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(11) EP 2 120 936 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/439 (2006.01) A61P 11/06 (2006.01) 22.06.2011 Bulletin 2011/25 A61P 11/08 (2006.01)

(21) Application number: 08707469.6 (86) International application number: PCT/EP2008/000782 (22) Date of filing: 31.01.2008 (87) International publication number: WO 2008/101591 (28.08.2008 Gazette 2008/35)

(54) NOVEL METHODS NEUE VERFAHREN NOUVELLES MÉTHODES

(84) Designated Contracting States: (74) Representative: Srinivasan, Ravi Chandran AT BE BG CH CY CZ DE DK EE ES FI FR GB GR J.A. Kemp & Co. HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT 14 South Square RO SE SI SK TR Gray’s Inn Designated Extension States: London WC1R 5JJ (GB) AL BA MK RS (56) References cited: (30) Priority: 21.02.2007 US 902843 P WO-A-2005/097126 WO-A-2005/115462

(43) Date of publication of application: • MOLFINO N A: "DRUGS IN CLINICAL 25.11.2009 Bulletin 2009/48 DEVELOPMENT FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE" RESPIRATION, (73) Proprietor: Almirall, S.A. KARGER, BASEL, CH, vol. 72, no. 1, 2005, pages 08022 Barcelona (ES) 105-112, XP008050164 ISSN: 0025-7931 • ALABASTER V A: "DISCOVERY & (72) Inventor: BELETA SUPERVIA, Jorge DEVELOPMENT OF SELECTIVE M3 E-08173 Sant Cugat del Valles (ES) ANTAGONISTS FOR CLINICAL USE" LIFE SCIENCES, PERGAMON PRESS, OXFORD, GB, vol. 60, no. 13/14, 1997, pages 1053-1060, XP001056370 ISSN: 0024-3205

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 2 120 936 B1

Printed by Jouve, 75001 PARIS (FR) 1 EP 2 120 936 B1 2

Description ness, drowsiness, and respiratory depression. It has been found that cholinesterase inhibitors, which inhibit Field of the Invention the breakdown of acetylcholine, are beneficial in Alzhe- imer’s disease and dementia, thus a physician may wish [0001] The invention relates to novel methods of anti- 5 to avoid drugs in such patients if feasible. cholinergic therapy, particularly for respiratory diseases Acetylcholine has a complicated role in Parkinson’s dis- such as and chronic obstructive pulmonary dis- ease patients. It is believed to have a role in facilitating ease (COPD), without causing the class- related adverse release, possibly through actions at the M4 effects of antimuscarinic compounds. and M5 muscarinic receptors in the brain, and on this 10 basis, cholinesterase inhibitors are sometimes pre- Background of the Invention scribed for Parkinson’s patients; yet especially before the advent of levodopa, were used to treat [0002] Aclidinium (3(R)-(2- hydroxy-2,2-dithien-2-ylac- the symptoms of Parkinson’s disease, possibly by block- etoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2] oc- ing the dopamine inhibiting activity of the M1 muscarinic tane) is a potent muscarinic receptor antagonist de-15 receptors. scribed, e.g., in WO 01/04118, WO 05/115467, WO [0006] Older patients are more likely to experience un- 05/115466, and WO 05/115462 the contents of which desired anticholinergic effects because their bodies pro- applications are incorporated herein by reference. Aclid- duce less acetylcholine. Also, cells in many parts of the inium is a long-acting intended for admin- body (such as the digestive tract) in older patients may istration by inhalation for treatment of respiratory diseas- 20 have fewer acetylcholine receptors. Thus, the acetylcho- es, especially asthma and COPD), currently in clinical line produced is less likely to have an effect, and the trials. effect of anticholinergic drugs is correspondingly greater. [0003] Currently available muscarinic receptor antag- Moreover, older patients may have reduced kidney onists include tiotropium ((1α,2β,4β,7β)-7-[(2-hydroxy- and/or liver function, and so may be prone to increased 2,2-dithienylacetoxy]-9,9-dimethyl-3-oxa-9-azoniatricy- 25 serum concentrations of many anticholinergic drugs,. As clo[3.3.1.02,4]nonane), ipratropium methyl- ([8- 8-(1- discussed below, a number of commonly prescribed methylethyl)-8-azoniabicyclo[3.2.1]oct-3-yl]3-hydroxy- have anticholinergic effects, so patients who 2-phenyl-propanoate), and glycopyrrolate ((1,1-dime- are taking multiple medications with anticholinegic side thyl-2,3,4,5-tetrahydropyrrol-3-yl) 2-cyclopentyl-2-hy- effects may be at elevated risk. Older men in particular droxy-2-phenyl-acetate). 30 may suffer adverse effects, because the urinary difficul- [0004] Acetylcholine is a neurotransmitter associated ties associated with anticholinergic activity may exacer- with parasympathetic innervation in the body and also bate or be exacerbated by an enlarged or obstructed with transmissions in the brain. It helps control the func- prostate. Overall, anticholinergic side effects are among tioning of the heart, blood vessels, airways, and organs the most common drug-related negative effects experi- of the urinary and digestive tracts. It is also involved in 35 enced by elderly people. memory, learning, and concentration. Antimuscarinic [0007] Currently marketed antimuscarinics may be un- compounds inhibit the effects of acetylcholine on mus- suitable for use in patients having a susceptibility to con- carinic receptors, which are by far the most common type ditions that may be exacerbated by systemic anticholin- of cholinergic receptors in the body. Compounds that in- ergic effects. Levels of systemic anticholinergic activity hibit acetylcholine activity at the M3 muscarinic receptors 40 that may be easily tolerated in a young, healthy person in the airways are very useful in the treatment of respi- may be unacceptable in such patients. Conditions that ratory diseases, as they inhibit the acetylcholine- mediat- may be exacerbated by systemic anticholinergic effects ed contraction of smooth muscle in the airways, resulting include schizophrenia, , dry eyes, enlarged or in bronchodilation, and also reduce mucus secretion in obstructed prostate, narrowing or obstructon of the small the lungs. 45 intestine, enlarged colon, chronic constipation, enlarged [0005] One problem with the use of antimuscarinic lower esophagus, heart disease (especially any condi- compounds in the treatment of respiratory diseases, tion that may be aggravated by , for example however, is the risk of side effects related to systemic restenosis or plaque in the coronary arteries, propensity suppression of cholinergic activity. These can include, toarrhythmias, damage resulting from prior heart attacks, for example, dry mouth, throat irritation, decreased50 and congestive heart failure), Parkinson’s disease, sweating, increased pupil size, blurred vision, increased Alzheimer’s disease, dementia, and myasthenia gravis. intraocular pressure, increased heart rate, chest pain, Antimuscarinics may also present special risks when co- decreased gastric motility, constipation difficulty starting administered with drugs which have anticholinergic ef- and continuing to urinate, and loss of bladder control due fects, for example atypical antipsychotics or tricyclic anti- to overflow incontinence. Anticholinergic activity can also 55 depressants. Antihistamines, particularly first generation have effects on the central nervous system, such as im- sedating antihistamines such as diphenhydramine, may paired concentration, confusion, agitation, anxiety, delir- bind muscarinic receptors in addition to histamine type- ium, attention deficit, impaired memory, light-headed- 1 receptors, and so may also have anticholinergic effects.

