US007759328B2
`
`(12) Ulllted States Patent
`Govind et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,759,328 B2
`Jul. 20, 2010
`
`(54) COMPOSITION FOR INHALATION
`
`(75)
`
`Inventors: Nayna Govind, Leicestershire (GB);
`Maria Marlow, Leicestershire (GB)
`
`(73) Assignee: AstraZeneca AB, Sodertalje (SE)
`
`( * ) Notice:
`
`.
`(21) App]. NO"
`.
`.
`(22) PCT F11ed'
`(86) PCT No:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`USC. 1540.)) by 0 days.
`10/502.1685
`
`Jam 29’ 2003
`PCT/SE03/00156
`
`§ 371 (OX1):
`(2): (4) Date:
`
`JUL 27: 2004
`
`(87) PCT Pub. No.: WO03/063842
`
`PCT Pub. Date: Aug. 7, 2003
`
`(65)
`
`(30)
`
`Prior Publication Data
`
`US 2005/0089478 A1
`
`Apr. 28, 2005
`
`Foreign Application Priority Data
`
`Feb. 1, 2002
`
`(SE)
`
`.................................. .. 0200312
`
`(51)
`
`Int. Cl.
`(2006.01)
`A01N 45/00
`(2006.01)
`A61K 31/335
`(52) U.S. Cl.
`..................................... .. 514/167; 514/463
`(58) Field of Classification Search ................. .. 424/45,
`424/46, 489, 48
`See application file for complete search history.
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`W0
`W0
`
`W0
`W0
`
`W0 00/53 188
`WO 01/78693
`
`9/2000
`10/2001
`
`10/2001
`W0 01/78737
`1/2002
`W0 02/03958
`OTHER PUBLICATIONS
`
`Vippagunta et al. “Crystalline Solids,” Advanced Drug Delivery
`Reviews, 2001, 43, PP~ 13*
`Calverley -et al., “Maintenance therapy with budesonide -and
`§()2rr9r11()£e;(il91r(12c011)r§))r11c obstructive pulmonary disease Eur". Respm J'.
`Cazzola et al., “Effect of salmeterol and formoterol in patients Wit11
`chronic obstructive pulmonary disease” Pulm Pharmacol. 7:103-7
`(1994).
`Lumry, “A review of the preclinical and clinical data of newer
`"tr
`1t
`'d
`d'thtrtmtf11 'h"t',”J'.All
`‘$1,-.21.“?,i7nZfZ?‘13liS§1§3-s?1§39) ffbfufcteiiiii.
`‘S
`‘W
`Milgrom and Taussig, “Keeping Children wit11 Exercise-Induced
`Ast11ma Active” Pediatrics 104:38-42 (1999).
`Pipkom et al., “Budesonide—a New Nasal Steroid” Rhinology
`18:171-175 (1980).
`Renkema et al., “Effects of long-term treatment Wit11 corticosteroids
`in COPD” Chest 10921156-62 (1996).
`Zettersttrom et al., “Improved asthma control wit11 budesonide/
`formoterol in a single inhaler, compared wit11 budesonide a1one”Eur.
`Respi/1 J'. 18:262-268 (2001).
`Brindley, “The chlorofluorocarbon to hydrofluoroalkane transition:
`The effect on pressurized metered dose inhaler suspension stability,”
`J. Allergy Clin. Immunol., vol. 104, pp. s22l-s226 (1999).
`Byron, “Respiratory Drug Delivery,” CRC Press, Inc., pp. 185-201
`(1990).
`Communication of a Notice of 0pposition against Patent No.
`EP14741 17 from the European Patent Office, dated Dec. 4, 2009 (27
`pages).
`Jinks, “A rapid technique for characterization of the suspension
`dynamics of metered dose inhaler formulations,” Proceedings of
`Drug Delivery to the Lungs VI., London: The Aerosol Society, 1995:
`Abstract supplied by The British Library (2 pages).
`Turbiscan MA 2000, Sci-Tec Inc., [online] Retrieved from http://sci-
`tec-inc.com/Turbiscan%20C1assic%20MA%202000 .htrn1
`Retrieved on Oct. 20, 2009 (3 pages).
`TurbiScan MA 2000 brochure (6 pages).
`
`* cited by examiner
`
`12/1999 Blondino et al.
`6,004,537 A
`6,309,623 B1 * 10/2001 Weers et al.
`................ .. 424/45
`
`2003/0018019 Al*
`1/2003 Meade et al.
`............. .. 514/171
`
`Primary Examiner—A1ton N Pryor
`(74) Attorney, Agent, or Firm—Fish & Richardson P.C.
`
`FOREIGN PATENT DOCUMENTS
`
`(57)
`
`ABSTRACT
`
`EP
`W0
`W0
`W0
`W0
`W0
`
`0 534 731
`W0 93/05765
`W0 93/11773
`W0 98/15280
`W0 98/21175
`W099/15182
`
`3/1993
`4/1993
`6/1993
`4/1998
`5/1998
`4/1999
`
`The invention relates to a formulation comprising formoterol
`and budesonide for use in the treatment of respiratory dis-
`eases. The composition further contains HFA 227, PVP and
`PEG, preferably PVP K25 and PEG 1000.
