PCT
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`WO 99/64014
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`(51) International Patent Classification 6 :
`A61K 31/57 II (A61K 31/57, 31:165)
`
`(11) International Publication Number:
`
`Al
`
`(43) International Publication Date:
`
`16 December 1999 (16.12.99)
`
`(21) International Application Number:
`
`PCT/SE99/01031
`
`(22) International :Filing Date:
`
`10 June 1999 (10.06.99)
`
`(30) Priority Data:
`9802073-8
`
`11 June 1998 (11.06.98)
`
`SE
`
`(71) Applicant (for all designated States except US): ASTRA
`AKTIEBOLAG [SE/SE]; S-151 85 S5dertillje (SE).
`
`(81) Designated States: AE, AL, AM, AT, AU, AZ, BA, BB, BG,
`BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, Fl, GB,
`GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG,
`KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK,
`MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI,
`SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA,
`ZW, ARIPO patent (GH, GM, KE, LS, MW, SD, SL, SZ,
`UG, ZW), Eurasian patent (AM, AZ, BY, KG,. KZ, MD,
`RU, TJ, TM), European patent (AT, BE, CH, CY, DE, DK,
`ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI
`patent (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR,
`NE, SN, TD, TG).
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only):
`EKSTROM, Tommy
`[SE/SE]; Astra Draco AB, P.O. Box 34, S-221 00 Lund Published
`With international search report.
`(SE).
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of the receipt of
`amendments.
`
`(74) Agent: ASTRA AKTIEBOLAG; Intellectual Property, Patents,
`S-151 85 S5dertalje (SE).
`
`(54) Title: USE OF A COMPOSITION COMPRISING FORMOTEROL AND BUDESONIDE FOR THE PREVENTION OR TREAT(cid:173)
`MENT OF AN ACUTE CONDITION OF ASTHMA
`
`(57) Abstract
`
`The present invention relates to use of a composition for symptomatic relief, when needed, comprising, in admixture (a) a first active
`ingredient which is formoterol, a pharmaceutically acceptable salt or solvate thereof or a solvate of such a salt; and (b) a second active
`ingredient which is budesonide; for the manufacture of a medicament for use in the prevention or treatment of an acute condition of asthma
`and/or intermittent asthma and/or episodes in chronic asthma. The invention further relates to a method for prevention or treatment of
`an acute condition of asthma and/or intermittent asthma and/or episodes in chronic asthma by administering, by inhalation, a composition
`comprising the first and second active ingredients as defined previously.
`
`Complex Ex. 1006
`
`1
`
`

`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`cu
`CZ
`DE
`DK
`EE
`
`Albania
`Annenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Cbte d'Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Gem1any
`Denmark
`Estonia
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People's
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`SI
`SK
`SN
`sz
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`us
`uz
`VN
`YU
`zw
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
`
`2
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`

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`WO 99/64014
`
`PCT/SE99/01031
`
`USE OF A COMPOSITION COMPRISING FORMOTEROL AND BUDESONIDE FOR THE PREVENTION OR TREAT(cid:173)
`MENT OF AN ACUTE CONDITION OF ASTHMA
`
`FIELD OF THE INVENTION
`
`s The present invention relates to use of a composition for symptomatic relief. when needed,
`
`comprising, in admixture
`
`(a) a first active ingredient which is formoterol. a pharmaceutically acceptable salt
`
`or solvate thereof or a solvate of such a salt; and
`
`(b) a second active ingredient which is budesonide:
`
`10
`
`for the manufacture of a medicament for use in the prevention or treatment of an acute
`
`condition of asthma and/or intermittent asthma and/or episodes in chronic asthma. The
`
`invention further relates to a method for prevention or treatment of an acute condition of
`
`asthma and/or intermittent asthma and/or episodes in chronic asthma by administering, by
`
`inhalation, a composition comprising the first and second active ingredients as defined
`
`15
`
`previously.
`
`BACKGROUND OF THE L'iVENTION
`
`Despite recent advances in the awareness of asthma and the introduction of powerful and
`
`10
`
`effective anti-asthma drugs, asthma remains a poorly understood and frequently poorly
`
`treated disease. There have been recent advances in the treatment of the disease which
`
`result from the recognition that asthma is a chronic inflammatory disease. Therapy is now
`
`aimed at both controlling the symptoms and reducing the inflammation. The symptoms
`
`may be controlled by 0:-adrenoceptor agonises such as terbutaline. salbutamol. formoterol
`
`2s
`
`and salmeterol. Prophylactic therapy is typically provided by steroids such as beclometha(cid:173)
`
`sone dipropionate, fluticasone propionate, mometasone furoate and budesonide.
