(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`13 December 2012 (13.12.2012)
`
`WIPOI PCT
`
`\9
`
`(10) International Publication Number
`
`WO 2012/168160 A1
`
`(51)
`
`International Patent Classification:
`A61K 31/138 (2006.01)
`A61K 45/06 (2006.01)
`A61K 31/439 (2006.01)
`A61P 11/06 (2006.01)
`A61K 31/58 (2006.01)
`A61P 11/08 (2006.01)
`
`(21)
`
`International Application Number:
`
`PCT/EP2012/060442
`
`(22)
`
`International Filing Date:
`
`(25)
`
`(26)
`
`(30)
`
`(71)
`
`(72)
`(75)
`
`(74)
`
`(81)
`
`Filing Language:
`
`Publication Language:
`
`1 June 2012 (01.06.2012)
`English
`
`English
`
`Priority Data:
`61/494,594
`
`8 June 2011 (08.06.2011)
`
`US
`
`Applicant O’or all designated States except US): GLAXO
`GROUP LIMITED [GB/GB]; Glaxo Wellcome House,
`Berkeley Avenue, Greenford, Middlesex UB6 ONN (GB).
`
`Inventor; and
`Inventor/Applicant Mir US only): CRATER, Glenn
`[US/CA]; GlaxoSmithKline,
`7333 Mississauga Road
`North, Mississauga, Ontario L5N 6L4 (CA).
`
`Agents: FOWLER, Gavin, James et a1.; GlaxoSmithK-
`line, Global Patents CN925.1, 980 Great West Road,
`Brenlford, Middlesex TW8 9GS (GB).
`
`Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, G11, GM, GT, 11N,
`HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME,
`MG, MK, MN, MW, MX, MY, MZ, NA, NG, N1, NO, NZ,
`OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84)
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ,
`UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,
`MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM,
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`ML, MR, NE, SN, TD, TG).
`Declarations under Rule 4.17:
`
`as to applicant’s entitlement to applyfor and be granted a
`patent (Rule 4.17(ii))
`
`as to the applicant’s entitlement to claim the priority ofthe
`earlier application (Rule 4.1 7(iii))
`
`of inventorship (Rule 4.1 7(iv))
`Published:
`
`with international search report (Art. 21(3))
`
`(54) Title: DRY POWDER INHALER COMPOSITIONS COMPRISING UMECLIDINIUM
`
`(57) Abstract: Dry powder inhalers comprising a muscarinic acetylcholine receptor antagonist and optionally a beta 2 agonist and/or
`a corticosteroid for use in the treatment of inflammatory or respiratory tract diseases, such as asthma or COPD.
`
`
`
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`PCT/EP2012/060442
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`DRY POWDER INHALER COMPOSITIONS COMPRISING UMECLIDINIUM
`
`FIELD OF THE INVENTION
`
`The present invention provides pharmaceutical products for use in the treatment of chronic obstructive
`
`pulmonary disease (COPD), asthma and related diseases.
`
`More specifically, the present invention provides dry powder inhalers comprising a muscarinic receptor
`
`antagonist,
`
`particularly
`
`4-[hydroxy(diphenyl)methyl]-1-{2—[(phenylmethyl)oxy]ethyl}-1-
`
`azoniabicyclo[2.2.2]octane bromide, present in an amount to deliver about 31 to 32 mcg/dose or about
`
`15 to 16mcg/dose of the free cation, and optionally a beta-2 adrenoreceptor agonist, particularly 4-
`
`{(1R)—2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol
`
`triphenylacetate,
`
`and/or
`
`optionally
`
`a
`
`corticosteroid,
`
`particularly
`
`60c,9(x-diflUOI’O-17oc-[(2-
`
`fu ra nylca rbonyl)oxy]- 1 18-hyd roxy- 1 6a-methyI-3-oxo-androsta- 1,4-diene— 17B-ca rbothioic
`
`acid
`
`5-
`
`fluoromethyl ester (fluticasone furoate) .
`
`BACKGROUND OF THE INVENTION
`
`Selective Bz-adrenoreceptor agonists have been used in the prophylaxis and treatment of clinical
`
`conditions for which a bronchodilating agent has been indicated. Such conditions include diseases
`
`associated with airflow obstruction such as chronic obstructive pulmonary diseases (COPD) (e.g.
