the invention: phosphate buffers in concentra- 30 [0057] In general, Polysorbate surfactants will be tions of 1 to 50 millimolar do not appear to adequately present in a formulation at about 50 to 500 Pg /mL. When prevent caking of the particulates in the suspension when the surfactant concentration is below about 20P g/mL, there is no added soluble salt. A citrate- citric acid buffer, the particles tend to form cakes which are not easily re- maintaining pH between about 4 and about 5, has been dispersed. used with particularly good effect for both maintaining pH 35 [0058] Suitable surfactants include polyether glycols during storage and preventing any particulate caking in such as Pluronic® F-68 (Poloxamer 188 a block copoly- the absence of soluble salts. mer of ethylene glycol and propylene glycols), Pluronic® [0063] The citrate-citric acid buffer may be present in F87 (Poloxamer 237), Pluronic ® F108 (Poloxamer 338), suspension formulations at concentrations at least about Pluronic® F127 (Poloxamer 407) and the like. Preferably, 2 and up to about 50 millimolar. While the literature has 40 Pluronic® F-68 is used. According to BASF Corporation’s some reports of cough being induced by such buffer sys- Technical Bulletin (1995), Pluronic ® is a registered trade- tems, this seems to occur primarily at the 150-200 milli- name for BASF Corporation’s block copolymers of eth- molar level, although one report attributed cough to only ylene oxide and propylene oxide represented by the a 35 millimolar concentration. [0064] Sterility or adequate antimicrobial preservation chemical structure HO(C2H4O)a(C3H6O)b(C2H4O)aH 45 wherein for: (a) Pluronic® F-68, a is 80 and b is 27; (b) of the final packaged formulation is needed for patient Pluronic® F87, a is 64 and b is 37; (c) Pluronic ® F108, a protection. The use of antimicrobial preservatives is less is 141 and b is 44; and Pluronic ® F127, a is 101 and b is desirable, since certain of these have been associated 56. The average molecular weights for these block co- with adverse clinical effects, such as bronchospasm. Al- polymers are: (a) Pluronic® F-68, 8400; (b) Pluronic® ternative processes which may be considered for achiev- 50 F87, 7700; (c) Pluronic® F108, 14600; and Pluronic® ing sterility usually will not include sterilization steps for F127, 12600. the micronized drug substance or formulation, since it [0059] Poloxamer surfactants are used at concentra- has been found that the drug undergoes degradation un- tions similar to those for the Polysorbates, although cer- der the influence of gamma-ray irradiation and sterilizing tain members are useful at concentrations up to about 1 heat conditions. Sterilization by filtration ordinarily will not 55 mg/mL. be feasible, due to the suspension nature of the formu- [0060] In general, the chosen surfactant should not lation. Thus, it is preferred to produce the pharmacolog- materially increase the viscosity of the suspension for- ically active agent, such asmometasone furoate mono- hydrate under sterile conditions, conduct the drug micro-