`
`In spite of modern maintenance treatment too many asthmatic patients are undenreated for
`
`a number of reasons with a negative impact on their quality of life. Too complicated
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`30
`
`therapy with different medications and devices may lead to misunderstanding and commu~
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`3
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`

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`WO 99/64014
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`PCT/SE99/0l031
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`j
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`nication problems between patient and doctor. Poor compliance is a common phenomenon.
`
`Improved patient education may partly counteract this. but does not completely solve the
`
`problem. A new and more simple approach to asthma treatment could thus be of tremen(cid:173)
`
`dous help for many patients suffering from respiratory disease, particularly asthma. The
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`5
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`combination of budesonide and formoterol in the same device as suggested in PCT
`
`applications WO 93/11773 and WO 98/15280 (both to Astra AB of Sweden) offers a
`
`favorable pathway to improve today's asthma management with an excellent safety profile.
`
`However, although having an adequate regular. e.g. bid. treatment with such acombina(cid:173)
`
`tion, many patients will now and then nm into acute situations with a higher frequency and
`
`10
`
`severity of exacerbations, when additional medication is needed. Such an additional
`
`medication is often a ~2-adrenoceptor agonise with fast onset, normally terbutaline or
`
`salbutamol. A second medicament is thus needed. and this can negatively affect the overall
`
`compliance of the patient. There is thus need for a neat way of handling maintenance
`
`treatment together with the treatment of acute situations which .
`
`15
`
`SUMMARY OF THE DJVENTION
`
`It is an object of the present invention to provide use of a suitable composition for the
`
`manufacture of a medicament for the treatment of acute episodes of asthma as a
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`20
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`complement to maintenance treatment.
`
`More specifically, according to the invention there is provided use of a composition for
`
`symptomatic relief when needed comprising, in admixture
`
`(a) a first active ingredient which is formoterol. a pharmaceutically acceptable salt
`
`25
`
`or solvate thereof or a solvate of such a salt: and
`
`(b) a second active ingredient which is budesonide;
`
`for the manufacture of a medicament for use in the prevention or treatment of an acute
`
`condition of asthma and/or intermittent asthma and/or episodes in chronic asthma.
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`4
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`

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`PCT/SE99/01031
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`3
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`Use of the present composition, when needed. relates to use of said composition during one
`
`or more of the following conditions:
`
`i) an acute condition of asthma, i.e. acute asthma attacks,
`
`ii) intermittent asthma and/or
`
`s
`
`iii) short periods (episodes) of acute attacks of bronchospasms in chronic asthma.
`
`Acute asthma attacks may occur on an irregular basis when exposed to an agent e.g. during
`
`the pollen season. a virus infection, cold air, perfumes or any other agent(s) triggering an
`
`asthma attack in the patient.
`
`IO
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`It lies within the scope of the present invention. to use the compositions comprising active
`
`compounds (a) and (b) for treating acute conditions of asthma. intermittent asthma and
`
`episodes in chronic asthma, in addition to treating chronic asthma on a regular basis, with
`
`the same active compounds (a) and (b) or one or more different active compounds,
`
`1s
`
`preferably selected from short-acting ~-agonises, long-acting ~-agonists and
`
`glucocorticosteroids.
`
`We contemplate preventive use when the patient expects to encounter asthma inducing
`
`conditions e.g. intends to take exercise or go into smoky conditions.
`
`20
`
`According to a further aspect of the invention a method of prevention or treatment of an
`
`acute condition of asthma and/or intermittent asthma and/or episodes in chronic asthma,
`
`when needed, which comprises administering, by inhalation. to a patient an effective
`
`amount of a composition comprising, in admixture:
`
`2s
`
`(a)
`
`a first active ingredient which is formoterol, a pharmaceutically acceptable salt or
`
`solvate thereof or a solvate of such a salt: and
`
`(b) a second active ingredient which is budesonide.
`
`According to the present invention it has surprisingly been found that the medicament can
`
`JO
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`be administered when needed to a patient with an acute attack of asthma.