`
`chronic and wheezy bronchitis, emphysema), asthma,
`
`respiratory tract
`
`infection and upper
`
`respiratory tract disease (e.g. rhinitis, including seasonal and allergic rhinitis).
`
`In particular, asthma and other related disorders are typically treated with beta-2 adrenergic
`
`receptor agonists (beta-2 agonists) as they provide a bronchodilator effect to the patient, resulting
`
`in relief from the symptoms of breathlessness. Within the beta—2 agonist class there are presently
`
`available short acting compounds for immediate relief, such as salbutamol, biltolterol, pirbuterol and
`
`terbutaline. There are also longer acting compounds commercially available, such as salmeterol and
`
`formoterol. Salmeterol is available by prescription for use twice daily in the treatment of asthma.
`
`Over the last two decades,
`
`inhaled anticholinergic agents have become well established as well-
`
`tolerated and effective bronchodilators for the treatment of COPD. Treatment with anticholinergics
`
`significantly improves FEV1,
`
`(forced expiratory volume in 1 second) resting and dynamic lung
`
`hyperinflation, symptoms and exercise capacity, and reduces COPD exacerbations. Currently, only a
`
`few inhaled anticholinergic bronchodilators are available:
`
`the short—acting ipratropium bromide
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`(ipratropium; dosed four-times-a-day) and oxitropium bromide, and the long-acting tiotropium
`
`bromide (tiotropium; dosed once-daily).
`
`WO 03/024439 describes compounds of the general formula:
`
`HOCH2
`
`HO
`
`CHCHZNHCR4R5(CH2)m —O—(CH2)n —OCR6R7
`OH
`
`(I)
`
`and salts, solvates, and physiologically functional derivatives thereof.
`
`The compound 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]—1-hydroxyethyl}-2-
`
`10
`
`(hydroxymethyl)phenol
`
`is
`
`specifically described in WOO3/024439,
`
`as are pharmaceutically
`
`acceptable salts thereof,
`
`in particular
`
`the acetate,
`
`triphenylacetate, d-phenylcinnamate,
`
`1-
`
`naphthoate and (R)-mandelate salts.
`
`WOZOOS/ 104745 describes compounds of the formulae:
`
`+/R1
`
`N
`
`H0
`
`15
`
`R3
`
`R2
`
`W02005/104745
`
`specifically
`
`describes
`
`the
`
`compound
`
`4-[hydroxy(diphenyl)methyI]—1—{2-
`
`[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane bromide.
`
`20
`
`SUMMARY OF THE INVENTION
`
`The present invention is directed to a dry powder inhaler comprising a compound of formula (I):
`
`

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`
`
`(I)
`
`wherein X' is a pharmaceutically acceptable anion and wherein the free cation of the compound of
`
`formula (I) is present in an amount of about 31 to 32mcg/dose or about 15 to 16mcg/dose.
`
`In a further embodiment, the present invention is directed to a dry powder inhaler as described
`
`above, which further comprises a compound of formula (II):
`
`HOCH2
`
`HO
`
`0'
`
`‘CHCHZNH(CH2)6O(CH2)ZOCH2
`OH
`
`(3|
`
`(II)
`
`or a pharmaceutically acceptable salt thereof.
`
`In one
`
`embodiment,
`
`the
`
`compound
`
`of
`
`formula
`
`(I)
`
`is 4-[hydroxy(diphenyl)methyl]—1-{2-
`
`[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane bromide.
`
`In another embodiment, the pharmaceutically acceptable salt of the compound of formula (II) is the
`
`triphenylacetate salt.
`
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`The dry powder inhalers of the present invention may further comprise an inhaled corticosteroid, e.g.
`
`fluticasone propionate, mometasone furoate, budesonide, ciclesonide, or 6a,9a-difluoro-17a-[(2-
`
`furanylcarbonyl)oxy]—11B-hydroxy—16a-methyI—3—oxo-androsta—1,4—diene—17B—carbothioic
`
`acid
`
`.9
`
`fluoromethyl ester (fluticasone furoate).
`
`In
`
`one
`
`embodiment,
`
`a
`
`dry
`
`powder
`
`inhaler
`
`of
`
`the
`
`present
`
`invention
`
`comprises
`
`4-
`
`[hydroxy(diphenyl)methy|]-1-{2-[(phenylmethy|)oxy]ethy|}-1-azoniabicyc|o[2.2.2]octane
`
`bromide
`
`present in an amount to deliver about 31 to 32mcg/dose or about 15 to 16mcg/dose of the free cation,
`
`4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]—1-hydroxyethyl}-2-
`
`(hydroxymethy|)pheno| triphenylacetate and 60c,90c—difluoro—17a—[(2—furanylcarbony|)oxy]—1lB—hydroxy—
`
`160c-methyI-3-oxo-androsta-1,4-diene-17B-carbothioic acid S-fluoromethyl ester (fluticasone furoate).