7 13 EP 2 484 382 A1 14 nization in a sterile environment, and perform a sterile tive or limiting to the precise forms disclosed. Many mod- packaging operation. ifications and variations undoubtedly will occur to those [0065] Methods are known for reducing particle sizes having skill in the art. It is intended that the scope of the into the micrometer range, including mechanical milling, invention shall be fully defined solely by the appended application of ultrasonic energy and other techniques. 5 claims. Mechanical milling frequently generates high surface [0069] Preferred embodiments of the present inven- temperatures on the particles, and this is undesirable for tion are described below and are referred to as embod- Mometasone Furoate Monohydrate, a long acting beta iments E1 to E37. agonist and/or Glycopyrrolate which tends to lose some part of its hydration under the influence of high temper- 10 E1. A medicament comprising, separately or togeth- atures. Ultrasonic techniques are quite slow in their ac- er, (A) an anticholinergic, (B) a corticosteroid, and tion, generally requiring very long processing times, but (C) a long acting beta agonist, for simultaneous or are capable of producing acceptable suspensions. sequential administration in the prevention or treat- [0066] Suspensions of drug particles can rapidly un- ment of a respiratory, inflammatory or obstructive dergo particulate size reduction when subjected to "jet 15 airway disease, each of (A), (B), and (C) being in an milling" (high pressure particle in liquid milling) tech- inhalable form. niques. A presently preferred jet milling procedure for producing the formulations of the invention involves the E 2. The medicament of E 1 which is a pharmaceu- use of the "Microfluidizer" system sold by Microfluidics tical composition comprising an inhalable mixture of International Corporation of Newton, Mass., U.S.A. This 20 effective amounts of (A) and (B) and (C), optionally device divides a fluid stream, flowing under high pres- together with a pharmaceutically acceptable carrier. sures (up to about 40,000 pounds per square inch, or 2.76.times.108 newton/meter2), between two separate E 3. The medicament of E2, which is an aerosol com- microchannel paths and then recombines them from gen- prising a mixture of (A) and (B) and (C) in solution erally perpendicular directions to create very high shear, 25 or dispersion in a propellant, or a combination of an impact and cavitation forces. By continuously recirculat- aerosol containing (A) in solution or dispersion in a ing suspensions through the system for a predetermined propellant with an aerosol containing (B) in solution time period, it is possible to reproducibly create desired or dispersion in a propellant with an aerosol contain- distributions of micron- and submicron-sized particles. ing (C) in solution or dispersion in a propellant. Since the particles are always completely surrounded by 30 liquid, their surfaces will not develop high temperatures E4. The medicament of E 3, in which (A) or (B) or under the influence of the size reduction forces, and the (C), or (A) and (B) and (C), are in dispersion in the hydration water in the drug crystals will remain intact. propellant, which is a halogen-substituted hydrocar- Other useful equipment which utilizes related technology bon. is available from Avestin Inc., Ottawa, Ontario, Canada. 35 [0067] In another embodiment, the pharmaceutically E5. The medicament of E 4, in which (A) or (B) or active agents may be solubilized utilizing cyclodextrins. (C), or each of (A) and (B) and (C), has an average One such cyclodextrin, for instance, is sold under the particle diameter of up to 10 microns. name Captisol. More specifically, Captisol® is a sul- fobutyl ether derivative of beta-cyclodextrin with an av- 40 E 6. The medicament of E 3, which is a nebulizable erage of seven sulfobutyl ether groups per cyclodextrin composition comprising a dispersion of (A) and (B) molecule. Because of the very low pKa of the sulfonic and (C) in an aqueous, organic or aqueous/organic acid groups, Captisol® carries multiple negative charges medium or a combination of a dispersion of (A) in at physiologically compatible pH values. The four- carbon said medium with a dispersion of (B) in said medium butyl chain coupled with repulsion of the end group neg- 45 with a dispersion of (C) in said medium. ative charges allows for an extension" of the cyclodextrin cavity. This often results in an increased possibility of E7. The medicament of E2, which is a dry powder inclusion complexation of the active agents with a rela- comprising finely divided (A) or (B) or (C), or finely tively large molecular volume than has been demonstrat- divided (A) and (B) and (C), optionally together with ed with other modified cyclodextrins. In addition, these 50 a pharmaceutically acceptable carrier in finely divid- derivatives impart exceptional solubility to the molecule.. ed form. The product is available Cydex, Inc. of Overland Park, Kansas. It may be prepared in accordance with the pro- E8. The medicament of E 7, in which the carrier is cedures set forth in International Patent Application WO present and is a saccharide. 91/11172, incorporated by reference in it’s entirety. 55 [0068] The foregoing descriptions of various embodi- E 9. The medicament of E 8, in which the carrier is ments of the invention are representative of various as- lactose. pects of the invention, and are not intended to be exhaus-

8 15 EP 2 484 382 A1 16

E 10. The medicament of E9, in which (A) or (B) or able salt or hydrate thereof. (C), or each of (A) and (B) and (C), has an average particle diameter up to 10 microns. E 16. The medicament of E 1, wherein the corticos- teroid is Mometasone Furoate; Beclomethasone Di- E 11. A medicament comprising, separately or to- 5 propionate; Budesonide; Fluticasone; Dexametha- gether, (A) an anticholinergic, (B) a corticosteroid, sone; Flunisolide; Triamcinolone; (22R)-6.alpha., and (C) a long acting beta agonist, for simultaneous 9.alpha.-difluoro-11.beta.,21-dihydroxy-16.alpha., or sequential administration in the prevention or- 17.alpha. -propylmethylenedioxy-4-pregnen-3,20- treatment of a respiratory, inflammatory or obstruc- dione, Tipredane, GSK685698, GSK799943 or a tive airway disease, each of (A), (B), and (C) being 10 pharmaceutically acceptable salt or hydrate of any in inhalable form, wherein the anticholinergic is (R)- of the above, or a combination of two or more of the 3-[2-hydroxy-2,2-(dithien-2-yl)acetoxy]-1-1[2-(phe- above. nyl)ethyl]-1-azoniabicyclo[2.2.2] octane or a phar- maceutically acceptable salt or hydrate thereof, E 17. The medicament of E 14, wherein the corticos- wherein the corticosteroid is Mometasone Furoate 15 teroid is Mometasone Furoate or a pharmaceutically or a pharmaceutically acceptable salt or hydrate acceptable salt or hydrate thereof. thereof, and wherein the long acting beta agonist is Carmoterol, Indacaterol or a pharmaceutically ac- E 18. The medicament of E15, wherein the corticos- ceptable salt or hydrate of any of the above, or a teroid is Mometasone Furoate or a pharmaceutically combination of two or more of the above. 20 acceptable salt or hydrate thereof.