`
`15 Claims, 16 Drawing Sheets
`
`1
`
`Complex Ex. 1001
`Complex Ex. 1001
`
`1
`
`

`
`U.S. Patent
`
`mm
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`US 7,759,328 B2
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`U.S. Patent
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`Jul. 20, 2010
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`Sheet 2 of 16
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`US 7,759,328 B2
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`
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`

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`U.S. Patent
`
`Jul. 20, 2010
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`Sheet 3 of 16
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`US 7,759,328 B2
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`U.S. Patent
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`Jul. 20, 2010
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`Sheet 4 of 16
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`US 7,759,328 B2
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`Averages of Turbiscan data for formulation containing 160/4.5ug
`Budesonide/Formoterol. 0.3% w/w PEG 1000.
`
`0.0001% — 0.05% w/w PVP K25, in HFA 227.
`
`Percentage
`
`(%) 6.0
`
`14.00
`
`16.00
`
`.0 1.0 12.00
`
`Time (min)
`
`-0- 160/4.5ug. 0.0001%. (Trans)
`
`-1-— 160/4.5ug. 0.01% (Trans)
`
`—.— 160/4.5ug. 0.00o5%. (Trans)''
`—— 160/4.5ug. 0.03% (Trans)
`
`—xt-— 160/4.5ug. 0.001% (Trans)
`
`—-— 160/4.5ug. 0.05% (Trans)
`
`4
`
`5
`
`

`
`U.S. Patent
`
`Jul. 20, 2010
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`Sheet 5 of 16
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`US 7,759,328 B2
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`Averages of Turbiscan data for
`formulation containing 80/4.5ug
`Budesonide/Formoterol. 0.3% w/w PEG 1000.
`
`0.0001% - 0.05% w/w PVP K25, in HFA 227.
`
`34.0000
`
`29.0000
`
`24.0000
`
`14.0000
`
`
`
`Percentage(%)
`
`Time (min)
`
`F|G_ 5
`
`-+-
`
`80/4.5ug. 0.0001% (Trans)
`
`—+——
`80/4.5ug. 0.01% (Trans)
`—-— 80/4.5ug. o.ooo5% (Trans)
`—-— 80/4.5ug. 0.03% (Trans)
`
`—eI<——
`
`80/4.5ug 0.001% (Trans)
`
`—-—— 80/4.5ug. 0.05% (Trans)
`
`6
`
`

`
`U.S. Patent
`
`Jul. 20, 2010
`
`Sheet 6 of 16
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`US 7,759,328 B2
`
`Averages of Turbiscan data for
`formulation containing 40/4.5ug
`BudesonidelFormoteroI. 0.3% w/w PEG 1000.
`
`0.0001% - 0.05% w/w PVP K25, in HFA 227.
`
`
`
`Percentage(%)
`
`0
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`14
`
`16
`
`18
`
`Time (min)
`
`—o— 40/4.5ug 0.0001 % (Trans)
`
`-1-
`
`40/4.5ug 0.01%(Trans)
`
`—.»— 40/4.5ug 0.0005% (Trans)
`——— 40/4.5ug 0.03% (Trans)
`—->o<—
`40/4.5ug 0.001% (Trans)
`
`—-— 40/4.5ug 0.05% (Trans)
`
`6
`
`7
`
`

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`U.S. Patent
`
`Jul. 20, 2010
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`Sheet 7 of 16
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`US 7,759,328 B2
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`
`
`Returnforceat0.5mm(N)
`
`Actuation number
`
`-4- 0.1% PEG 1000
`
`F|G_ 7
`
`—- 0.3% PEG 1000
`..u- 0.5% PEG 1000
`
`8
`
`

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`U.S. Patent
`
`Jul. 20, 2010
`
`Sheet 8 of 16
`
`US 7,759,328 B2
`
`Averages of Turbiscan data for formulation
`containing 80/4.5ug Budesnoide/Formoterol.
`
`0.001% w/w PVP K25. 0.005% - 0.5% w/w PEG 1000, in HFA 227.