`
`In
`
`a
`
`further
`
`embodiment,
`
`a dry powder
`
`inhaler
`
`of
`
`the present
`
`invention
`
`comprises 4-
`
`[hydroxy(diphenyl)methy|]-1-{2-[(phenylmethy|)oxy]ethy|}-1-azoniabicyc|o[2.2.2]octane
`
`bromide
`
`present in an amount to deliver 31.25mcg/dose or 15.625mcg/dose of the free cation, 4-{(1R)-2-[(6-{2-
`
`[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]—1-hydroxyethyl}-2-(hyd roxymethyl)phenol
`
`triphenylacetate
`
`and
`
`60c,90c—difluoro—17a—[(2—furanylcarbony|)oxy]—11B—hydroxy—16a—methyl—3—oxo—
`
`androsta-1,4-diene-17B-carbothioic acid S—fluoromethyl ester (fluticasone furoate).
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`The present invention is directed to a dry powder inhaler comprising a compound of formula (I):
`
`
`
`(I)
`
`wherein X' is a pharmaceutically acceptable anion and wherein the free cation of the compound of
`
`formula (I) is present in an amount of about 31 to 32mcg/dose or about 15 to 16mcg/dose.
`
`10
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`WO 2012/168160
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`In a further embodiment, the present invention is directed to a dry powder inhaler, wherein the free
`
`cation of the compound of formula (I) is present in an amount of about 31.25mcg/dose or about
`
`15.6mcg/dose.
`
`In yet a further embodiment, the present invention is directed to a dry powder inhaler, wherein the
`
`free cation of the compound of formula (I)
`
`is present
`
`in an amount of 31.25mcg/dose or
`
`15.6mcg/dose.
`
`In yet a further embodiment, the present invention is directed to a dry powder inhaler, wherein the
`
`10
`
`free cation of the compound of formula (I) is present in an amount of 15.625mcg/dose.
`
`In a further embodiment, the present invention is directed to a dry powder inhaler as described
`
`directly above, which further comprises the compound of formula (II):
`
`HOCHZ
`
`HO
`
`‘CHCHZNH(CH2)BO(CH2)2OCH2
`
`OH
`
`0'
`
`CI
`
`(11)
`
`or a pharmaceutically acceptable salt thereof .
`
`The pharmaceutically acceptable anion depicted by X' may be selected from chloride, bromide,
`
`iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate,
`
`oxalate, succinate, mandelate, methanesulfonate or p-toluenesulfonate.
`
`In one embodiment the
`
`pharmaceutically acceptable anion X' is bromide.
`
`For purposes herein, the free cation of the compound of formula (I) is also referred to as 4-
`
`[hydroxy(diphenyl)methy|]—1—{2—[(phenylmethy|)oxy]ethy|}—1—azoniabicyc|o[2.2.2]octane.
`
`The
`
`compound
`
`of
`
`formula
`
`(II)
`
`is
`
`also
`
`referred
`
`to
`
`as
`
`4-{(1R)—2-[(6-{2-[(2,6-
`
`dichlorobenzyl)oxy]ethoxy}hexyl)amino]—1-hydroxyethyl}-2-(hydroxymethyl)phenol.
`
`In one
`
`embodiment,
`
`the
`
`compound
`
`of
`
`formula
`
`(I)
`
`is 4-[hydroxy(dipheny|)methy|]-1-{2-
`
`[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane bromide.
