United States Patent [191
`Carling et a1.
`
`[11] Patent Number:
`[45] Date of Patent:
`
`l|| lllll |l||||||
`
`“
`
`‘ USOO5674860A
`
`ll llll lllllll lllllllll llll lllll ||| llllll
`5,674,860
`Oct. 7, 1997
`
`[54] COMBINATION OF A BRONCHODILATOR
`AND A STEROIDAL ANTI-INFLAMMATORY
`DRUG FOR THE TREATMENT OF
`RESPIRATORY DISORDERS
`
`[75] Inventors: Christer Carl Gustav Carling. Dalby;
`Jan William 'lrot'ast. Lund. both of
`Sweden
`
`[73] Assignee: Astra Aktiebolag. Sodertalje. Sweden
`
`[21] Appl. N0.: 317.407
`[22] Filed:
`Oct. 3, 1994
`
`Related US. Application Data
`
`[63] Continuation of Ser. No. 992,089, Dec. 17, 1992, aban
`doned.
`Foreign Application Priority Data
`[30]
`Dec. 18, 1991 [EP]
`European Pat O?'.
`
`91311761
`
`[51] Int. C16 ....................... .. A61K 31/56; A61K 31/135
`[52] US. Cl.
`514/171; 514/174; 514/653;
`514/826
`514/171. 174.
`514/653. 826
`
`[58] Field of Search
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`Bond. New Zealand Medical Journal. p. 369. Aug. 28. 1991.
`Dahl. et al.. J. Allergy Clin. Immunol. 83. 811-815 (1989).
`Dal Negro. et al.. Current Therapeutic Research 35. 561-565
`(1984).
`Wallin. et al.. Thorax 45. 259-261 (1990).
`Lorentzen. et al.. Thorax 45. 733-735 (1990).
`Ebden. et al.. Thorax 41. 869-874 (1986).
`Morris. et al.. J. Allergy Clin. Immunol. 75. 1-14 (1985).
`Holst. et al.. New Zealand Medical Journal 79. 769-773
`(1974).
`Morris. et al.. Chest 88. 1338-1418 (1985).
`Flenley. Respiration 55. 4-9 (1989).
`Lurie. et al.. Lung Suppl.. 154-167 (1990).
`Paterson. et al.. Am. Rev. Resp. Dis. 120. 1149-1188 (1979).
`O’Loughlin. Postgraduate Medicine 82. 231-238 (1987).
`Sta?ord. Postgraduate Medicine 84. 85-98 (1988).
`Lacronique. et al.. Rev. Mal. Resp. 6. 15-30 (1989).
`Quaglia. et al.. Folia Allergol. Immunol. Clin. 24. 318-327
`(1977).
`Jean H. Marsac. “Inhaled beta agonists and inhaled steroids
`in the treat of asthma”. Ann. of Allmgy. 63(3). Sep. 1989.
`pp. 220-224.
`Nils Svedmyr. “The current place of beta agonists in the
`mngmt. of asthma”. Lung (USA). 168 no. supp. 1990. NY
`pp. 105-110.
`
`.. 514/174
`
`.. 564/170
`
`Primary Examiner-Raymond Henley. 111
`Attorney Agent, or Firm-White & Case
`
`[57]
`
`ABSTRACT
`
`
`
`3,983,233 3,994,974 11/1976 Murakami et a1. .... .. 9/1976 Brattsand et al.
`
`
`
`FOREIGN PATENT DOCUMENTS
`
`0416950 3/1991 European Pat. 01f. .
`0416951
`3/1991 European Pat. Oil. .
`
`UI‘ HER PUBLICATIONS
`
`Marsac. et al.. Annals of Allergy 63. 220-224 (1989).
`Maesen. et al.. Chest 97. 590-594 (1990).
`McDonald. et al.. Current Medical Research and Opinion 11.
`116-122 (1988).
`
`Effective amounts of formoterol and/or a physiologically
`acceptable salt and/or solvate thereof and budesonide are
`used in combination for simultaneous. sequential or separate
`administration by inhalation in the treatment of an in?am
`matory respiratory disorder. such as asthma.
`
`36 Claims, No Drawings
`
`Complex Ex. 1005
`
`1
`
`

`
`1
`COMBINATION OF A BRONCHODILATOR
`AND A STEROIDAL ANTI-INFLAMMATORY
`DRUG FOR THE TREATMENT OF
`RESPIRATORY DISORDERS
`
`This application is a continuation of application Ser. No.