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`5
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`PCT/SE99/01031
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`4
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`The recommended dose regimen described in the prior an as disclosed above is twice a
`
`day. This dose recommendation was :.i result of a concern not to have too high an admini(cid:173)
`
`stration of the active compounds. However. in the present invention it has been found that
`
`5
`
`it is possible for the patient to administer this mixture as often as needed.
`
`The combination of formoterol and budesonide can be used as a rescue medication.
`
`Worsening of symptoms can be counteracted by incremental use of the combination for
`
`symptom relief. e.g. during exacerbations with the additional steroid component coming in
`
`10
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`as early as possible to suppress the enhanced airway inflammation. The long duration of
`
`formoterol will reduce the risk of too frequent dosing. When taking the combination
`
`budesonide/formoterol when needed the severity of exacerbations can be reduced. The as
`
`needed use (Pro Re Nata. PRN) will also minimize the difficulty of predicting which
`
`patients will be controlled on a low dose of inhaled steroid rather than increasing the
`
`1s
`
`steroid dose before adding a long-:.icting ~2-agonist. Under-treatment with inhaled
`
`glucocorticosteroids following a too low maintenance dose will be more or less "self(cid:173)
`
`corrected" by the rescue usage according to the present invention. The PR.'\ use of the
`
`combination will always give some beneficial anti-inflammatory effects even if it is used
`
`by the patient only for rescue purposes. A treatment for patients suffering from respiratory
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`20
`
`disease, particularly asthma ( including allergic conditions, e.g. episodic or intermittent
`
`asthma), will therefore be to use the combination formoterol/budesonide for maintenance
`
`therapy as well as on an as needed basis (for rescue purposes), e.g. for prevention of
`
`exercise and/or allergen induced asthma.
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`6
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`

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`WO 99/64014
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`PCT/SE99/01031
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`5
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`DETAILED DESCRIPTION OF THE INVENTION
`
`Formoterol is a compound which can exist in several stereochemical forms. The present
`
`invention includes the individual stereoisomers as well as mixtures thereof. It is intended
`
`s
`
`that the present invention includes geometrical isomers, rotational isomers, racemates.
`
`diastereomers and enantiomers, in particular the R.R enantiomer of formoterol.
`
`Suitable physiologically salts of formoterol include acid addition salts derived from
`
`inorganic and organic acids such as the hydrochloride. hydrobromide, sulfate. phosphate,
`
`10 maleate. fumarate, tartrate. citrate. benzoate. 4-methoxybenzoate. 2- or 4-hydroxybenzoate,
`
`4-chlorobenzoate, p-toluenesulphonate. methanesulphonate, ascorbate. salicylate. acetate.
`
`succinate. lactate. glutarate. gluconate, tricarballylate, hydroxy-naphthalene-carboxylate or
`
`oleate. Formoterol is preferably used in the form of its fumarate salt and as a dihydrate of
`
`this salt.
`
`IS
`
`The present invention also encompasses compositions comprising the 22R epimer of
`
`budesonide as the second active ingredient.
`
`A suitable unit dose of formoterol (as fumarate di hydrate) is in the range of from l ,ug to 48
`
`20
`
`µg, preferably from 2 µg to 24 µg, and more preferably between 3 µg and 12 µg. The daily
`
`dose of formoterol (as furnarate dihydrate). including maintenance therapy, should be in the
`
`range of from 1 µg to l 00 µg, preferably from 2 µg to 60 µg, and more preferably from 3
`
`µg to of 48 µg.
`
`2s
`
`A suitable unit dose of budesonide is in the range of from 20 µg to 1600 µg, suitably from
`
`30 µg to 800 µg, preferably from 50 µg to -+00 µg, and more preferably between 100 µg
`
`and 200 µg. The daily dose of budesonide. including maintenance therapy, should be in the
`
`range of 20 µg to 4800 µg, preferably from 30 µg to 3200 µg, and more preferably from 40
`
`µg to 1600 µg. The particular dose regimen will depend on the patient (age, sex, weight
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`Jo
`
`etc.) and the severity of the disease ( mild. moderate, severe asthma etc. l.
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`7
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`6
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`The molar ratio of the first active ingredient (as formoterol) to the second active ingredient
`
`of the invention. suitably lies in the range of from 1: 1 to 1: 100, preferably from 1: 1 to 1 :70,
`
`and more preferably from 1: 1 to 1 :50.