2 3 EP 2 120 936 B1 4

In extreme cases, anticholinergic drugs can trigger anti- Typically, the patient is suffering from or susceptible to cholinergic delerium, a medical emergency character- one or more conditions selected from ized by hot, dry skin, dry mucus membranes, dilated pu- pils, absent bowel sounds, and tachycardia. Finally, sys- a. schizophrenia, impaired concentration, confusion, temically active antimuscarinics may interfere with the 5 agitation, delirium, attention deficit, impaired mem- action of drugs intended to enhance acetylcholine func- ory, respiratory depression. tion, for example cholinesterase inhibitors and choliner- b. glaucoma, dry eye, increased pupil size, blurred gic . vision, increased intraocular pressure, [0008] Accordingly, there is a need for antimuscarinic c. enlarged or obstructed prostate, difficulty urinat- therapy, particularly for respiratory diseases, especially 10 ing, overflow incontinence, asthma and chronic obstructive pulmonary disease d. narrowing or obstruction of the small intestine, en- (COPD), which does not cause the class- related adverse larged colon, chronic constipation, enlarged lower effects of systemically active antimuscarinic compounds. esophagus, decreased gastric motility, constipation, WO 2005/115462 relates to a combination which com- e. dry mouth, throat irritation, impaired sweating prises (a) a PDE4 inhibitor and (b) an antagonist of M3 15 f. (including any of resteno- muscarinic receptors which is 3(R)-(2-hydroxy-2,2-dith- sis, arteriosclerosis, prior stroke or heart attack, con- ien- 2- ylacetoxy)- 1 (3- phenoxypropyl)- 1- azoniabicyclo gestive heart failure), , tachycardia, [2.2.2]oct ane, in the form of a salt having an anion X, g. Parkinson’s disease, Alzheimer’s disease, de- which is a pharmaceutically acceptable anion of a mono mentia, and/or or polyvalent acid 20 h. myasthenia gravis WO 2005/097126 relates to the use of anticholinergic agents for producing a medicament for the prophylaxis Typically, the patient is a male. Further, the patient is and treatment of proliferative processes. typically over sixty years old. Molfino N A, Respiration, 2005, 72, 105-112 relates to In a further embodiment of the invention, the medicament the use of selective M3 antagonists in the treatment of 25 is for administration to a patient who intends to drive or COPD and asthma. operate machinery during the course of treatment. In a further embodiment of the invention, the patient is Summary of the Invention receiving a second drug which is a systemically active anticholinergic agent, or an agent which may cause or [0009] It has now been discovered that aclidinium may 30 exacerbate any of the conditions listed above. Typically, be used in the treatment of respiratory diseases without the second drug is selected from antipsychotics, tricyclic exposing patients to the class-related adverse effects of , and antihistamines. systemically active antimuscarinic compounds. Although In a further embodiment of the invention, the patient is aclidinium has the same ester moiety as, e.g., tiotropium receiving a drug which is intended to enhance acetylcho- (2-hydroxy-2,2-dithien-2-ylacetoxy), aclidinium adminis- 35 linefunction, e.g., a cholinesterase inhibitor or cholinergic tered by inhalation is surprisingly much more subject to , e.g., as set forth below. degradation in plasma to its inactive acid and alcohol Typically, the aclidinium is in the form of a salt with an metabolites. Consequently, systemic exposure to the anion X, wherein X is a pharmaceutically acceptable an- compound is negligible. Because of aclidinium’s rapid ion of a mono or polyvalent acid. More typically, X is an metabolization, it is unlikely to result in undesirable sys- 40 anion derived from an inorganic acid, such as hydrochlo- temic anticholinergic effects. Aclidinium nevertheless ric acid, hydrobromic acid, sulphuric acid and phosphoric has a long duration of action at the receptor and is ca- acid, or an organic acid such as methanesulphonic acid, pable of providing long-acting benefits of antimuscarinic acetic acid, fumaric acid, succinic acid, lactic acid, citric therapy to lungs and airways. acid and maleic acid. Preferably, the aclidinium is in the Accordingly, the invention provides, in a first embodi-45 form of . ment, aclidinium, for use in the treatment or prevention Typically, the aclidinium is in the form of a dry powder of a respiratory disease or condition in a patient by inha- suitable for inhalation. lation, which patient is suffering from or susceptible to a Typically, the medicament comprises a pharmaceutically condition which may be exacerbated by systemic an- acceptable carrier selected from mono-, di- or polysac- timuscarinic activity. 50 charides and sugar alcohols. Preferably, the carrier is Typically, the respiratory disease is a disease that may lactose. be treated, ameliorated or inhibited by a muscarinic re- Typically, the patient receives one or more additional ceptor antagonist. More preferably, the respiratory dis- for treatment of the respiratory disease or ease or condition is selected from acute or chronic bron- condition. More typically, the additional medication for chitis, emphysema, asthma and chronic obstructive pul- 55 treatment of the respiratory disease or condition is se- monary disease, especially asthma and chronic obstruc- lected from beta- agonists, or tive pulmonary disease, most especially chronic obstruc- , PDE IV inhibitors, antihistamines, anti- tive pulmonary disease. IgE antibodies, leukotriene D4 inhibitors, inhibitors of