E 12. A medicament comprising, separately or to- E 19. The medicament of E 1, wherein the long acting gether, (A) an anticholinergic, (B) a corticosteroid, beta agonist is Carmoterol, Indacaterol, TA-2005, Al- and (C) a long acting beta agonist, for simultaneous buterol, Terbutaline, Salmeterol, Bitolterol, Formot- or sequential administration in the prevention or25 erol, Fenoterol, Metaprotenerol, GSK159802, treatment of a respiratory, inflammatory or obstruc- GSK642444, GSK159797, GSK597901, tive airway disease, each of (A), (B), and (C) being GSK678077, or a pharmaceutically acceptable salt in inhalable form, wherein the anticholinergic is Gly- or hydrate of any of the above, or a combination of copyrrolate or a pharmaceutically acceptable salt or two or more of the above. hydrate thereof, wherein the corticosteroid 30 is Mometasone Furoate or a pharmaceutically accept- E 20. The medicament of E 1, wherein the long acting able salt or hydrate thereof, and wherein the long beta agonist is Carmoterol or a pharmaceutically ac- acting beta agonist is Carmoterol, Indacaterol or a ceptable salt or hydrate thereof. pharmaceutically acceptable salt or hydrate of any of the above, or a combination of two or more of the 35 E 21. The medicament of E 1, wherein the long acting above. beta agonist is Indacaterol or a pharmaceutically ac- ceptable salt or hydrate thereof. E 13. The medicament of E 1, wherein the anticholin- ergic is (R)-3-[2-hydroxy-2,2-(dithien-2-yl)acetoxy]- E 22. The medicament of E 20, wherein the corticos- 1-1 [2-(phenyl)ethyl]-1-azoniabicyclo[2.2.2] octane, 40 teroid is Mometasone Furoate or a pharmaceutically Glycopyrrolate, Ipratropium Bromide, Oxitropium acceptable salt or hydrate thereof. Bromide, Atropine Methyl Nitrate, Atropine Sulfate, Ipratropium, Belladonna Extract, Scopolamine, Sco- E23. The medicament of E 21, wherein the corticos- polamine Methobromide, Methscopolamine, Homa- teroid is Mometasone Furoate or a pharmaceutically tropine Methobromide, Hyoscyamine, Isopriopra- 45 acceptable salt or hydrate thereof. mide, Orphenadrine, Benzalkonium Chloride, Tio- tropium Bromide, GSK202405, or a pharmaceutical- E 24. The medicament of E1, in admixture with a ly acceptable salt or hydrate of any of the above, or polyanionic beta-cyclodextrin derivative with about a combination of two or more of the above. one to about seven sodium sulfonate groups sepa- 50 rated from the lipophilic cavity of the polyanionic be- E 14. The medicament of E 1, wherein the anticholin- ta-cyclodextrin derivative by at least one butyl ether ergic is (R)-3-[2-hydroxy-2,2-(dithien-2-yl)acetoxy]- spacer group. 1-1 [2-(phenyl)ethyl]-1-azoniabicyclo[2.2.2] octane or a pharmaceutically acceptable salt or hydrate E25. The medicament of E 1, further comprising, (D) thereof. 55 a phosphodiesterase IV inhibitor, wherein (D) is in an inhalable form. E 15. The medicament of E1, wherein the anticholin- ergic is Glycopyrrolate or a pharmaceutically accept- E26. The medicament of E25, wherein the phos-