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`5
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`Preferably the mixture comprises one or more pharmaceutically acceptable additives,
`
`diluents or carriers, more preferably in an amount of from 50 µg to 4000 µg in each dose.
`
`most preferably in an amount of from 100 µg to 2000 µg and most preferably from 100 µg
`
`to 1000 µg. Examples of suitable additives, diluents or carriers include lactose. dextran.
`
`10 mannitol or glucose. Preferably lactose is used, and more preferably as the monohydrate.
`
`One or more of the ingredients of the mixture may be in the form of dry powder. more
`
`preferably a small particle dry powder, most preferably an agglomerated small particle dry
`
`powder. Alternatively one or more of the active ingredients (a) or (b) are in the form of an
`
`1s
`
`ordered mixture with diluent, additive or carrier. The ingredients used in the invention can
`
`be obtained in these preferred forms using methods known to those skilled in the art. The
`
`particle size of the active ingredients is preferably less than 10 µm.
`
`Administration may be by inhalation orally or intranasally. The ingredients of the system
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`20
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`are preferably adapted to be administered from a dry powder inhaler. a pressurized metered
`
`dose inhaler. or a nebulizer.
`
`When the ingredients of the system are adapted to be administered from a pressurized
`
`inhaler, they are preferably in a smali particle form. They are dissolved, or. preferably.
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`25
`
`suspended in a liquid propellant mixture. The propellants which can be used include
`
`chlorofluorocarbons. hydrocarbons or hydrofluorocarbons. Especially preferred propellants
`
`are PI34a (tetrafluoroethane), P152a (difluoroethane) and P227 (heptafluropropane) each
`
`of which may be used alone or in combination. They are optionally used in combination
`
`with one or more other propellants and/or one or more surfactants and/or one or more other
`
`30
`
`excipients, for example ethanol. a lubricant. an antioxidant and/or a stabilizing agent.
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`8
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`

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`WO 99/64014
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`PCT/SE99/01031
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`7
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`When the ingredients of the system of the invention are adapted to be administered via a
`
`nebulizer they may be in the form of a nebulized aqueous suspension or solution, with or
`
`without suitable pH or tonicity adjustment. either as a unit dose or multidose formulation.
`
`EXAMPLES
`
`The ingredients can be formulated as illustrated by the following examples which are not
`
`intended to limit the scope of the invention.
`
`In the examples micronization is carried out in a conventional manner such that the particle
`
`size range for each component is suitable for administration by inhalation. Turbuhale? is a
`
`trademark of Astra AB.
`
`EXANIPLE 1
`
`5
`
`10
`
`15
`
`4.5 Parts by weight of formoterol fumarate dihydrate were mixed with 915 parts by weight
`
`of lactose monohydrate. The blend was micronized using a high pressure air jet mill and
`
`then conditioned using the process of EP-A-717 616. 80 Parts by weight of micronized
`
`20
`
`budesonide were added to the conditioned product by mixing and homogenizing with a low
`
`pressure jet mill. The mixture was then spheronized using the process of EP-A-721 331
`
`and filled into the storage compartment of Turbuhaler. ~
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`25
`
`EXANIPLE 2
`
`9 Parts by weight of formoterol fumarate dihydrate were mixed with 831 parts by weight of
`
`lactose monohydrate. The blend was micronized using a high pressure air jet mill and then
`
`conditioned using the process of EP-A-717 616. 160 Parts by weight of micronized bude(cid:173)
`
`sonide were added to the conditioned product by mixing and homogenizing with a low
`
`9
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`

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`W099/640I4
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`PCT/SE99/01031
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`8
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`pressure jet mill. The mixture was then spheronized using the process of EP-A-721 331
`
`and filled into the storage compartment of Turbuhaler. ,~
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`5
`
`EXAMPLE3
`
`6 Parts by weight of forrnoterol fumarate dihydrate were mixed with 894 parts by weight of
`
`lactose monohydrate. The blend was micronized using a high pressure air jet mill and then
`
`conditioned using the process of EP-A-717 616. 100 Parts by weight of micronized bude(cid:173)
`
`sonide were added to the conditioned product by mixing and homogenizing with a low
`
`10
`
`pressure jet mill. The mixture was then spheronized using the process of EP-A-7'21 331
`
`and filled into the storage compartment of Turbuhaler.