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`Pharmaceutically acceptable acid addition salts of the compound of formula (II) include those
`
`formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic,
`
`trifluoroacetic,
`
`triphenylacetic, phenylacetic, substituted phenyl acetic eg. methoxyphenyl acetic,
`
`sulphamic, sulphanilic,
`
`succinic, oxalic,
`
`fumaric, maleic, malic, glutamic, aspartic, oxaloacetic,
`
`methanesulphonic,
`
`ethanesulphonic,
`
`arylsulponic
`
`(for
`
`example
`
`p-toluenesulphonic,
`
`benzenesulphonic, naphthalenesulphonic or naphthalenedisulphonic), salicylic, glutaric, gluconic,
`
`tricarballylic, mandelic, cinnamic, substituted cinnamic (for example, methyl, methoxy, halo or
`
`phenyl substituted cinnamic, including 4-methyl and 4-methoxycinnamic acid and (x-phenyl cinnamic
`
`acid), ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1- or 3-hydroxy—2—naphthoic),
`
`naphthaleneacrylic (for example naphthalene—Z—acrylic), benzoic, 4—methoxybenzoic,
`
`2— or
`
`4—
`
`hydroxybenzoic,
`
`4-chlorobenzoic,
`
`4-phenylbenzoic,
`
`benzeneacrylic
`
`(for
`
`example
`
`1,4-
`
`benzenediacrylic) and isethionic acids.
`
`In one embodiment,
`
`the pharmaceutically acceptable salt of the compound of formula (II) is
`
`selected from the acetate, 1-naphthoate and (R)-mandelate salts.
`
`In another embodiment, the pharmaceutically acceptable salt of the compound of formula (II) is the
`
`d-phenylcinnamate salt.
`
`In another embodiment, the pharmaceutically acceptable salt of the compound of formula (II) is the
`
`triphenylacetate salt.
`
`4—[hydroxy(diphenyl)methyl]—1—{2—[(phenylmethyl)oxy]ethyl}—1—azoniabicyclo[2.2.2]octane bromide
`
`has been the subject of studies in animal models, and in humans, and has been found to be a long
`
`acting high-affinity pan-active muscarinic receptor antagonist which has potential for once-daily
`
`administration.
`
`4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]—1-hydroxyethyl}-2-
`
`(hydroxymethyl)phenol and its salts has been extensively tested in animal and human studies and
`
`has been found to demonstrate sustained bronchodilation over a 24 hour period in conjunction with
`
`a favourable safety profile and thus has the potential for once-daily administration.
`
`The dry powder inhalers of the present invention, comprising the compound of formula (I) present
`
`in an amount to deliver about 31 to 32mcg/dose or 15 to 16mcg/dose of the free cation and
`
`optionally the compound of formula (II), or a pharmaceutically acceptable salt thereof, and/or
`
`optionally a corticosteroid, may have use in the treatment of inflammatory or respiratory tract
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`diseases such as chronic obstructive pulmonary disease, chronic bronchitis, asthma, chronic
`
`respiratory obstruction, pulmonary fibrosis, pulmonary emphysema, allergic rhinitis, small airways
`
`disease, bronchiectasis and cystic fibrosis.
`
`COPD is a chronic disease characterised by airways obstruction and reduced maximum expiratory
`
`flow from the lungs that manifests as persistent daily symptoms, such as shortness of breath
`
`(dyspnoea), and limitation of the ability to perform daily activities or exertion. Furthermore, there
`
`are periodic exacerbations of the condition that result in worsening of the day-to-day symptoms and
`
`activity limitation, and can also lead to hospitalisation of the patient because of the severity of the
`
`worsening symptoms/limitation. In addition, there is a progressive decline in lung function (disease
`
`progression) over several years.
`
`Bronchodilator treatment in COPD includes but is not necessarily limited to reducing symptoms,
`
`particularly dyspnoea, to allow a patient to undertake more daily activities and other activities that
`
`require exertion, and preventing exacerbations.
`
`Asthma is a chronic condition, which is characterised by widespread, variable and reversible airflow
`
`obstruction. Symptoms include coughing, wheezing, breathlessness and/or a tight feeling in the
`
`chest. Asthma attacks are generally caused by exposure to a trigger, such as pollen, dust or other
`
`allergens, which causes constriction of the airways (bronchoconstriction).
`
`It will be appreciated that
`
`a subject suffering from a condition such as asthma, may variously from time to time display no
`
`overt symptoms of the condition, or may suffer from periodic attacks during which symptoms are
`
`displayed or may experience exacerbations or worsening of the condition.
`
`In this context the term
`
`‘treatment’ is intended to encompass prevention of such periodic attacks or exacerbations of the
`
`existing condition. Such treatment may be referred to as ‘maintenance treatment’ or ‘maintenance
`
`thera py’.
`
`In one embodiment, the dry powder inhalers of the present invention are useful for the treatment of
`
`asthma or COPD.