3 5 EP 2 120 936 B1 6 egfr-kinase, p38 kinase inhibitors and/or NK1-receptor [0013] Medications which enhance cholinergic activi- antagonists; e.g., selected from the compounds identi- ty, include fied below. Preferably, the additional medication is se- lected from corticosteroids and/or beta-adrenergic ago- a. Reversible cholinesterase inhibitors, e.g., edro- nists. 5 phonium, tacrine, donepizil, physostigmine, pyri- [0010] The invention further provides use of aclidin- dostigmine, rivastigmine, galantamine, neostigmine, ium, as defined above, in the manufacture of a medica- b. Cholinergic agonists, e.g., methacholine, betha- ment for use in the treatment or prevention, by inhalation, nachol, pilocarpine of a respiratory disease or condition, as defined above. [0011] The invention further provides a pharmaceuti- 10 [0014] Beta-adrenergic agonists that can be combined cal composition for use in the treatment or prevention, with aclidinium in the present invention particularly in- by inhalation, of a respiratory disease or condition as clude β2 adrenergic agonists useful for treatment of res- defined above in a patient as defined above, which phar- piratory diseases or conditions, for example, selected maceutical composition comprises a pharmaceutically from the group consisting of , , acceptable carrier, and, as active principle aclidinium, as 15 , , , , dopexam- defined above. ine, , ,, ibuterol,isopre- naline, , meluadrine, nolomirole, , Detailed description of the invention , , , , rimoterol, , , sibenadel, sulfonterol, terbuta- [0012] Medications which may have anticholinergic ef- 20 line, , GSK-597901,GSK-159797,KUL- fectsor make patients more susceptible to anticholinergic 1248,TA-2005 and QAB-1491, in free or pharmaceutica- effects, include, for example, ly acceptable salt form. Preferably, the β2 adrenergic ag- onistis a long-acting β2 , e.g., selected a. Drugs for nausea or dizziness, especially anti- from the group consisting of formoterol, salmeterol and cholinergic agents, e.g., (Phenergan), 25 QAB-149 in free or pharmaceutically acceptable salt (Compazine), trimethobenzamide form. (Tigan), meclizine (Antivert), cyclizine (Marezine), [0015] Corticosteroids that can be combined with ac- scopalamine lidinium in the present invention particularly include those b. Drugs for Parkinson’s Disease, especially anti- suitable for administration by inhalation in the treatment cholinergic agents, e.g., benztropine; biperiden; pro- 30 of respiratory diseases or conditions, e.g., , cyclidine; trihexyphenidyl; ethoproprazine ,, , deflaza- c. Antidepressants, especially tricyclics, e.g., am- cort, halopredone acetate, , beclomethasone itriptyline (Elavil), (Sinequan), dipropionate, , acetonide, (Tofranil), (Surmontil), acetonide, , (Pametor), (Vivactil). (Asen- 35 pivalate, methylprednisolone aceponate, dexametha- din), (Ludiomil), (Ana- sone palmitoate, , , franil); (Norpramin) , dipropionate, halometa- d. Antihistamines, especially first-generation sedat- sone, methylprednisolone suleptanate, ing antihistamines, e.g., diphenhydramine (Benadr- furoate, , prednisolone farnesylate, cicleso- yl) chlorpheniramine (Chlor-Trimeton), 40 nide, propionate, propionate, (Atarax/Vistaril), (Periactin) halobetasol propionate, etabonate, betame- e. Muscle relaxants, e.g., metaxalone (Skelaxin) cy- thasone butyrate propionate, , , clobenzaprine (flexeril), orphenadrine (Norflex) dexamethasone sodium phosphate, triamcinolone, bet- f. Certain anti- migrane medications, e.g., belladonna amethasone 17-valerate, , betametha- alkaloids 45 sone dipropionate, , hydrocorti- g. Certain anti-diarrhea drugs, e.g., diphenoxylate/ sone sodium succinate, prednisolone sodium phosphate atropine (Lomotil) and hydrocortisone probutate. Budesonide and mometa- h. Urinary and GI Antispasmodics, e.g., oxybutynin sone are especially preferred. (Ditropan), flavoxate (Urispas), dicyclomine[0016] PDE4 inhibitors that can be combined with ac- (Bentyl), hyoscyamine; belladonna alkaloids; tol-50 lidinium in the present invention include denbufylline, rol- terodine (Detrol), trospium, clindinium; propanthe- ipram, cipamfylline, , , , line, pirenzepine, telenzepine, mesopram, hydrochloride, lirimilast, roflum- i. Antiarrhythmic drugs, e.g., disopyramide (Nor- ilast, , 6-[2-(3,4-Diethoxyphenyl)thiazol-4-yl] pace), procainamide (Pronestyl), , atropine pyridine-2-carboxylic acid, (R)-(+)-4-[2-(3-Cyclopenty- j. Antipsychotics, e.g., (Thorazine), 55 loxy-4-methoxyphenyl)-2-phenylethyl]pyridine, N-(3,5- (Mellaril), (Clozaril), fluphen- Dichloro- 4- pyridinyl)- 2-[1-(4- fluorobenzyl)- 5- hydroxy- azine (Stelazine), thiothixene (Navane) 1H-indol-3-yl]-2-oxacetamide, 9-(2-Fluorobenzyl)-N6- methyl-2-(trifluoromethyl)adenine, N-(3,5-Dichloro-4-