`
`EXAMPLE4
`
`1s
`
`12 Parts by weight of fonnoterol fumarate dihydrate were mixed with 788 parts by weight
`
`of lactose monohydrate. The blend was micronized using a high pressure air jet mill and
`
`then conditioned using the process of EP-A-717 616. 200 Parts by weight of micronized
`
`budesonide were added to the conditioned product by mixing and homogenizing with a low
`
`pressure jet mill. The mixture was then spheronized using the process of EP-A-721 331
`
`20
`
`and filled into the storage compartment of Turbuhaler."
`
`EXAMPLES
`
`A patient on maintenance treatment with the fixed combination formoterol fumarate
`
`2s
`
`dihydrate/budesonide in a dose of 4.5/80 µg or 4.5/ 160 µg bid additionally uses the same
`
`combination either for rescue purposes once or twice daily to treat sporadic breakthrough
`
`symptoms, or as needed to treat exacerbations during one or two weeks, with a maximum
`
`daily dose of 36/640 µg (8 puffs of 4.5/80 µg) and 36/1280 µg (8 puffs of 4.5/160 µg).
`
`respectively.
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`30
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`10
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`9
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`EXAMPLE 6
`
`A patient with intermittent asthma uses the fixed combination formoterol fumarate
`
`dihydrate/budesonide as sole medication to be taken as needed until the asthma resolves.
`
`s The highest recommended daily dose will be either 36/640 µg (8 puffs of 4.5/80 µg) or
`
`36/1280 µg (8 puffs of 4.5/160 µg) for a period not exceeding 8-120 weeks. If symptoms
`
`still persist after that period of time - regular maintenance therapy should be considered.
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`10
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`CLAIMS
`
`l.
`
`Use of a composition for symptomatic relief, when needed, comprising, in
`
`admixture
`
`5
`
`(a) a first active ingredient which is formoterol, a pharmaceutically acceptable salt
`
`or solvate thereof or a solvate of such a salt; and
`
`(b) a second active ingredient which is budesonide;
`
`for the manufacture of a medicament for use in the prevention or treatment of an acute
`
`condition of asthma and/or intermittent asthma and/or episodes in chronic asthma.
`
`10
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`2.
`
`Use according to claim 1, wherein the molar ratio of (a) to (b) calculated as
`
`formoterol to budesonide is from 1: 1 to 1: l 00, preferably from 1: 1 to 1:70.
`
`3.
`
`Use according to claim 1 or 2, wherein the first active ingredient is formoterol
`
`t5
`
`fumarate dihydrate.
`
`4.
`
`Use according to any previous claim, wherein the first active ingredient is the R,R
`
`enantiomer of formoterol.
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`20
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`5.
`
`Use according to any previous claim, wherein a unit dose of formoterol lies in the
`
`range of from 1 µg to 48 µg, preferably between 3 µg to 12 µg, calculated as formoterol
`
`fumarate dihydrate.
`
`6.
`
`Use according to any previous claim, wherein the daily dose of formoterol,
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`25
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`including maintenance therapy, lies in the range of from 1 µg to 100 µg, preferably from 2
`
`µg to 60 µg, calculated as formoterol fumarate dihydrate.
`
`7.
`
`Use according to any previous claim, wherein the second active ingredient is the
`
`22R epimer of budesonide.
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`30
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`12
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`11
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`8.
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`Use according to any previous claim, wherein a unit dose of budesonide lies in the
`
`range of from 20 µg to 1600 µg, preferably between 50 µg to 400 µg.
`
`9.
`
`Use according to any previous claim, wherein the daily dose of budesonide,
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`5
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`including maintenance therapy, lies in the range of from 20 µg to 4800 µg, preferably from
`
`30 µg to 3200 µg.
`
`10.
`
`Use according to any previous claim, wherein the particle size of the active
`
`ingredients ( a) and (b) is less than 10 µm.
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`10
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`11.
`
`Use according to any previous claim, wherein the composition additionally
`
`comprises one or more pharmaceutically acceptable additives, diluents or carriers.
`
`12.
`
`Use according to claim 1 L wherein the pharmaceutically acceptable additive,
`
`15
`
`diluent or carrier is lactose monohydrate.
`
`13.