`
`The present invention provides dry powder inhalers comprising the compound of formula (I) and
`
`optionally the compound of
`
`formula
`
`(II), or
`
`a pharmaceutically acceptable salt
`
`thereof.
`
`Administration may be via the mouth or nose. In one embodiment, inhalation is via the mouth.
`
`In one embodiment, the compound of formula (I) and specifically (4-[hydroxy(diphenyl)methyl]—1-
`
`{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane bromide, may be administered by dry
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`
`powder inhaler at a dose of about 31 to 32mcg or about 15 to 16mcg of the free cation, for example
`
`about 31.25mcg or about 15.6mcg of the free cation, and particularly 31.25mcg and 15.625mcg of
`
`the free cation, once—daily or twice—daily. In general, administration will be once—daily.
`
`The compound of formula (II), or a pharmaceutically acceptable salt thereof, may for example be
`
`administered by inhalation at a close of from about 1mcg to about 400mcg/day (calculated as the
`
`free base).
`
`In one embodiment, the compound of formula (II), or a pharmaceutically acceptable
`
`salt
`
`thereof,
`
`and
`
`specifically 4-{(1R)—2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]—1-
`
`hydroxyethyl}—2—(hydroxymethyl)phenol
`
`triphenylacetate, may be administered by dry powder
`
`inhaler at a close of from about 1mcg to 100 mcg/day, for example 3, 6.25, 12.5, 25, 50 or 100
`
`mcg/day (calculated as the free base).
`
`In general,
`
`the compound of
`
`formula (II), or a
`
`pharmaceutically acceptable salt thereof, will be administered once-daily. In one embodiment, the
`
`compound of formula (II), or a pharmaceutically acceptable salt thereof, may be administered by
`
`dry powder inhaler at a dose of 12.5mcg/day.
`
`In another embodiment, the compound of formula
`
`(II), or a pharmaceutically acceptable salt thereof, may be administered by dry powder at a dose of
`
`25 mcg/day.
`
`In another embodiment,
`
`the compound of formula (II), or a pharmaceutically
`
`acceptable salt thereof, may be administered by dry powder inhaler at a close of 50 mcg/day.
`
`In
`
`a
`
`further
`
`embodiment,
`
`4—{(1R)—2—[(6—{2—[(2,6—dichlorobenzyl)oxy]ethoxy}hexyl)amino]—1—
`
`hydroxyethyl}-2-(hydroxymethyl)phenol
`
`triphenylacetate, may be administered by dry powder
`
`inhaler, once-daily, at a dose of 25mcg per day.
`
`In a further embodiment, the present invention provides a dry powder inhaler comprising 4-{(1R)—2-
`
`[(6-{2—[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol
`
`triphenylacetate present in an amount of about 25mcg/dose, and (4-[hydroxy(diphenyl)methyl]—1-
`
`{2—[(phenylmethyl)oxy]ethyl}—1—azoniabicyclo[2.2.2]octane bromide present in an amount to deliver
`
`about 31.25mcg/dose of the free cation.
`
`In a further embodiment, the present invention provides a dry powder inhaler comprising 4—{(1R)—2—
`
`[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol
`
`triphenylacetate present
`
`in an amount of 25mcg/dose, and (4-[hydroxy(diphenyl)methyl]—1-{2-
`
`[(phenylmethyl)oxy]ethyl}—1—azoniabicyclo[2.2.2]octane bromide present in an amount to deliver
`
`31.25mcg/dose of the free cation.
`
`In a further embodiment, the present invention provides a dry powder inhaler comprising 4-{(1R)—2—
`
`[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol
`
`triphenylacetate present in an amount of about 25mcg/dose, and (4-[hydroxy(diphenyl)methyl]—1-
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`{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane bromide present in an amount to deliver
`
`about 15.625mcg/dose of the free cation.
`
`In a fUIther embodiment, the present invention provides a dry powder inhaler comprising 4-{(1R)-2-
`
`[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol
`
`triphenylacetate present
`
`in an amount of 25mcg/dose, and (4—[hydroxy(diphenyl)methyl]—1—{2—
`
`[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane bromide present in an amount to deliver
`
`15.625mcg/dose of the free cation.
`
`The dry powder inhalers of the present invention may further comprise an inhaled corticosteroid, e.g.