4 7 EP 2 120 936 B1 8 pyridinyl)-8-methoxyquinoline-5-carboxamide, N-[9-Me- will vary depending on, e.g., the individual, the mode and thyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk] frequency of administration, and the nature and severity [1,4] benzodiazepin- 3 (R)-yl] pyridine- 4- carboxamide, of the condition to be treated. Daily dosages for a 40 kg 3-[3-(Cyclopentyloxy)- 4- methoxybenzyl]- 6-(ethylami- adult human may typically for example be on the order no)-8-isopropyl-3H-purine hydrochloride, 4-[6,7-Di- 5 of 100-1000 micrograms of active agent in the form of ethoxy- 2,3- bis (hydroxymethyl) naphthalen- 1- yl]- 1-(2, dry powder for inhalation. methoxyethyl)pyridin-2(1H)-one, 2-carbomethoxy-4-cy- ano- 4-(3- cyclopropylmethoxy- 4- difluroromelhoxyphe- Example 1. nyl)cylohexan1-one, cis [4-cyano-4-(3-cyclopropylmeth- oxy-4-difluoromethoxyphenyl)cyclohexan-1-ol, ONO- 10 [0020] In vitro stability of aclidinium compared with ti- 6126 (Eur Respir J 2003, 22(Suppl. 45): Abst 2557) and otropium and ipratropium and glycolpymolate stability in the compounds claimed in the PCT patent applications human plasma. number WO03/09761 and PCT/EP03/14722 and in the [0021] The in vitro experiments are carried out at 36°C Spanish patent application number P200302613. and at a concentration of 5P g/ml (6 Pl of a 1 mg/ml [0017] LTD4 antagonists that can be combined with 15 dimethyl sulfoxide solution of each substance is added aclidinium in the present invention include tomelukast, to a final volume of 1.2 ml). After 3 minutes of pre-incu- , pobilukast, hydrate, , ri- bation, reaction is started by addition of the test substanc- tolukast, verlukast, sulukast, cinalukast, iralukast sodi- es. At pre-defined times of 0, 5, 15, 30 and 60 min., al- um, sodium, 4-[4-[3-(4-Acetyl-3-hydroxy-2- iquots of 100 Pl of the plasma are separated and the propylphenoxy)propylsulfonyl]phenyl]-4-oxobutyric ac- 20 reaction stopped by the addition of 1 ml of a 20 mM, pH id, [[5-[[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propyl] 4.0 sodium acetate buffer solution. The test substances thio]-1,3,4-thiadiazol-2-yl]thio]acetic acid, 9-[(4-Acetyl- are replaced with buffer for the control reactions. Human 3-hydroxy-2-n-propylphenoxy)methyl]-3-(1H-tetrazol-5- plasma is obtained from volunteers by written informed yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 5-[3-[2-(7-Chloro- consent. The blood is collectedin tubes containing lithium quinolin-2-yl)vinyl]phenyl]-8-(N,N-dimethylcarbamoyl)- 25 heparin as anticoagulant, immediately centrifuged at 4°C 4,6-dithiaoctanoic acid sodium salt; 3-[1-[3-[2-(7- Chloro- and the resultant plasma stored at -20°C when not in use. quinolin-2-yl)vinyl]phenyl]-1-[3-(dimethylamino)-3-oxo- [0022] The determination of aclidinium, tiotropium, propylsulfanyl]methylsulfanyl]propionic acid sodium salt, ipratropium and glycolpyrrolate in human plasma (100 6-(2-Cyclohexylethyl)-[1,3,4]thiadiazolo[3,2-a]-1,2,3-tri- Pl) is carried out by high-performance liquid chromatog- azolo[4,5-d]pyrimidin-9(1)-one, 4-[6-Acetyl-3-[3-(4- 30 raphy (HPLC) using UV detection, at 238 mn for aclidin- acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propyl- ium and tiotropium, and 203 nm for Ipratropium, and an phenoxy]butyric acid, 3- (R)-Methoxy-4-[1-methyl- automated online solid-phase extraction and injection 5-[N-(2-methyl-4,4,4-trifluorobutyl)carbamoyl]indol-3-yl- procedure. A suitable chromatographic system consists methyl]-N-(2-methylphenylsulfonyl)benzamide, (R)- of a high-pressure pump (model 322 Kontron for aclidin- 3-[2- Methoxy- 4-[N-(2- methylphenylsulfonyl) carbamyl] 35 ium and tiotropium and model 515 Waters for ipratro- benzyl]- 1- methyl- N-(4,4,4- trifluoro- 2- methylbutyl) in- pium), a Prospekt system (Spark Holland) assisted by a dole-5-carboxamide, (+)-4(S)-(4-Carboxyphenylthio)- 233XL sampling injector (Gilson Medical Electronics), a 7-[4-(4-phenoxybutoxy)phenyl]-5(Z)-heptenoic acid and tunable absorbance detector (model 2487, Waters Ass.), the compounds claimed in the PCT patent application and a Digital Alpha Server 1000 4/266 computer with number PCT/EP03/12581. 40 Acces*Chrom software (Perkin Elmer Nelson Systems, [0018] The words "treatment" and "treating" are to be Inc.). Chromatography for aclidinium and tiotropium de- understood as embracing treatment and/or amelioration termination is carried out on a Spherisorb ODS2, 5 Pm, of symptoms of a disease or condition as well as treat- 150 x 4.6 mm column (Waters Ass.) with a Guardapack ment of the cause of the disease or condition. Reference PBondapak CN Precolumn (Waters Ass.) and a mobile to "prevention" of a disease embraces prophylaxis and/or 45 phase (50:50 v/v for ACLIDINIUM and 22:78 v/v for tio- inhibition of the disease. tropium) of acetonitrile: 20 mM, pH 3.0 sodium phosphate [0019] The aclidinium for use according to the inven- buffer solution containing 0.2% triethylamine at a flow tion may be administered by any suitable route to provide rate of 1 ml/min. The approximate retention times for ac- local antimuscarinic action. It is preferably administered lidinium and tiotropium are 9.8 and 9.5 minutes respec- by inhalation, e.g., as a powder, spray, or aerosol, pref- 50 tively. Chromatography for ipratropium determination is erably as a dry powder. Pharmaceutical compositions carried out on a Symmetry C18, 5P m, 150 x 4.6 mm comprising aclidinium may be prepared using conven- column (Waters Ass.) and a mobile phase (12: 88, v/v) of tional diluents or excipients and techniques known in the acetonitrile:20 mM, pH 3.0 sodium phosphate buffer so- galenic art. For example, dry powder formulations may lution containing 0.2% triethylamine at a flow rate of 1 contain a powder mix for inhalation comprising the aclid- 55 ml/min. The approximate retention time of tiotropium is inium and a suitable powder base (carrier substance) 9.5 minutes. The extraction of aclidinium, tiotropium and such as lactose or starch. Use of lactose is preferred. ipratropium from plasma is performed on C2 cartridges Suitable inhaler devices are known in the art. Dosages (Baker) activated with 1.5 ml of acetonitrile and condi-