`
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`Time (Min)
`
`1
`
`12
`
`14
`
`16
`
`-6- 80/4.5ug. 0.005% w/W PEG 1000. (Trans)
`
`——x+— 80/4.5ug. 0.3% w/w PEG 1000. (Trans)
`
`—— 80/4.5ug. 0.5% w/w PEG 1000. (Trans)
`+ 80/4.5ug. 0.05% PEG 1000. (Trans)
`—+— 80/4.5ug. 0.35% w/w PEG 1000. (Trans)
`
`8
`
`9
`
`

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`U.S. Patent
`
`Jul. 20, 2010
`
`Sheet 9 of 16
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`US 7,759,328 B2
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`Jul. 20, 2010
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`Sheet 10 of 16
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`Jul. 20, 2010
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`Sheet 11 of 16
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`US 7,759,328 B2
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`U.S. Patent
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`Jul. 20, 2010
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`Sheet 12 of 16
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`US 7,759,328 B2
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`FIG.12
`
`0SECONDS
`
`13
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`

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`U.S. Patent
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`Jul. 20, 2010
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`Sheet 13 of 16
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`US 7,759,328 B2
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`Jul. 20, 2010
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`Sheet 14 of 16
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`US 7,759,328 B2
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`U.S. Patent
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`Jul. 20, 2010
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`Sheet 15 of 16
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`US 7,759,328 B2
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`U.S. Patent
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`Jul. 20, 2010
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`Sheet 16 of 16
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`US 7,759,328 B2
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`17
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`17
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`

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`US 7,759,328 B2
`
`2
`
`1
`COMPOSITION FOR INHALATION
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a national phase application under 35
`U.S.C. §371 of PCT International Application No. PCT/
`SE2003/000156, filed on Jan. 29, 2003, which claims priority
`to Swedish Application Serial No. 0200312-7, filed Feb. 1,
`2002.
`
`10
`
`FIELD OF THE INVENTION
`
`The present invention relates to a formulation comprising
`formoterol and budesonide for use in the treatment of inflam-
`
`15
`
`matory conditions/disorders, especially respiratory diseases
`such as asthma, COPD and rhinitis.
`
`BACKGROUND OF THE INVENTION
`
`Stability is one of the most important factors which deter-
`mines whether a compound or a mixture of compounds can be
`developed into a therapeutically useful pharmaceutical prod-
`uct.
`Combinations of formoterol and budesonide are known in
`
`the art, see for example W0 93/ 1 1773 discloses such a com-
`bination that is now marketed as Symbicort® in a dry powder
`inhaler. There are a variety of other inhalers by which a
`respiratory product can be administered, such as pressurised
`metered dose inhalers (pMDI’s). Formulations for pMDI’s
`may require certain excipients as disclosed in WO 93/05765.
`It has now been found that certain HFA formulations com-
`
`prising formoterol and budesonide together with polyvi-
`nylpyrrolidone (PVP) and polyethylene glycol (PEG) exhibit
`excellent physical suspension stability.
`
`DESCRIPTION OF THE INVENTION
`
`In accordance with the present invention, there is provided
`a pharmaceutical composition comprising formoterol, budes-
`onide, HFA 227 (1,1,1,2,3,3,3-heptafluoropropane), PVP and
`PEG characterized in that the PVP is present from about
`0.0005 to about 0.03% w/w and the PEG is present from about
`0.05 to about 0.35% w/w.
`
`Preferably the PVP is present in an amount of 0.001% w/w.
`Preferably the PVP is PVP K25 (PVP having a nominal
`K-value of 25).
`Preferably the PEG is present in an amount of 0.3% w/w.
`Preferably the PEG is PEG 1000 (PEG having an average
`molecular weight of 1000 Daltons).
`Preferably the concentrations of formoterol/budesonide
`are such that the formulation delivers formoterol/budesonide
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`at 4.5/40 mcg, 4.5/80 mcg, 4.5/160 mcg or 4.5/320 mcg per
`actuation.
`The formoterol can be in the form of a mixture of enanti-
`
`55
`
`omers. Preferably the formoterol is in the form of a single
`enantiomer, preferably the R, R enantiomer. The formoterol
`can be in the form of the free base, salt or solvate, or a solvate
`of a salt, preferably the formoterol is in the form of its fuma-
`rate dihydrate salt. Other suitable physiologically salts that
`can be used include chloride, bromide, sulphate, phosphate,
`maleate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- or
`4-hydroxybenzoate, 4-chlorobenzoate, p-toluenesulphonate,
`benzenesulphonate, ascorbate, acetate, succinate,
`lactate,
`glutarate, gluconate, tricaballate, hydroxynapaphthalenecar-
`boxylate or oleate.
`
`60
`
`65
`
`Preferably the second active ingredient is budesonide,
`including epimers, esters, salts and solvates thereof. More
`preferably the second active ingredient is budesonide or an
`epimer thereof, such as the 22R-epimer of budesonide.
`The pharmaceutical compositions according to the inven-
`tion can be used for the treatment or prophylaxis of a respi-
`ratory disorder, in particular the treatment or prophylaxis of
`asthma, rhinitis or COPD.
`In a further aspect the invention provides a method of
`treating a respiratory disorder, in particular asthma, rhinitis or
`COPD, in a mammal, which comprises administering to a
`patient a pharmaceutical composition as herein defined.
`The compositions ofthe invention can be inhaled from any
`suitable MDI device. Doses will be dependent on the severity
`ofthe disease and the type ofpatient, but are preferably 4.5/80
`mcg or 4.5/160 mcg per actuation as defined above.