`07/992089 ?led Dec. 17. 1992 now abandoned.
`
`FIELD OF THE INVENTION
`
`This invention relates to improvements in the treatment of
`mild as well as severe asthma and other respiratory disor
`ders. More particularly. it relates to the use of a bronchodi
`lator in combination with a steroidal anti-in?ammatory drug
`for the treatment of respiratory disorders such as asthma. and
`to pharmaceutical compositions containing the two active
`ingredients. It emphasizes the use of a long-acting bron
`chodilator which provides rapid relief of symptoms.
`
`15
`
`BACKGROUND OF THE INVENTION
`There have recently been signi?cant advances in our
`understanding of asthma. Despite many advances. both in
`awareness of the disease by doctors and patients alike,
`coupled with the introdction of very powerful and effective
`anti-asthma drugs. asthma remains a poorly understood and
`often poorly treated disease. Previously. contraction of air
`way smooth muscles has been regarded as the most impor
`tant feature of asthma. Recently there has been a marked
`change in the way asthma is managed. stemming from the
`fact that asthma is recognized as a chronic in?ammatory
`disease. Uncontrolled airway in?ammation may lead to
`mucosal damage and structural changes giving irreversible
`narrowing of the airways and ?brosis of the lung tissue.
`Therapy should therefore be aimed at controlling symptoms
`so that normal life is possible and at the same time provide
`basis for treating the underlying in?ammation.
`The most common cause for poor control of asthma is
`poor compliance with the long-term management of chronic
`asthma. particularly with prophylactic treatments. such as
`inhaled steroids. which do not give immediate symptom
`relief. Patients will readily take BZ-agonist inhalers. since
`these provide rapid relief of symptoms. but otten do not take
`prophylactic therapy. such as inhaled steroids. regularly
`because there is no immediate symptomatic bene?t. They
`also counteract down regulation of liz-adrenoceptor ago
`nists.
`Formoterol. (N-[2-hydroxy-5-[l-hydroxy-2-[[2-(4
`methoxyphenyb-l-rnethylethyl]aminolethy?phenyl]
`formamide). is an adrenoceptor agonist which selectively
`stimulates ?z-receptors. thus producing relaxation of bron
`chial smooth muscle. inhibition of the release of endogenous
`spasmogens. inhibition of oedema caused by endogenous
`mediators. and increased mucociliary clearance. Inhaled
`formoterol fumarate acts rapidly. usually within minutes
`which gives the patient immediate con?rmation that he has
`taken an adequate dose and thereby avoiding overdosing of
`both B-agonist and steroid. Inhaled formoterol also exerts a
`prolonged bronchodilation. which in clinical trials has been
`demonstrated as up to 12 hours.
`Budesonide. (16. l7-butylidenebis(oxy)- ll.
`2 l-dihydroxypregna-1.4-dieue-3.20-dione). may be given in
`a high inhaled dose (up to 2 mg daily) with very low
`systemic e?’ects. possibly because of its rapid metabolism.
`The high rapid systemic elimination of budesonide is due to
`extensive and rapid hepatic metabolism. Long term clinical
`studies have shown that inhaled budesonide is a pharmaco
`logically safe drug. High doses of inhaled budesonide are
`
`25
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`35
`
`45
`
`50
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`55
`
`5,674,860
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`2
`highly effective and well tolerated when used in oral steroid
`replacement therapy. Budesonide represents a logical safe
`and e?’ective therapy for long term control of asthma.
`The inhaled route of administration enables the dose to be
`delivered directly to the airways. By this type of
`administration. it is possible to give a small dose and thereby
`minimizing unwanted side-e?’ects. The drawbacks of the
`currently available bronchodilators are their relatively short
`duration of action. By using a compound with long duration
`e.g. formoterol it would be possible to avoid the nocturnal
`asthma. which so often causes considerable anxiety and
`debility to the patients. Formoterol gives less nocturnal
`waking than the commonly used short-acting agonists like
`salbutamol. terbutaline and thelike. Formoterol has been
`registered for oral administration in Japan since 1986.
`Pharmaceutical combinations of long-acting liz-agonists
`and steroids are disclosed in two European applications. EP
`416950 which discloses the combination of salmeterol and
`beclomethasone. and EP 416951 which discloses the com
`bination of salmetcrol and ?uticasone propionate.