5 9 EP 2 120 936 B1 10 tioned with 1.5 ml of water. Plasma samples, previously reported. diluted with 1 ml of a 20 mM, pH 4.0 sodium acetate buffer [0028] Conclusion: Aclidinium produces significant solution, were loaded into the C2 cartridges. After wash- and long-lasting protection against methacholine-in- ing out the cartridges with 1 ml of water and 1 ml of ac- duced bronchoconstriction in healthy male volunteers, etonitrile:water (40:60, v/v) for aclidinium, or 3 ml of water 5 demonstrating its suitability for once-daily dosing, not- for tiotropium, or 1 ml of water and 1 ml of acetonitrile: withstanding that plasma levels are not even detectable. water (10:90, v/v) for ipratropium, the remaining compo- nents are eluted with the mobile phase over 1 minute. Example 3 There are no significant endogenous peaks at retention times of the analytes that would interfere with their quan- 10 [0029] Clinical Phase II study: A double-blind, ran- titation. The recovery of aclidinium is about 95% from domised, placebo-controlled, cross-over trial assesses human plasma. The recovery of tiotropium and ipratro- the pharmacodynamics, and tolerabil- pium from plasma is between 80-100%. Glycopyrrolate ity of aclidinium and its effects in COPD patients stability in human plasma is using essentially the same [0030] Methods: Men with COPD (FEVI <65% predict- procedures as for the other three drugs. The lower limit 15 ed) with demonstrated airway reversibility to ipratropium of quantitation is established at 5 ng/ml for all analytes. are randomised to 1 of 4 treatment sequences compris- [0023] Aclidinium is rapidly hydrolyzed in human plas- ing single doses of aclidinium (100, 300 and 900 micro- ma in its alcohol and acid metabolites. Both metabolites grams) and placebo administered by dry powder inhaler of aclidinium are assayed on binding for M1, M2, M3, and with a washout period of 1 week between doses. Lung M4 human muscarinic receptors and are devoid of sig- 20 function measurements include FEVI and FVC. nificant affinity for these receptors. The plasma half life [0031] Results: 17 males (mean age 63.5 y, mean of aclidinium in plasma is lower than 5 minutes for human. FEV, 1.63 L) participate in the study. Aclidinium (100, Moreover, aclidinium is stable in acid aqueous solutions 300 and 900 micrograms) significantly increases mean (pH s 4) and the hydrolytic cleavage of the ester bond FEVi Auk(0-24)/24 compared with placebo (1.800 takes place at neutral and basic pHs. 25 [p=0.002], 1.798 [p<0.0001] and 1.827 [p0.0001] L vs [0024] In contrast, the other three antimuscarinic es- 1.597 L, respectively). The increase in FEVI are statisti- ters are quite resistant to degradation by esterases in cally significant at 24 h for all doses. Aclidinium 300 and plasma. Plasma degradation for tiotropium (16%), iprat- 900 micrograms producesgreater peak FEV1 effectsand ropium (0%), glycolpyrrolate (9%) is not biologically sig- the time to maximal onset occurres earlier than with the nificant during the time of this study (60 min). 30 100 micrograms dose. Similar trends are seen with FVC. No plasma levels of aclidinium or its alcohol metabolite Example 2 are detected; low levels of its acid metabolite can be de- tected following the 900 microgram dose. Aclidinium is [0025] Clinical Phase I study: Aclidinium bromide is well tolerated: only 6 cases of mild or moderate headache tested in a Phase I, double- blind, partial cross-over, pla- 35 (vs 2 with placebo) and 1 of mildly increased sweating cebo controlled study to assess the activity, pharmacok- appear possibly related to treatment. inetics and tolerability of aclidinium. [0032] Conclusion: Single doses of aclidinium (100, [0026] Methods: 12 healthy male volunteers are ran- 300 and 900 micrograms) produce a rapid and long- last- domly assigned to 1 of 4 treatment sequences compris- ing bronchodilation in patients with COPD, notwithstand- ing single doses of aclidinium (50, 300 and 600 micro- 40 ing that plasma levels are not detectable. grams) or placebo administered by dry powder inhaler. The washout period between administrations is at least 6 days. Efficacy endpoints are specific airway conduct- Claims ance (sGaw), airway resistance (Raw) and bronchial hy- perresponsiveness (PC35 sGaw methacholine). 45 1. Aclidinium, for use in the treatment or prevention of [0027] Results: Aclidinium significantly increases a respiratory disease or condition in a patient by in- sGaw at all timepoints (1-24 h, p<0.001 vs placebo). Cor- halation, which patient is suffering from or suscepti- respondingly, Raw is significantly decreased by aclidin- ble to a condition which may be exacerbated by sys- ium at all timepoints except 1 h and 24 h (p0.001 vs pla- temic antimuscarinic activity. cebo). Aclidinium 300 and 600 micrograms also signifi- 50 cantly reduces PC35 sGaw methacholine at all post-ad- 2. Aclidinium, for use according to claim 1, wherein the ministration timepoints (p<0.001 vs placebo): the meth- respiratory disease or condition is selected from acholine doses required to decrease sGaw by 235% acute or chronic bronchitis, emphysema, asthma were 142.7 and 181.7 vs 27.1 mg/mL, for aclidinium 300 and chronic obstructive pulmonary disease, espe- and 600 micrograms vs placebo, respectively, at 24 h; 55 cially asthma and chronic obstructive pulmonary dis- and 207.1 and 256.0 vs 35.5 mg/mL, respectively, at 2 ease. h. Neither aclidinium nor its metabolites are detected in plasma and no study-drug-related adverse events are 3. Aclidinium, for use according to any of the preceding