`The concentration of PVP (0.001% w/w) used in this for-
`mulation has been found to give consistently stable formula-
`tions over the required dose range, incorporating a wide range
`of concentrations of the active components, and at a much
`lower concentration than indicated in the prior art.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a schematic drawing of an Optical Suspension
`Characterisation (OSCAR) setup.
`FIGS. 2-3 are graphs showing the averages of OSCAR data
`(lower sensor) for formulations in HFA 227 containing 4.5 ug
`formoterol; 0.3% w/w PEG 1000; 0.0001%-0.05% w/w PVP
`K25; and 160 pg budesonide (FIG. 2) or 80 pg budesonide
`(FIG. 3).
`FIGS. 4-6 are graphs showing the averages of Turbiscan
`data for formulations in HFA 227 containing 4.5 ug formot-
`erol; 0.3% w/w PEG 1000; 0.0001%-0.05% w/w PVP K25;
`and 160 pg budesonide (FIG. 4), 80 pg budesonide (FIG. 5),
`or 40 pg budesonide (FIG. 6).
`FIG. 7 is a graph showing the effect of PEG 1000 concen-
`tration on stem return force for formulations containing 4.5
`pg formoterol; 160 pg budesonide; and 0.1%, 0.3%, or 0.5%
`w/w PEG 1000.
`
`FIG. 8 is a graph showing the averages of Turbiscan data
`for formulations in HFA 227 containing 80 pg budesonide;
`4.5 pg formoterol; 0.0001% PVP K25; and 0.005%-0.5%
`w/w PEG 1000.
`
`FIGS. 9-11 are a series of digital photographs, taken after
`standing times of 0 seconds (FIG. 9), 30 seconds (FIG. 10),
`and 60 seconds (FIG. 11), of suspensions in HFA 227 con-
`taining budesonide (160 ug/actuation); formoterol (4.5 p.g/ac-
`tuation); 0.3% PEG 1000; and PVP K25 at 0.0001%,
`0.0005%, 0.001%, 0.01%, 0.03%, and 0.05% w/w.
`FIGS. 12-14 are a series of digital photographs, taken after
`standing times of 0 seconds (FIG. 12), 30 seconds (FIG. 13),
`and 60 seconds (FIG. 14), of suspensions in HFA 227 con-
`taining budesonide (80 p.g/actuation); formoterol (4.5 p.g/ac-
`tuation); 0.3% PEG 1000; and PVP K25 at 0.0001%,
`0.0005%, 0.001%, 0.01%, 0.03%, and 0.05% w/w.
`FIGS. 15-16 are digital photographs, taken after standing
`times of 0 minutes (FIG. 15) and 10 minutes (FIG. 16), of
`suspensions in HFA 227 containing budesonide (80 ug/actua-
`tion); formoterol (4.5 p.g/actuation); 0.001% PVP K25; and
`PEG 1000 at 0.005, 0.05, 0.35, and 0.5% w/w.
`The invention is illustrated by the following examples.
`
`EXPERIMENTAL SECTION
`
`Two methods can be used to evaluate physical suspension
`stability: Optical suspension characterisation (OSCAR), and
`
`18
`
`18
`
`

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`US 7,759,328 B2
`
`3
`TURBISCAN. Both methods are used to semi-quantify sedi-
`mentation/crearning rates. OSCAR measurements are per-
`formed using the PET bottles directly. For TURBISCAN
`analysis, the suspensions are transferred to custom designed
`pressure cells for measurement of light transmittance and
`backscattering.
`
`Methodology
`Oscar
`
`Optical Suspension Characterisation (OSCAR) equipment
`is custom designed for the rapid and reproducible semi-quan-
`tification of metered dose inhaler suspension characteristics.
`The OSCAR equipment utilises changes in light transmis-
`sion with time, to characterise a pre-agitated suspension for-
`mulation (a schematic diagram of the equipment is shown in
`FIG. 1). The equipment consists of a twin headed test assem-
`bly. The head on the left side of the equipment is used with
`dilute suspensions and the right for concentrated suspensions.
`The selector switch mounted between the two test heads is
`
`used to alternate concentration choice. The output from the
`selected test head is directed to the equipment mounted volt-
`age display and to the computer for data logging. The ana-
`logue signals from photodetectors are digitised and the values
`collected in data files, these are then processed using a suit-
`able software package. There are two equipment mounted
`voltage displays, one each for the upper and lower photode-
`tectors. The upper and lower photodetectors are height adjust-
`able and a position readout display is provided to indicate the
`set height for each test run.
`The Reagecon Turbidity standards (2500-4000 NTU) are
`used to calibrate the sensitivity of the OSCAR equipment. In
`this case, the 3000 NTU turbidity calibration standard is used
`as a standard calibration check. However any of the turbidity
`standards can be used to adjust the sensitivity ofthe probes to
`a specific voltage appropriate to the formulation.