`
`fluticasone
`
`propionate,
`
`mometasone
`
`furoate,
`
`budesonide
`
`or
`
`6a,90c-difluoro-17a-[(2-
`
`fu ra nylca rbonyl)oxy]— 1 1 B-hyd roxy- 1 6a-methyl-3-oxo-androsta- 1,4-diene— 17B-ca rbothioic
`
`acid
`
`fluoromethyl ester (fl uticasone fu roate).
`
`In
`
`one
`
`embodiment,
`
`a
`
`dry
`
`powder
`
`inhaler
`
`of
`
`the
`
`present
`
`invention
`
`comprises
`
`4-
`
`[hydroxy(diphenyl)methyl]—1—{2—[(phenylmethyl)oxy]ethyl}—1—azoniabicyclo[2.2.2]octane
`
`bromide
`
`present in an amount to deliver 31.25mcg/dose or 15.625mcg/dose of the free cation, 4-{(1R)-2-
`
`[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol
`
`triphenylacetate and 6a,90rdifluoro-17a—[(2-furanylcarbonyl)oxy]—11B-hydroxy-16cx-methyl-3-oxo-
`
`androsta—1,4—diene—17B—carbothioic acid Srfluoromethyl ester (fluticasone furoate).
`
`When the combination additionally includes an inhaled corticosteroid, this may be used at doses
`
`compatible with those known for monotherapy. When the inhaled corticosteroid is fluticasone
`
`furoate this may be administered by inhalation at a close of from about 25mcg to about 800mcg
`
`daily, and if necessary in divided doses. Thus, the daily dose of fluticasone furoate may be for
`
`example 25, 50, 100, 200, 300, 400, 600 or 800 mcg,
`
`in general as a once-daily close. In one
`
`embodiment, the daily dose of fluticasone furoate is 200mcg. In a further embodiment, the daily
`
`dose of fluticasone furoate is 100mcg. In yet a further embodiment, the daily dose of fluticasone
`
`furoate is 50mcg.
`
`The individual compounds of a dry powder inhaler as described herein may be administered either
`
`sequentially or simultaneously. When administered simultaneously the individual compounds may be
`
`in separate compositions or a combined composition (i.e. admixed). In general, such compositions
`
`will include pharmaceutical carriers or excipients as described hereinafter, but combinations of the
`
`compounds without any excipients are also within the ambit of this invention.
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`In a further embodiment, the present invention provides a dry powder inhaler comprising the
`
`compound of formula (I) and the compound of formula (II), or a pharmaceutically acceptable salt
`
`thereof, presented separately for sequential or simultaneous administration.
`
`In yet a further embodiment, the present invention provides a dry powder inhaler comprising the
`
`compound of formula (I) and the compound of formula (II), or a pharmaceutically acceptable salt
`
`thereof, presented in admixture with each other for simultaneous administration.
`
`In each of the two cases directed above, each of the compound of formula (I) and the compound of
`
`formula (II), or a pharmaceutically acceptable salt thereof, may be formulated with or without
`
`pharmaceutically acceptable carriers or excipients.
`
`The present invention further provides a dry powder inhaler comprising the compound of formula (I)
`
`and the compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein at least
`
`one of these compounds is formulated with a pharmaceutically acceptable carrier or excipient. The
`
`carrier(s) or excipient(s) for each compound may be the same or different.
`
`The present invention further provides a dry powder inhaler comprising the compound of formula (I)
`
`and the compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein each
`
`compound is formulated with a pharmaceutically acceptable carrier or excipient. The carrier(s) or
`
`excipient(s) for each compound may be the same or different.
`
`When the dry powder inhaler of the invention additionally includes an inhaled corticosteroid, eg
`
`60c, 90c-difluoro-17oc-[(2-fura nylca rbonyl)oxy]- 1 1 B-hyd roxy- 1 6a-methyl-3-oxo—a nd rosta- 1,4-d iene-
`
`17B-carbothioic acid S—fluoromethyl ester (fluticasone furoate) this may likewise be formulated
`
`separately, either with or without one or more pharmaceutical carriers or excipients, and presented
`
`for either sequential or simultaneous administration, or the inhaled corticosteroid may be admixed
`
`with either the compound of formula (I) and/or the compound of formula (II). 6a,9a-Difluoro-17a-
`
`[(2-furanylcarbonyl)oxy]—11B-hydroxy-16a-methyl-3-oxo-androsta-1,4-diene-17B-carbothioic acid 5-
`
`fluoromethyl ester may be formulated for example as described in W002/12265, or as described
`
`hereinafter.