6 11 EP 2 120 936 B1 12

claims wherein the patient is suffering from or sus- gic agonists, corticosteroids or glucocorticoids, PDE ceptible to one or more selected from IVinhibitors, antihistamines, anti- IgEantibodies, leu- kotriene D4 inhibitors, inhibitors of egfr-kinase, p38 i. schizophrenia, impaired concentration, confu- kinase inhibitors and/or NK1-receptor antagonists. sion, agitation, delirium, attention deficit, im- 5 paired memory, respiratory depression, 10. Aclidinium, for use according to claim 9, wherein the ii. glaucoma, dry eye, increased pupil size, additional medication is selected from corticoster- blurred vision, increased intraocular pressure, oids and/or beta-adrenergic agonists. iii. enlarged or obstructed prostate, difficulty uri- nating, 10 11. Use of aclidinium, as defined in any one of claims 1, iv. narrowing or obstruction of the small intes- 6 and 7, in the manufacture of a medicament, for use tine, enlarged colon, chronic constipation, en- in the treatment or prevention, by inhalation, of a larged lower esophagus, decreased gastric mo- respiratory disease or condition as defined in claim tility, constipation, 1 or 2, in a patient as defined in any one of claims v. dry mouth, throat irritation, impaired sweating, 15 1, 3 to 5 and 8 to 10. vi. cardiovascular disease (including any of res- tenosis, arteriosclerosis, prior stroke or heart at- 12. A pharmaceutical composition, for use in the treat- tack, congestive heart failure), arrhythmia, tach- ment or prevention, by inhalation, of a respiratory ycardia, disease or condition as defined in claim 1 or 2, in a vii. Parkinson’s Disease, Alzheimer’s Disease, 20 patient as defined in any one of claims 1, 3 to 5 and dementia, and 8 to 10, which pharmaceutical composition compris- viii. myasthenia gravis es a pharmaceutically acceptable carrier and, as ac- tive principle, aclidinium, as defined in any one of 4. Aclidinium, for use according to any of the preceding claims 1, 6 sand 7. claims, wherein: 25 13. A pharmaceutical composition for use according to the patient is a male; and/or claim 12, wherein the pharamceuticall acceptable the patient is over sixty years old; and/or carrier is selected from mono-, di- or polysaccharide the patient intends to drive or operate machinery and sugar alcohols, preferably lactose during the course of treatment; and/or 30 the patient is receiving a second drug which is a systemically active anticholinergic agent, or Patentansprüche an agent which may cause or exacerbate any of the conditions defined in claim 3, which sec- 1. Aclidinium zur Verwendung beider Behandlung oder ond drug is preferably selected from atypical an- 35 Prävention einer respiratorischen Krankheit oder ei- tipsychotics, tricyclic antidepressants, and anti- nes respiratorischen Zustandes bei einem Patienten histamines. durch Inhalation, wobei der Patient an einem Zu- stand, der durch systemische antimuskarinische Ak- 5. Aclidinium, for use according to claim 4, wherein the tivität verschlimmert werden kann, leidet oder dafür patient is receiving a drug which is intended to en- 40 anfällig ist. hance acetylcholine function. 2. Aclidinium zur Verwendung gemäß Anspruch 1, wo- 6. Aclidinium, for use according to any of the preceding bei die respiratorische Krankheit oder der respirato- claims, wherein the aclidinium is in the form of ac- rische Zustand aus akuter oder chronischer Bron- lidinium bromide. 45 chitis, Emphysem, Asthma und chronisch-obstrukti- ver Lungenkrankheit, speziell Asthma und chro- 7. Aclidinium, for use according to any of the preceding nisch-obstruktiver Lungenkrankheit, ausgewählt ist. claims wherein the aclidinium is in the form of a dry powder suitable for inhalation. 3. Aclidinium zur Verwendung gemäß einem der vor- 50 angehenden Ansprüche, wobei der Patient an einer/ 8. Aclidinium, for use according to any of the preceding einem oder mehreren, ausgewählt aus claims, wherein the patient receives one or more ad- ditional medications for treatment of the respiratory i. Schizophrenie, beeinträchtigter Konzentrati- disease or condition. on, Verwirrtheit, Agitation, Aufmerksamkeitsde- 55 fizit, gestörtem Erinnerungsvermögen, Atemde- 9. Aclidinium, for use according to claim 8, wherein the pression, additional medication for treatment of the respiratory ii. Glaukom, trockenem Auge, vergrößerter Pu- disease or condition is selected from beta-adrener- pille, Sehtrübung, erhöhtem intraokulärem