`
`A method of prevention or treatment of an acute condition of asthma and/or
`
`intermittent asthma and/or episodes in chronic asthma, when needed, which comprises
`
`administering, by inhalation, to a patient an effective amount of a composition comprising,
`
`20
`
`in admixture:
`
`(a)
`
`a first active ingredient which is formoterol, a pharmaceutically acceptable salt or
`
`solvate thereof or a solvate of such a salt; and
`
`(b)
`
`a second active ingredient which is budesonide.
`
`25
`
`14.
`
`The method according to claim 13, wherein the molar ratio of (a) to (b) calculated
`
`as formoterol to budesonide is from 1: 1 to 1: 100, preferably from l: 1 to 1:70.
`
`15.
`
`The method according to claim 13 or 14, wherein the first active ingredient is
`
`farmoterol fumarate dihydrate.
`
`30
`
`13
`
`

`
`WO 99/64014
`
`PCT/SE99/01031
`
`12
`
`16.
`
`The method according to any of claims 13 to 15, previous claim, wherein the first
`
`active ingredient is the R,R enantiomer of formoterol.
`
`17.
`
`The method according to any of claims 13 to 16, wherein a unit dose of formoterol
`
`5
`
`lies in the range of from 1 µg to 48 µg, preferably between 3 µg to 12 µg, calculated as
`
`formoterol fumarate dihydrate.
`
`18.
`
`The method according to any of claims 13 to 17, wherein the daily dose of
`
`formoterol, including maintenance therapy, lies in the range of from 1 µg to 100 µg,
`
`10
`
`preferably from 2 µg to 60 µg, calculated as formoterol fumarate dihydrate.
`
`19.
`
`The method according to any of claims 13 to 18, wherein the second active
`
`ingredient is the 22R epimer of budesonide.
`
`15
`
`20.
`
`The method according to any of claims 13 to 19, wherein a unit dose of budesonide
`
`lies in the range of from 20 µg to 1600 µg, preferably between 50 µg to 400 µg.
`
`21.
`
`The method according to any of claims 13 to 20, wherein the daily dose of
`
`budesonide. including maintenance therapy, lies in the range of from 20 µg to 4800 µg,
`
`20
`
`preferably from 30 µg to 3200 µg.
`
`22.
`
`The method according to any of claims 13 to 21, wherein the particle size of the
`
`active ingredients ( a) and (b) is less than 10 µm.
`
`25
`
`23.
`
`The method according to any of claims 13 to 22, wherein the composition
`
`additionally comprises one or more pharmaceutically acceptable additives, diluents or
`
`carriers.
`
`24.
`
`The method according to claim 23, wherein the pharmaceutically acceptable
`
`30
`
`additive, diluent or carrier is lactose monohydrate.
`
`14
`
`

`
`1
`INTER.i'IATlONAL SEARCH REPORT
`
`--International application No.
`
`PCT/SE 99/01031
`
`A. CLASSIFICATION OF SUBJECT MATIER
`
`IPC6: A61K 31/57 // ~A61K 31/57, 31:165)
`According to International Patent
`Jassification (IPC) or to both national classification and !PC
`
`B. FIELDS SEARCHED
`
`Minimum documentation searched (classification system followed by classification symbols)
`
`IPC6: A61K
`Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
`SE,DK,FI,NO classes as above
`
`Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)
`
`C. DOCUMENTS CO:\SIDERED TO BE RELEVANT
`
`Category• Citation of document, with indication, where appropriate, of the relevant passages
`
`Relevant to claim No.
`
`X
`
`X
`
`WO 9311773 Al (AKTIEBOLAGET ASTRA), 24 June 1993
`(24.06.93), See page 1409 - page 1410
`--
`The New England Journal of Medicine, Volume 337,
`No 20, November 1997, Romain A. Pauwels et al,
`"Effect of Inhaled Formoterol and Budesonide on
`Exacerbations of Asthma" page 1405 - page 1411
`--
`--------
`
`1-24
`
`1-24
`
`D Further documents are listed in the continuation of Box C.
`
`[] See patent family annex.