9 17 EP 2 484 382 A1 18 phodiesterase IV inhibitor is Cilomilast, Roflumilast, E 32. A medicament comprising phosphodiesterase Tetomilast, 1-[[5-(1(S)-aminoethyl)-2-[8-methoxy- IV inhibitor in an inhalable form. 2-(trifluoromethyl)-5-quinolinyl]-4-oxazolyl]carbon- yl]-4(R)-[(cyclopropylcarbonyl)amino]-L-proline, E 33. The medicament of E 32, wherein the phos- ethyl ester or a pharmaceutically acceptable salt or 5 phodiesterase IV inhibitor is Cilomilast, Roflumilast, hydrate of any of the above, or a combination of two Tetomilast, 1-[[5-(1(S)-aminoethyl)-2-[8-methoxy- or more of the above. 2-(trifluoromethyl)-5-quinolinyl]-4-oxazolyl]carbon- yl]-4(R)-[(cyclopropylcarbonyl)amino]-L-proline, E27. The medicament of E 25, wherein the phos- ethyl ester or a pharmaceutically acceptable salt or phodiesteraseIV inhibitor is 1-[[5-(1 (S)-aminoethyl)- 10 hydrate of any of the above, or a combination of two 2-[8-methoxy-2-(trifluoromethyl)-5-quinolinyl]-4-ox- or more of the above. azolyl]carbonyl]-4(R)-[(cyclopropylcarbonyl)ami- no]-L-proline, ethyl ester or a pharmaceutically ac- E 34. The medicament of E 32, wherein the phos- ceptable salt or hydrate thereof. phodiesteraseIV inhibitor is1-[[5-(1 (S)-aminoethyl)- 15 2-[8-methoxy-2-(trifluoromethyl)-5-quinolinyl]-4-ox- E 28. The medicament of E 25, wherein the phos- azolyl]carbonyl]-4(R)-[(cyclopropylcarbonyl)ami- phodiesterase IV inhibitor is a xinafoate salt of no]-L-proline, ethyl ester or a pharmaceutically ac- 1-[[5-(1 (S)-aminoethyl)-2-[8-methoxy-2-(trifluor- ceptable salt or hydrate thereof. omethyl)-5-quinolinyl]-4-oxazolyl]carbonyl]-4 (R)-[(cyclopropylcarbonyl)amino]-L-proline, ethyl20 E 35. The medicament of E32, wherein the phos- ester. phodiesterase IV inhibitor is a xinafoate salt of 1-[[5-(1(S)-aminoethyl)-2-[8-methoxy-2-(trifluor- E 29. The medicament of E 25, wherein the anti- omethyl)-5-quinolinyl]-4-oxazolyl]carbonyl]-4 cholinergic is Glycopyrrolate or a pharmaceutically (R)-[(cyclopropylcarbonyl)amino]-L-proline, ethyl acceptable salt or hydrate thereof, wherein the cor- 25 ester. ticosteroid is Mometasone Furoate or a pharmaceu- tically acceptable salt or hydrate thereof, wherein the E 36. A pharmaceutical kit comprising (A) as defined long acting beta agonist is Carmoterol, Indacaterol in E1, and (B) as defined in E1, and (C) as defined or a pharmaceutically acceptable salt or hydrate of in E 1, in separate unit dosage forms, said forms any of the above, or a combination of two or more 30 being suitable for administration of (A) and (B) and of the above, and wherein the phosphodiesterase IV (C) in effective amounts, together with one or more inhibitor is a xinafoate salt of 1-[[5-(1 (S)-aminoe- inhalation devices for administration of (A) and (B) thyl)-2-[8-methoxy-2-(trifluoromethyl)-5-quinolinyl]- and (C), and instructions for administering (A) and 4-oxazolyl]carbonyl]-4(R)-[(cyclopropylcarbonyl) (B) and (C). amino]-L-proline, ethyl ester. 35 E37. A pharmaceutical kit comprising (A) as defined E 30. The medicament of E25, wherein the anti- in E 25, and (B) as defined in E25, and (C) as defined cholinergic is (R)-3-[2-hydroxy-2,2-(dithien-2-yl)ac- in E 25, and (D) as defined in E 25, in separate unit etoxy]-1-1 [2-(phenyl)ethyl]-1-azoniabicyclo[2.2.2] dosage forms, said forms being suitable for admin- octane or a pharmaceutically acceptable salt or hy- 40 istration of (A) and (B) and (C) and (D) in effective drate thereof, wherein the corticosteroid is Mometa- amounts, together with one or more inhalation de- sone Furoate or a pharmaceutically acceptable salt vices for administration of (A) and (B) and (C) and or hydrate thereof, wherein the long acting beta ag- (D), and instructions for administering (A) and (B) onist is Carmoterol, Indacaterol or a pharmaceuti- and (C) and (D). cally acceptable salt or hydrate of any of the above, 45 or a combination of two or more of the above, and wherein the phosphodiesterase IV inhibitor is a xin- Claims afoate salt of 1-[[5-(1(S)-aminoethyl)-2-[8-methoxy- 2-(trifluoromethyl)-5-quinolinyl]-4-oxazolyl]carbon- 1. A medicament comprising a phosphodiesterase IV yl]-4(R)-[(cyclopropylcarbonyl)amino]-L-proline, 50 inhibitor in an inhalable form. ethyl ester. 2. The medicament of claim 1, wherein the phosphodi- E31. The medicament of E25, in admixture with a esterase IV inhibitor is 1-[[5-(1 (S)-aminoethyl)- 2-[8- polyanionic beta-cyclodextrin derivative with about methoxy- 2-(trifluoromethyl)- 5- quinolinyl]- 4- oxa- one to about seven sodium sulfonate groups sepa- 55 zolyl] carbonyl]- 4 (R)-[(cyclopropylcarbonyl) ami- rated from the lipophilic cavity of the polyanionic be- no]-L-proline, ethyl ester, Cilomilast, Roflumilast, ta-cyclodextrin derivative by at least one butyl ether Tetomilast, or a pharmaceutically acceptable salt or spacer group. hydrate of any of the above, or a combination of two