7 13 EP 2 120 936 B1 14

Druck, schen Zustandes aus betaadrenergen Agonisten, iii. vergrößerter oder obstruierter Prostata, Mik- Corticosteroiden oder Glucocorticoiden, PDE- IV-In- tionsstörung, hibitoren, Antihistaminen, Anti-IgE-Antikörpern, iv. Verengung oder Obstruktion des Dünn- Leukotrien-D4-Inhibitoren, Inhibitoren von egfr-Ki- darms, vergrößertem Colon, chronischer Obsti- 5 nase, p38-Kinase-Inhibitoren und/oder NK1-Rezep- pation, vergrößertem unteren Ösophagus, her- tor-Antagonisten ausgewählt ist. abgesetzter Magenmotilität, Obstipation, v. trockenem Mund, Irritationen des Rachens, 10. Aclidinium zur Verwendung gemäß Anspruch 9, wo- gestörtem Schwitzen, bei die zusätzliche Medikation aus Corticosteroiden vi. kardiovaskulärer Erkrankung (einschließlich 10 und/oder betaadrenergen Agonisten ausgewählt ist. einer von Restenose, Arteriosklerose, vor Schlaganfall oder Herzattacke, kongestivem 11. Verwendung von Aclidinium, wie es in einem der An- Herzversagen), Arrhythmie, Tachykardie, sprüche 1, 6 und 7 definiert ist, bei der Herstellung vii. Parkinsonscher Krankheit, Alzheimerscher eines Medikaments zur Verwendung bei der Be- Krankheit, Demenz und 15 handlung oder Prävention einer respiratorischen viii. Myasthenia gravis, Krankheit oder eines respiratorischen Zustandes, wie in Anspruch 1 oder 2 definiert, durch Inhalation leidet oder dafür anfällig ist. bei einem Patienten, wie in einem der Ansprüche 1, 3 bis 5 und 8 bis 10 definiert. 4. Aclidinium zur Verwendung gemäß einem der vor- 20 angehenden Ansprüche, wobei: 12. Pharmazeutische Zusammensetzung zur Verwen- dung bei der Behandlung oder Prävention einer re- der Patient ein Mann ist und/oder spiratorischen Krankheit oder eines respiratorischen der Patient über sechzig Jahre alt ist und/oder Zustandes, wie in Anspruch 1 oder 2 definiert, bei der Patient im Verlauf der Behandlung Auto fah- 25 einem Patienten, wie in einem der Ansprüche 1, 3 ren möchte oder Maschinen bedienen möchte bis 5 und 8 bis 10 definiert, durch Inhalation, wobei und/oder die pharmazeutische Zusammensetzung einen der Patient ein zweites Arzneimittel, das ein sy- pharmazeutischverträglichen Träger und als aktiven stemisch aktives anticholinerges Mittel ist oder Wirkstoff Aclidinium, wie in einem der Ansprüche 1, ein Mittel, das einen der in Anspruch 3 definier- 30 6 und 7 definiert, umfasst. ten Zustände verursachen oder verschlimmern kann, einnimmt, wobei das zweite Arzneimittel 13. Pharmazeutische Zusammensetzung zur Verwen- vorzugsweise aus atypischen Antipsychotika, dung gemäß Anspruch 12, wobei der pharmazeu- trizyklischenAntidepressiva und Antihistaminen tisch verträgliche Träger aus Mono-, Di- oder Poly- ausgewählt ist. 35 saccharid und Zuckeralkoholen ausgewählt ist, vor- zugsweise Laktose ist. 5. Aclidinium zur Verwendung gemäß Anspruch 4, wo- bei der Patient ein Arzneimittel einnimmt, das dazu bestimmt ist, die Acetylcholinfunktion zu erhöhen. Revendications 40 6. Aclidinium zur Verwendung gemäß einem der vor- 1. Aclidinium, pour utilisation dans le traitement ou la angehenden Ansprüche, wobei das Aclidinium in der prévention d’une maladie respiratoire ou d’un état Form von Aclidiniumbromid ist. chez un patient par inhalation, lequel patient souffre ou est sensible à un état qui peut être exacerbé par 7. Aclidinium zur Verwendung gemäß einem der vor- 45 une activité antimuscarinique systémique. angehenden Ansprüche, wobei das Aclidinium in der Form eines trockenen Pulvers ist, das zur Inhalation 2. Aclidinium, pour utilisation selon la revendication 1, geeignet ist. dans laquelle la maladie respiratoire ou l’état est choisi parmi une bronchite aiguë ou chronique, l’em- 8. Aclidinium zur Verwendung gemäß einem der vor- 50 physème, l’asthme et une maladie pulmonaire obs- angehenden Ansprüche, wobei der Patient eine oder tructive chronique, en particulier l’asthme et une ma- mehrere zusätzliche Medikationen zur Behandlung ladie pulmonaire obstructive chronique. der respiratorischen Krankheit oder des respiratori- schen Zustands erhält. 3. Aclidinium, pour utilisation selon l’une quelconque 55 des revendications précédentes dans lesquelles le 9. Aclidinium zur Verwendung gemäß Anspruch 8, wo- patient souffre ou est sensible à une ou plusieurs bei die zusätzliche Medikation zur Behandlung der affections parmi respiratorischen Krankheit oder des respiratori-