`
`*
`SpeCJal categories of Cited documents:
`"A" document defining the general state of the art wluch 1s not considered
`to be of particular relevance
`"E" erher document but pubhshed on or after the mtemaoonal filing date
`"L" document which may throw doubu on pnonty clrum(s) or which is
`cited to establish the pubhcation date of another CJtallon or other
`.special rea~on (a~ .specified)
`·o· document referring to an oral disclosure, use, exlub1llon or other
`means
`•p• document published prior to the international filing date but later than
`the prionty date claimed
`
`"T"
`
`later document pubhshed after the internauonal filing date or pnonty
`date and not m conflict with the application but Cited to understand
`the pnnCJple or theory underlying the invention
`
`"X'' document of particular relevance: the claimed invention cannot be
`considered novel or cannot be considered to involve an mvenove
`step when the document 1s taken alone
`"Y" document of particular relevance: the claimed invention cannot be
`conSJdered to involve an inventive step when the document is
`combined with one or more other such documents, such combination
`being obvious to a person skilled in the art
`"&" document member of the same patent family
`
`Date of the actual completion of the international search
`
`Date of mailing of the international search report
`
`20 Sent 1999
`Name and mailing address of the ISA,'
`Swedish Patent Office
`Box 5055, S-102 42 STOCKHOLM
`Facsimile No. + 46 8 666 02 86
`Form PCT/ISA/210 (second sheet) (July 1992)
`
`1 1 -10- 1999
`
`I
`
`Authorized officer
`
`Anna Sjolund/Els
`Telephone No. +46 8 782 25 00
`
`15
`
`

`
`- INTERNATIONAL SEARCH REPORT
`
`International !lpplication No.
`PCT/SE99/01031
`
`Box I
`
`Observations where certain claims were found unsearchable (Continuation of item 1 of first sheet)
`
`This international search report has not been established in respect of certain claims under Article l 7(2Xa) for the following reasons:
`
`I.
`
`l2SJ Claims Nos.: 13-24
`because they relate to subject matter not required to be searched by this Authority, namely:
`see next sheet
`
`i. D
`
`Claims Nos.:
`because they relate to parts of the international application that do not comply with the prescribed requirements to such
`an extent that no meaningful international search can be carried out, specifically:
`
`Box II
`
`Observations where unity ofinvention is lacking (Continuation ofitem 2 of first sheet)
`
`This International Searching Authority found multiple inventions in this international application, as follows:
`
`i. D
`2. D
`3. D
`
`As all required additional search fees were timely paid by the applicant, this international search report covers all
`searchable claims.
`
`As all searchable claims could be searched without effort justi(ying an additional fee, this Authority did not invite payment
`of any additional fee.
`
`As only some of the required additional search fees were tin1ely paid by the applicant, this international search report
`covers only those claims for \Vhich fees were paid, specifically claims Nos.:
`
`4. D
`
`No required additional search fees were timely paid by the applicant. Consequently, this international search report is
`restricted to the invention first mentioned in the claims; it is covered by claims Nos.:
`
`Remark on Protest
`
`D · The additional search fees were accompanied by the applicant's protest.
`O No protest accompanied the payment of additional search fees.
`Fonn PCT/ISA/210 (contmuallon of first sheet (1)) (Julyl992)
`
`16
`
`

`
`- INTERNATIONAL SEARCH REPORT
`
`International application No.
`PCT/SE99/01031
`
`Claims 13-24 relate to methods of treatment of the human or animal
`body by surgery or by therapy/diagnostic methods practised on the
`human or animal body/Rule 39.1. (iv). Nevertheless, a search has
`been executed for these claims. The search has been based on the
`alleged effects of the compounds/compositions.
`
`fonn PCT/ISA/210 (e>..1ra sheet) (Julyl992)
`
`17
`
`

`
`30/08/99
`
`Patent family
`member(s)
`
`673660 B
`3085892 A
`2123909 A
`9401434 A
`0613371 A
`921445 A
`75156 A
`9401843 D
`7502036 T
`942116 A
`246050 A
`48301 A
`73394 A
`5674860 A
`
`International ~pplication No.
`PCT/SE 99/01031
`I
`
`Publication
`date
`21/11/96
`19/07/93
`24/06/93
`15/12/94
`07/09/94
`31/12/94
`28/04/97
`00/00/00
`02/03/95
`07/06/94
`21/12/95
`17/04/98
`08/03/95
`07/10/97
`
`INTERNATIONAL SEARCH REPORT
`Information on patent family members
`
`Patent document
`cited in search report
`WO
`
`9311773 Al
`
`I
`
`Publication
`date
`24/06/93
`
`I
`
`AU
`AU
`CA
`CZ
`EP
`HR
`HU
`HU
`JP
`NO
`NZ
`SG
`SK
`us
`
`Form PCT/ISA/210 (patent family annex) (July 1992)
`
`18