`
`The compositions for delivery by a dry powder inhaler may be prepared by any of the methods well
`
`known in the art of pharmacy. In general, said methods include the step of bringing the active
`
`ingredient(s) into association with the carrier which constitutes one or more accessory ingredients.
`
`In general the compositions are prepared by uniformly and intimately bringing into association the
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`active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary,
`
`shaping the product into the desired composition.
`
`Active ingredients for administration by inhalation desirably have a controlled particle size. The
`
`optimum particle size for inhalation into the bronchial system is usually 1-10um, preferably 2-5um.
`
`Particles having a size above 20pm are generally too large when inhaled to reach the small airways.
`
`To achieve these particle sizes the particles of the active ingredient as produced may be size
`
`reduced by conventional means e.g. by micronization. The desired fraction may be separated out
`
`by air classification or sieving. Preferably, the particles will be crystalline.
`
`Dry powder compositions generally contain a powder mix for inhalation of the active ingredient and
`
`a suitable powder base (carrier/diluent/excipient substance) such as mono-, di or poly-saccharides
`
`(e.g.
`
`lactose or starch). Use of lactose is preferred. The lactose may be for example anhydrous
`
`lactose or Cl-lactose monohydrate.
`
`In one embodiment, the carrier is d-lactose monohydrate.
`
`Dry powder compositions according to the invention may comprise a carrier. The carrier when it
`
`is
`
`lactose e.g. Cl-lactose monohydrate, may form from about 91 to about 99%, e.g. 97.7 — 99.0% or 91.0
`
`— 99.2% by weight of the formulation.
`
`In general, the particle size of the carrier, for example lactose,
`
`will be much greater than the inhaled medicament within the present invention. When the carrier is
`
`lactose it will typically be present as milled lactose, having a MMD (mass median diameter) of 60—
`
`90pm.
`
`The lactose component may comprise a fine lactose fraction. The ‘fine’ lactose fraction is defined as
`
`the fraction of lactose having a particle size of less than 7 pm, such as less than 6 pm, for example
`
`less than 5pm. The particle size of the ‘fine' lactose fraction may be less than 4.5 pm. The fine
`
`lactose fraction,
`
`if present, may comprise 2 to 10% by weight of the total lactose component, such
`
`as 3 to 6% by weight fine lactose, for example 4.5% by weight fine lactose.
`
`Dry powder compositions may also include, in addition to the active ingredient and carrier, a further
`
`excipient (eg a ternary agent) such as a sugar ester, calcium stearate or magnesium stearate.
`
`Alternatively, the active ingredient may be presented without exclplents.
`
`Magnesium stearate, if present in the composition,
`
`is generally used in an amount of about 0.2 to
`
`2%, e.g. 0.6 to 2% or 0.5 to 1.75%, e.g. 0.6%, 0.75%, 1%, 1.25% or 1.5 %w/w, based on the
`
`total weight of the composition. The magnesium stearate will typically have a particle size in the
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`range 1 to 50pm, and more particularly 1 - 20pm, e.g.1-10um. Commercial sources of magnesium
`
`stearate include Peter Greven, Covidien/Mallinckodt and FACI.
`
`The present invention further provides a dry powder inhaler comprising the compound of formula (I)
`
`and the compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein at least
`
`one of these two compounds is formulated with a pharmaceutically acceptable carrier and a ternary
`
`agent
`
`In another embodiment the present invention further provides a dry powder inhaler comprising the
`
`compound of formula (I) and the compound of formula (II), or a pharmaceutically acceptable salt
`
`thereof, wherein both compounds are formulated separately or together with a pharmaceutically
`
`acceptable carrier and a ternary agent.
`
`The present
`
`invention further provides a dry powder inhaler comprising 4-{(1R)—2-[(6-{2-[(2,6-
`
`dichlorobenzyl)oxy]ethoxy}hexyl)amino]—1-hydroxyethyl}-2-(hydroxymethyl)phenol
`
`triphenylacetate
`
`and
`
`(4—[hydroxy(diphenyl)methyl]—1—{2—[(phenylmethyl)oxy]ethyl}—1—azoniabicyclo[2.2.2]octane
`
`bromide each formulated separately with a pharmaceutically acceptable carrier and a ternary agent
`
`for
`
`sequential
`
`or
`
`simultaneous
`
`administration, wherein
`
`(4-[hydroxy(diphenyl)methyl]—1-{2-
`
`[(phenylmethyl)oxy]ethyl}—1—azoniabicyclo[2.2.2]octane bromide is present in an amount to deliver
`
`about 31.25mcg/dose or 15.625mcg/dose of the free cation.