`Samples for test on the OSCAR equipment are presented in
`PET bottles crimped with non-metering valves.
`For background information and prior art for this method
`refer to papers from Drug Delivery to the Lungs IX, 1997,
`Method Development of the OSCAR technique for the char-
`acterization ofmetered dose inhaler formulations, Authors N.
`Govind, P. Lambert And Drug delivery to the Lungs VI, 1995,
`A Rapid Technique for Characterisation of the Suspension
`Dynamics of metered Dose Inhaler Formulations, Author, PA
`Jinks (3M Healthcare Ltd)
`Turbiscan
`
`Turbiscan MA 2000 is a concentrated dispersion and emul-
`sion stability and instability analyser, or a vertical scan mac-
`roscopic analyser. It consists of a reading head moving along
`a flat-bottomed, 5 ml cylindrical glass cell, which takes read-
`ings of transmitted and backscattered light every 40 um on a
`maximum sample height of 80 mm. The scan can be repeated
`with a programmable frequency to obtain a macroscopic fin-
`gerprint of the sample.
`The reading head uses a pulsed near infrared light source
`(wavelength:850 nm) and two synchronous detectors:
`Transmission detector: Picks up light transmitted through
`the solution in the tube, at 0 °
`Backscattering detector: Receives the light back scattered
`by the product at 135°.
`The profile obtained characterises the samples homogenie-
`ity, concentration and mean particle diameter. It allows for
`quantification of the physical processes the sample is under-
`going. As well as detecting destabilisation, Turbiscan allows
`comparison of, for example, the sedimentaion rate of differ-
`ent suspensions.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`
`Turbiscan may be used in several modes, eg transmitted or
`backscattering modes. Turbiscan has been used here in these
`examples to measure the transmitted light as a funtion oftime
`Dispersion instability is the result of two physical pro-
`cesses: a) particle size increases as a result ofthe formation of
`aggregates, due to flocculation b) particle migration resulting
`in crearning or sedimentation. When a product is stable (ie no
`flocculation, crearning or sedimentation), the transmitted and
`backscattered light will remain constant i.e. scans of these
`will show a constant level profile. If the product undergoes
`changes in particle size, variations in the transmitted/back-
`scattered light show as change in the direction of the scan
`from horizontal or steady state profile.
`For pressurised systems a cell capable of handling pres-
`surised samples is required; Such a cell was used for the
`evaluations of these HFA formulations. The scans were per-
`formed in the AUTO mode.
`
`The % transmission averages shown in the figure (see later)
`were taken from a zone around the middle of the suspension
`sample.
`lnitial Evaluation
`
`For the initial evaluation, only OSCAR was used.
`Formulations containing forrnoterol fumarate dihydrate,
`budesonide, 0.001% w/w PVP K25 and either 0.1% w/w or
`0.3% PEG 1000 in HFA-227 were prepared in polyethylene
`terephlate (PET) bottles crimped with a continuous valve. For
`all formulations, the forrnoterol fumurate dihydrate concen-
`tration remained constant at 0.09 mg/ml (equivalent to 4.5
`mcg forrnoterol fumurate dihydrate per actuation) and the
`budesonide concentration varied between approximately 1
`mg/ml to 8 mg/ml (equivalent to 40 mcg to 320 mcg per
`actuation).
`
`Early OSCAR data for Syrnbicort pMDI formulations
`Transmittance
`(IHV)
`Lower sensor
`PEG concn
`% w/w
`
`PVP K25
`concen-
`tration
`
`Time
`
`Budesonide
`dose
`
`Formoterol
`dose
`
`ex-actuator
`
`ex-actuator
`
`(% w/w)
`
`seconds
`
`0.1
`
`40 pg
`
`80 pg
`
`4.5 pg
`
`4.5 pg
`
`160 pg
`
`4.5 pg
`
`320 pg
`
`4.5 pg
`
`0.001
`
`0.001
`0.002
`
`0.001
`0.002
`
`0.001
`0.002
`
`30 seconds
`60 seconds
`30 seconds
`60 seconds
`30 seconds
`60 seconds
`30 seconds
`60 seconds
`30 seconds
`60 seconds
`30 seconds
`60 seconds
`30 seconds
`60 seconds
`
`202
`240
`184
`185
`208
`304
`248
`327
`
`0.3
`
`257
`264
`
`114
`191
`
`475
`570
`930
`1443
`
`OSCAR analysis of these formulations gave relatively low
`light transmittance values at the lower sensor, which is indica-
`tive of stable suspensions with low flocculation characteris-
`tics. Early indications were that the 0.001% w/w PVP with
`0.3% PEG 1000 would give the best suspension.
`FUTHER EVALUATION: various concentrations of PVP
`K25 with a constant PEG 1000 concentration of 0.3% w/w.