10 19 EP 2 484 382 A1 20

or more of the above.

3. The medicament of claim 2, wherein the phosphodi- esterase IV inhibitor is 1-[[5-(1 (S)-aminoethyl)- 2-[8- methoxy- 2-(trifluoromethyl)- 5- quinolinyl]- 4- oxa- 5 zolyl] carbonyl]- 4 (R)-[(cyclopropylcarbonyl) ami- no]-L-proline, ethyl ester or a pharmaceutically ac- ceptable salt or hydrate thereof.

4. The medicament of claim 2, wherein the phosphodi- 10 esterase IV inhibitor is a xinafoate salt of 1-[[5-(1 (S)-aminoethyl)-2-[8-methoxy-2-(trifluoromethyl)-5- quinolinyl]-4 oxazolyl]carbonyl]-4(R)-[(cyclopropyl- carbonyl)amino]-L-proline, ethyl ester. 15 5. The medicament of any one of the preceding claims further comprising, separately or together, (A) an an- ticholinergic, (B) a corticosteroid, and (C) a long act- ing beta agonist, each of (A), (B), and (C) being in an inhalable form. 20

6. The medicament of any one of the preceding claims, for use in the treatment or prevention of a respiratory, inflammatory or obstructive airway disease. 25 7. A pharmaceutical kit comprising (A) as defined in claim 5, (B) as defined in claim 5, (C) as defined in claim 5, and (D) a phosphodiesterase IV inhibitor in an inhalable form, in separate unit dosage forms, said forms being suitable for administration of (A) 30 and (B) and (C) and (D) in effective amounts, togeth- er with one or more inhalation devices for adminis- tration of (A) and (B) and (C) and (D), and instructions for administering (A) and (B) and (C) and (D). 35 8. The kit of claim 7, wherein the phosphodiesterase IV inhibitor is as defined in any one of claims 2 to 4.

9. The kit of claim 7, wherein the phosphodiesterase IV inhibitor is a xinafoate salt of 1-[[5-(1 (S)-aminoe- 40 thyl)-2-[8-methoxy-2-(trifluoromethyl)-5-quinolinyl]- 4 oxazolyl]carbonyl]-4(R)-[(cyclopropylcarbonyl) amino]-L-proline, ethyl ester.

10. The kit of any one of claims 7 to 9, for use in the45 treatment or prevention of a respiratory, inflamma- tory or obstructive airway disease.

11. A compound which is a xinafoate salt of 1-[[5-(1 (S)-aminoethyl)-2-[8-methoxy-2-(trifluoromethyl)-5- 50 quinolinyl]-4-oxazolyl]carbonyl]-4(R)-[(cyclopropyl- carbonyl)amino]-L-proline, ethyl ester.

12. The compound of claim 11 for use in the treatment or prevention of a respiratory, inflammatory or ob- 55 structive airway disease.

11 EP 2 484 382 A1

12 EP 2 484 382 A1

13 EP 2 484 382 A1

14 EP 2 484 382 A1

15 EP 2 484 382 A1

16 EP 2 484 382 A1

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.

Patent documents cited in the description

• WO 0104118 A [0031] • US 6503537 B [0046] • US 6750226 B [0031] • US 6240918 B [0047] • US 4579854 A [0037] • US 5687710 A [0047] • US 3341594 A [0039] • US 5829434 A [0047] • US 3938838 A [0040] • EP 1420759 A [0048] • US 4341593 A [0040] • WO 9111172 A [0067]

Non-patent literature cited in the description

• O’MAHONEY. IDrugs, 2005, vol. 8 (6), 502-507 [0043]

17