`
`In one embodiment said ternary agent is magnesium stearate.
`
`The present
`
`invention further provides a dry powder inhaler comprising 4-{(1R)—2-[(6-{2-[(2,6-
`
`dichlorobenzyl)oxy]ethoxy}hexyl)amino]—1-hydroxyethyl}-2-(hydroxymethyl)phenol
`
`triphenylacetate
`
`and
`
`(4—[hydroxy(diphenyl)methyl]—1—{2—[(phenylmethyl)oxy]ethyl}—1—azoniabicyclo[2.2.2]octane
`
`bromide each formulated separately with lactose, as a pharmaceutically acceptable carrier, and
`
`magnesium stearate, as a ternary agent for sequential or simultaneous administration, wherein (4-
`
`[hydroxy(diphenyl)methyl]—1—{2—[(phenylmethyl)oxy]ethyl}—1—azoniabicyclo[2.2.2]octane bromide is
`
`present in an amount to deliver 31.25mcg/dose or 15.625mcg/dose of the free cation.
`
`The dry powder inhalers of the present invention may be, for example, reservoir dry powder
`
`inhalers, unit-dose dry powder inhalers, or pre—metered multi-dose dry powder inhalers.
`
`The compositions may be presented in unit dosage form for delivery by an appropriate dry powder
`
`inhaler. Dry powder compositions for topical delivery to the lung by inhalation may, for example, be
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`presented in capsules and cartridges of for example gelatine, or blisters of for example laminated
`
`aluminium foil.
`
`Each capsule, cartridge or blister may generally contain about 31 to 32mcg or 15 to 16mcg, for
`
`example about 31.25mcg or about 15.6mcg, such as 31.25mcg or 15.625mcg of the free cation of
`
`the compound of formula (I) and/or between 1mcg—400mcg, for example 1 to 100 mcg, such as
`
`25mcg of the compound of formula (II), or a pharmaceutically acceptable salt thereof. Packaging of
`
`the formulation may be suitable for unit dose or multi-dose delivery. As indicated above,
`
`the
`
`compound of formula (I) and the compound of formula (II), or a pharmaceutically acceptable salt
`
`thereof, may be formulated independently or
`
`in admixture.
`
`Said compounds may thus be
`
`incorporated in separate unit doses or may be combined in a single unit dose with or without
`
`additional excipients as deemed necessary.
`
`In a further embodiment, each capsule, cartridge or blister may contain 31.25mcg or 15.625mcg of
`
`the free cation of the compound of formula (I) and/or 25mcg of the compound of formula (II), or a
`
`pharmaceutically acceptable salt thereof.
`
`In yet a further embodiment, each capsule, cartridge or blister may contain 31.25mcg or 15.625mcg
`
`of
`
`the
`
`free
`
`cation
`
`of
`
`(4—[hydroxy(diphenyl)methyl]—1—{2—[(phenylmethyl)oxy]ethyl}—1—
`
`azoniabicyclo[2.2.2]octane
`
`bromide
`
`and/or
`
`25mcg
`
`of
`
`4-{(1R)—2-[(6-{2-[(2,6-
`
`dichlorobenzyl)oxy]ethoxy}hexyl)amino]—1-hydroxyethyl}-2-(hydroxymethyl)phenol triphenylacetate.
`
`In one embodiment, a composition suitable for inhaled administration may be incorporated into a
`
`plurality of sealed dose containers provided on medicament pack(s) mounted inside an appropriate
`
`dry powder inhaler. The containers may be rupturable, peelable or otherwise openable one-at-a-
`
`time and the doses of the dry powder composition administered by inhalation on a mouthpiece of
`
`the inhalation device, as known in the art. The medicament pack may take a number of different
`
`forms, for instance a disk-shape or an elongate strip. Representative inhalation devices are the
`
`DISKHALERTM and DISkusTM devices, marketed by GlaxoSmithKline.
`
`The DISKUSTM inhalation
`
`device is, for example, described in GB 2242134A.
`
`A composition suitable for inhaled administration, may also be provided as a bulk reservoir in an
`
`inhalation device, the device then being provided with a metering mechanism for metering a dose of
`
`the composition from the reservoir to an inhalation channel where