`
`OSCAR, Turbiscan and photographic methods were used
`to evaluate the formulations. OSCAR and Turbiscan tech-
`
`19
`
`19
`
`

`
`US 7,759,328 B2
`
`6
`
`-continued
`
`Dose
`pg/shot
`Budesonide
`
`Time
`Sec/mins
`
`PVP concentration % w/w
`
`0.0001
`
`0.0005
`
`0.001
`
`0.01
`
`0.03
`
`0.05
`
`5
`4-5
`
`uomm
`
`1
`
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`
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`
`3
`4-5
`
`mm
`.°>-
`
`D-‘D-‘-JKUJUJIQIQIOOUJIQD-tlIQl|gpd©-J5-¥>l\)[0l\)b-A
`
`Nb)»-k.nk.nk.n-J>.bJts)t—Ak.nk.nk.nkn-I:-NNk.nk.nk.nk.n
`
`Ix)
`
`Ln.J>.J>-LI»
`
`mmmJ>.wmNmm.;>.mwN>-mmmmmwwmmmm
`
`J:-rL»NN>-LnLnLnmJ>.NNmmLnm
`
`12
`
`
`
`wrote:r->->-an
`
`E;Nt—Ak.nk.nk.nk.n.J>.bJNk.nk.nk.nk.nk.nuJuJk.nLnk.nJ>-
`
`iw-°E
`
`90
`
`25
`
`10
`15
`30
`60
`90
`
`25
`
`10
`15
`30
`60
`90
`
`25
`
`10
`15
`30
`60
`90
`
`25
`
`10
`
`160
`
`80
`
`40
`
`Suspensions considered excellent are highlighted in bold.
`It can be seen that the formulations with 0.001% w/w PVP
`
`gave the best suspension stability overall.
`
`Oscar Data (Graphs of Light Transmission Versus Time)
`FIG. 2 shows the average OSCAR transmission readings
`(lower sensor only) for various concentrations of PVP K25. A
`low transmission reading indicates that the suspension is
`dispersed preventing light being transmitted. Hence, it can be
`seen that the lowest line is the most stable formulation. This is
`
`the 0.001% PVP sample.
`In FIG. 3, the bottom line, again with low transmission
`readings, clearly shows that
`the formulation containing
`0.001% PVP is the most stable.
`
`Turbiscan Data (Graphs of Percentage (%) Light Transmis-
`sion Versus Time)
`Data from the Turbiscan can be intepretated in a similar
`vein to the OSCAR data in that a low percentage (%) trans-
`mission indicates the suspension is dispersed . The % trans-
`mission averages quoted here were taken from a zone around
`the middle ofthe suspension sample. In FIG. 4 the most stable
`formulation is the lowest line with the lowest % transmission,
`i.e. the bold black line with 0.001% w/w PVP
`
`FIGS. 5 and 6 show that the suspension with 0.001% w/w
`PVP is the most stable (bottom bold line) with the lowest %
`transmission.
`
`Further Evaluation: Determination of the optimum PEG
`1000 concentration.
`
`For this evaluation, photography, turbiscan and force to fire
`data (valve performance) was used to determine the optimum
`PEG concentration.
`
`Methodology—Force to Fire (Return Force at 0.5 mm Stem
`Return)
`Force to fire testing was performed using the Lloyd LRX
`testing machine. The pMDI unit to be tested was placed valve
`down in a can holder on the lower platform of the unit. The
`upper crosshead was then moved to just above the base of the
`can. Can actuations were performed using a standard proto-
`
`5
`niques have been described earlier. Samples with varying
`concentrations of PVP were analysed to determine suspen-
`sion stability over time.
`
`Photographic Analysis
`For the photographic analysis, samples were prepared in
`PET bottles and photographed digitally over time, using a
`black background. These photographs (some of which are
`shown here) show the behaviour of the suspension over time
`and allow easy comparison of the effectiveness ofthe various
`concentrations of PVP. The concentration ofPVP varied from
`
`0.0001 to 0.05% w/w. From left to right on the photographs
`the concentration of PVP is as follows:
`
`0.0001
`far left
`
`0.0005
`
`0.001
`
`0.01
`
`0.03
`
`0.05
`far right
`
`Digital Photography of Formulations Showing Degree of
`Dispersion Over Time
`FIGS. 9, 10 and 11 show Budesonide 160 ug/shot, Formot-
`erol 4.5 p.g/shot with various PVP K25 concentrations and
`0.3% PEG 1000 at 0, 30, and 60 seconds standing time.
`FIGS. 12, 13 and 14 shows Budesonide 80 pg/shot, For-
`moterol 4.5 p.g/shot with various PVP K25 concentrations
`and 0.3% PEG 1000 at 0, 30, and 60 seconds standing time.
`
`Table of Degree of Dispersion of Suspensions Over Time:
`(All Samples)
`Photographs were taken of all doses (320 p.g/4.5 p.g to 40
`p.g/4.5 pg) at 0, 15, 30, 60, 90 seconds, and 2, 5 and 10
`minutes. As this produced too many photographs to repro-
`duce here, a chart has been constructed to give a reprentation
`of the degree of dispersion over time.