8 15 EP 2 120 936 B1 16

i. schizophrénie, troubles de la concentration, supplémentaires pour le traitement de la maladie confusion, agitation, délire, déficit d’attention, respiratoire ou de l’état. troubles de la mémoire, dépression respiratoire, ii. glaucome, kératoconjonctivite sèche, aug- 9. Aclidinium, pour utilisation selon la revendication 8, mentation de la taille de la pupille, vision floue, 5 dans laquelle le médicament supplémentaire pour augmentation de la pression intraoculaire, le traitement de la maladie respiratoire ou de l’état iii. augmentation de la taille et obstruction de la est choisi parmi des agonistes bêta-adrénergiques, prostate, difficulté d’uriner, des corticostéroïdes ou des glucocorticoïdes, des iv. rétrécissement ou obstruction de l’intestin inhibiteurs de PDE IV, antihistaminiques, anticorps grêle, élargissement du côlon, constipation10 anti-IgE, inhibiteurs de leucotriènes D4, inhibiteurs chronique, élargissement de l’oesophage infé- d’egfr-kinase, inhibiteurs de p38-kinase et/ou anta- rieur, réduction de la motilité gastrique, consti- gonistes des récepteurs NK1. pation, v. sécheresse buccale, irritation de la gorge, 10. Aclidinium, pour utilisation selon la revendication 9, troubles des la sudation, 15 dans laquelle le médicament supplémentaire est vi. maladie cardiovasculaire (y compris l’une choisi parmi des corticostéroïdes et/ou des agonis- quelconque parmi resténose, artériosclérose, tes bêta-adrénergiques. AVC primaire ou crise cardiaque, insuffisance cardiaque congestive), arythmie, tachycardie, 11. Utilisation d’aclidinium, comme défini dans l’une vii. maladie de Parkinson, maladie d’Alzheimer, 20 quelconque des revendications 1, 6 et 7, dans la démence, et préparation d’un médicament, pour utilisation dans viii. myasthénie grave le traitement ou la prévention, par inhalation, d’une maladie respiratoire ou d’un état tel que défini dans 4. Aclidinium, pour utilisation selon l’une quelconque la revendication 1 ou 2, chez un patient tel que défini des revendications précédentes, dans laquelle : 25 dans l’une quelconque des revendications 1, 3 à 5 et 8 à 10. le patient est de sexe masculin ; et/ou le patient a plus de soixante ans ; et/ou 12. Composition pharmaceutique, pour utilisation dans le patient a l’intention de conduire ou d’utiliser le traitement ou la prévention, par inhalation, d’une une machine pendant la durée du traitement ; 30 maladie respiratoire ou d’un état tel que défini dans et/ou la revendication 1 ou 2, chez un patient tel que défini on administre au patient un second médicament dans l’une quelconque des revendications 1, 3 à 5 qui est un agent anticholinergique systémique- et 8 à 10, laquelle composition pharmaceutique com- ment actif, ou prend un véhicule pharmaceutiquement acceptable un agent qui peut provoquer ou exacerber un 35 et, comme principe actif, de l’aclidinium, comme dé- quelconque des états définis dans la revendica- fini dans l’une quelconque des revendications 1, 6 tion 3, lequel second médicament est de préfé- et 7. rence choisi parmi des antipsychotiques atypi- ques, antidépresseurs tricycliques, et antihista- 13. Composition pharmaceutique pour utilisation selon miniques. 40 la revendication 12, dans laquelle le véhicule phar- maceutiquement acceptable est choisi parmi un mo- 5. Aclidinium, pour utilisation selon la revendication 4, no-, di- ou polysaccharide et des polyols, de préfé- dans laquelle on administre au patient un médica- rence le lactose. ment qui a pour but de stimuler la fonction acétyl- choline. 45

6. Aclidinium, pour utilisation selon l’une quelconque des revendications précédentes, dans laquelle l’acli- dinium est sous la forme de bromure d’aclidinium. 50 7. Aclidinium, pour utilisation selon l’une quelconque des revendications précédentes, dans laquelle l’acli- dinium est sous forme de poudre sèche convenant pour l’inhalation. 55 8. Aclidinium, pour utilisation selon l’une quelconque des revendications précédentes, dans laquelle on administre au patient un ou plusieurs médicaments

9 EP 2 120 936 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.

Patent documents cited in the description

• WO 0104118 A [0002] • WO 2005097126 A [0008] • WO 05115467 A [0002] • WO 0309761 A [0016] • WO 05115466 A [0002] • EP 0314722 W [0016] • WO 05115462 A [0002] • ES P200302613 [0016] • WO 2005115462 A [0008] • EP 0312581 W [0017]

Non-patent literature cited in the description

• Molfino N A. Respiration, 2005, vol. 72, 105-112 • Eur Respir J, 2003, vol. 22 (45), 2557 [0016] [0008]

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