`If the sample was fully suspended, the sample was rated 0
`e.g. at 0 minutes they were fully dispersed. From there, the
`samples have been rated in increments of 1-5 at 20% intervals
`to express the degree of dispersion i.e. 0 was fully suspended
`and 5 fully creamed. This allows some comparison across the
`whole dose range and PVP concentration range used.
`(Note concentration of Forrnoterol is 4.5 p.g/shot in all the
`samples)
`(Samples are all fully dispersed at 0 seconds and therefore all
`have a score of 0)
`Fully dispersed-0
`More than 80% dispersed ie less than 20% clear liquidpresent
`1
`
`More than 60% dispersed ie less than 40% clear liquidpresent
`2
`
`Less than 40% dispersed ie more than 60% clear liquid
`present 3
`Less than 20% dispersed ie more than 80% clear liquid
`present 4
`Fully creamed 5
`
`Table of Degree of Dispersion of Suspensions Over Time: All
`Samples
`
`Dose
`pg/shot
`Budesonide
`
`320
`
`Time
`Sec/mins
`
`PVP concentration % w/w
`0.0005
`0.001
`0.01
`0.03
`
`0.0001
`
`15
`30
`60
`
`2
`3
`4
`
`1
`3
`4
`
`0-1
`2
`3-4
`
`0-1
`1-2
`2
`
`0-1
`2
`3
`
`0.05
`
`0-1
`2
`3-4
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`20
`
`20
`
`

`
`US 7,759,328 B2
`
`7
`col. During measurement, force data is captured by means of
`the load cell located at the top of the upper crosshead. This
`program was designed to output the return force at 0.5 mm
`stem return as this is the point at which the metering chamber
`is considered to refill.
`
`A low return force is indicative of high friction and poten-
`tial sticking problems. It also suggests there may be a problem
`with low actuation weights as the propellant enters the meter-
`ing chamber more slowly and has time to vaporise. Force to
`fire testing was performed at preset actuations.
`
`Data
`Force to Fire Data
`FIG. 7 shows the effect ofPEG 1000 concentration on stem
`
`return force for the 4.5/160 p.g formoterol/budesonide
`formulation
`
`5
`
`10
`
`15
`
`This shows that at 120 actuations, the return force is greater
`for the 0.3% w/w PEG 1000 concentration than for the other
`
`20
`
`concentrations of 0.5% and 0.1%. In general, the higher the
`return force the lesser the chance of the Valve stem sticking.
`The above data shows that in this case 0.3% would be pre-
`ferred.
`
`Turbiscan Data
`
`The Turbiscan data (FIG. 8) shows that there is little dif-
`ference between the stability of suspensions made with vary-
`ing levels of PEG 1000 except for the 0.005% w/w level
`which was unsatisfactory.
`
`Photographic Analysis
`Digital photographs of suspensions containing Budes-
`onide, Formoterol, HFA 227, 0.001% w/w PVP and varying
`levels of PEG 1000 show little variation in suspension stabil-
`ity over time (0 seconds to 10 minutes) except for the 0.005%
`w/w PEG level (in agreement with the Turbiscan data).
`FIGS. 15 and 16 show Budesonide 80 pg/shot, Formoterol
`4.5 ug/shot with 0.001% PVP K25 and various concentra-
`tions of PEG 1000 at 0 (1) and 10 minutes (2) standing time
`
`Product Performance Data
`
`In addition to the above, product performance data for
`formulations containing formoterol
`fumurate dihydrate/
`budesonide at the following strengths, 4.5/80 mcg per actua-
`tion and 4.5/160 mcg per actuation, with 0.001% PVP K25
`and either 0.1% or 0.3% PEG 1000 were stable for up to 12
`months at 25° C./60% RH.
`
`Product Performance Data for Symbicort Formulations Con-
`taining 0.001% PVP K25 and 0.1% PEG 1000 in HFA-227
`
`Fine particle fraction (% cumulative
`undersize for 4.7 gm cut-of:
`
`Product strength
`(pg)
`(FFD/budesonide) Drug
`4.5/80
`Budesonide
`FFD
`Budesonide
`FFD
`
`4.5/160
`
`25° C./
`60% RH
`6 months
`52.8
`53.5
`48.8
`52.1
`
`25° C./
`60% RH
`12 months
`62.0
`59.7
`47.0
`51.3
`
`Initial
`51.3
`55.4
`50.0
`54.2
`
`8
`Product Performance Data for Symbicort Formulations Con-
`taining 0.001% PVP K25 and 0.3% PEG 1000 in IHFA-227
`
`Fine particle fraction (% cumulative
`undersize for 4.7 gm cut-of:
`
`Product strength
`(pg)
`(FFD/budesonide) Drug
`4.5/80
`Budesonide
`FFD
`Budesonide
`FFD
`
`4.5/160
`
`25° C./
`60% RH
`6 months
`50.6
`57.6
`50.2
`59.1
`
`25° C./
`60% RH
`12 months
`51.3
`58.7
`52.3
`61.2
`
`Initial
`55.8
`64.2
`48.7
`55.6
`
`The invention claimed is:
`
`1. A pharmaceutical composition comprising formoterol
`fumarate dihydrate, budesonide, 1,1,1,2,3,3,3-heptafluoro-
`propane (HFA227), PVP K25 (polyvinyl pyrrolidone with a
`nominal K-value of 25), and PEG-1000 (polyethylene glycol
`with an average molecular weight of 1,000), wherein the
`formoterol fumarate dihydrate is present at a concentration of
`0.09 mg/ml, the budesonide is present at a concentration in
`the range of 1 mg/ml to 8 mg/ml, the PVP K25 is present at a
`concentration of 0.001 % w/w, and the PEG-1000 is present at
`a concentration of 0.3% w/w.
`
`2. A pharmaceutical composition according to claim 1, in
`which the formoterol fumarate dihydrate is the R, R-enanti-
`omer.
`
`3. A pharmaceutical composition according to claim 1, in
`which the budesonide is the 22R-epimer.
`4. A method oftreating symptoms of a respiratory disorder,
`comprising administering to a patient the pharmaceutical
`composition according to claim 1, wherein the respiratory
`disorder is asthma, rhinitis, or chronic obstructive pulmonary
`disease (COPD).
`5. The method of claim 4, wherein the respiratory disorder
`is asthma.
`
`25
`
`30
`
`35
`
`40
`
`6. The method of claim 4, wherein the respiratory disorder
`is rhinitis.
`
`7. The method of claim 4, wherein the respiratory disorder
`is COPD.
`8. The method of claim 4, wherein the concentration of
`budesonide is 1 mg/ml.
`9. The method of claim 4, wherein the concentration of
`budesonide is 2 mg/ml.
`10. The method of claim 4, wherein the concentration of
`budesonide is 4 mg/ml.
`11. The method of claim 4, wherein the concentration of
`budesonide is 8 mg/ml.
`12. A pharmaceutical composition comprising formoterol
`fumarate dihydrate, budesonide, HFA227, PVP K25, and
`PEG-1000, wherein the formoterol fumarate dihydrate is
`present at a concentration of 0.09 mg/ml, the budesonide is
`present at a concentration of 1 mg/ml, the PVP K25 is present
`at a concentration of 0.001% w/w, and the PEG-1000 is
`present at a concentration of 0.3% w/w.
`13. A pharmaceutical composition comprising formoterol
`fumarate dihydrate, budesonide, HFA227, PVP K25, and
`PEG-1000, wherein the formoterol fumarate dihydrate is
`present at a concentration of 0.09 mg/ml, the budesonide is
`present at a concentration of 2 mg/ml, the PVP K25 is present
`at a concentration of 0.001% w/w, and the PEG-1000 is
`present at a concentration of 0.3% w/w.
`14. A pharmaceutical composition comprising formoterol
`fumarate dihydrate, budesonide, HFA227, PVP K25, and
`PEG-1000, wherein the formoterol fumarate dihydrate is
`
`45
`
`50
`
`55
`
`60
`
`65
`
`21
`
`21
`
`

`
`US 7,759,328 B2
`
`9
`present at a concentration of 0.09 mg/ml, the budesonide is
`present at a concentration of 4 mg/ml, the PVP K25 is present
`at a concentration of 0.001% W/W, and the PEG-1000 is
`present at a concentration of 0.3% W/W.
`15. A pharmaceutical composition comprising formoterol
`fumarate dihydrate, budesonide, HFA227, PVP K25, and
`
`10
`PEG-1000, wherein the formoterol fumarate dihydrate is
`present at a concentration of 0.09 mg/ml, the budesonide is
`present at a concentration of 8 mg/ml, the PVP K25 is present
`at a concentration of 0.001% W/W, and the PEG-1000 is
`present at a concentration of 0.3% W/W.
`*
`*
`*
`*
`*
`
`5
`
`22
`
`22
`
`

`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`CERTIFICATE OF CORRECTION
`
`PATENT NO.
`APPLICATION NO.
`
`: 7,759,328 B2
`: 10/502685
`
`DATED
`INVENTOR(S)
`
`: July 20, 2010
`: Nayna Govind and Maria Marlow
`
`Page 1 of 1
`
`It is certified that error appears in the above—identified patent and that said Letters Patent is hereby corrected as shown below:
`
`On the Title Page Item (56) Line 14 — Delete “Pipkom” and insert -- Pipkorn -- therefor.
`
`On the Title Page Item (56) Line 18 — Delete “Zettersttr6m” and insert -- Zetterstrém -- therefor.
`
`Signed and Sealed this
`
`Second Day of November, 2010
`
`David J. Kappos
`Director ofthe United States Patent and Trademark Oflice
`
`23
`
`23