`In Ann. Allergy 1989. 63 (3). p. 220-224 the use of a
`?z-agonist. i.e. formoterol and a steroid. i.e. budesonide
`separately are mentioned. Not disclosed is a pharmaceutical
`combination including both formoterol and budesonide. or
`the use of the two compounds in combination therapy. The
`use of a ?fagonist and a steroid separately is also mentioned
`in Lung (1990). 168. no. supp. p. 105-110.
`OUTLINE OF THE INVENTION
`The present invention is based on the concept of a novel
`combination therapy whereby formoterol (and/or a physi
`ologically acceptable salt and/or solvate thereof) and budes
`onide are administered simultaneously. sequentially or sepa
`rately by inhalation. This combination has not only a greater
`e?iciency and duration of bronchodilator action but: the
`combination also has a rapid onset of action. This new
`feature is of utmost importance in order to establish a higher
`compliance for patients and it provides a rescue medicine
`thereby avoiding the necessity for the patient of carrying two
`different inhalers. ‘This simpli?es life for patients consider
`ably and makes life more comfortable and secure. The rapid
`onset of the long-acting Biz-agonist gives the patient imme
`diate con?rmation that he has taken an adequate dose and
`thereby avoiding overdosing of both ?z-agonist and steroid.
`Since the use of formoterol instead of salmoterol gives a
`much more rapid onset the combinations according to the
`invention have a number of advantages compared to the
`combinations disclosed i EP 416950 and EP 41651. The
`combination according to present invention permits a twice
`daily dosing regime as a basic treatment of asthma. particu
`larly nocturnal asthma.
`The present invention provides a medicament containing.
`separately. or together. (i) formoterol (and/or a physiologi
`cally acceptable salt and/or solvate thereof) and (ii) budes
`onide for simultaneous. sequential or separate administra
`tion by inhalation in the treatment of respiratory disorders.
`The invention also provides a pharmaceutical composi
`tion for administration by inhalation in the treatment of
`respiratory disorders which composition comprises formot
`erol (and/or a physiologically acceptable salt and/or solvate
`thereof) and budesonide.
`According to another aspect of the invention there are
`provided pharmaceutical compositions comprising eifective
`amounts of formoterol (and/or a physiologically acceptable
`salt and/or solvate thereof) and budesonide as a combined
`preparation for simultaneous. sequential or separate admin
`istration by inhalation in the treatment of respiratory
`disorders.
`
`2
`
`

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`5,674,860
`
`4
`The micronized mixture may be suspended or dissolved in
`a liquid propellant mixture which is kept in a container that
`is sealed with a metering valve and ?tted into a plastic
`actuator. The propellants used may be chloro?uorocarbons
`of di?m'ent chemical formulae. The most ?'equently used
`chloro?uorocarbon propellants are trichloromono?uo
`romethane (propellant 11). dichlorodi?uoromethane
`(propellant l2). dichlorotetra?uoroethane (propellant 114).
`tetra?uoroethane (propellant 134a) and LI-di?uoroethane
`(propellant 152a). Low concentrations of a surfactant such
`as sorbitan trioleate. lecithin. disodium dioctylsulphosucci
`nate or oleic acid may also be used to improve the physical
`stability.
`The invention is further illustrated by way of example
`with reference to the following Examples.
`
`3
`The invention further provides formoterol (and/or a physi
`ologically acceptable salt and/or solvate thereof) and budes
`onide for use in combination therapy by simultaneous.
`sequential or separate administration by inhalation in the
`treatment of respiratory disorders.
`Further the invention provides the use of formoterol
`(and/or a physiologically acceptable salt and/or solvate
`thereot) in the manufacture of a medicament for combina
`tion therapy where formoterol (and/or a physiologically
`acceptable salt and/or solvate thereof) and budesonide are
`administered simultaneously. sequentially or separately by
`inhalation in the treatment of respiratory disorders and the
`use of budesonide in the manufacture of a medicament for
`combination therapy where formoterol (and/or a physiologi
`cally acceptable salt and/or solvate thereof) and budesonide
`are administered simultaneously. sequentially or separately
`by inhalation in the treatment of respiratory disorders.
`The invention additionally relates to the use of formoterol
`(and/or a physiologically acceptable salt and/or solvate
`thereof) and budesonide in the manufacture of a medicament
`for combination therapy for simultaneous. sequential or
`separate administration of formoterol and budesonide by
`inhalation in the treatment of respiratory disorders.
`According to a further feature of the invention there is
`provided a method of treating respiratory disorders which
`comprises the simultaneous. sequential or separate admin
`istration by inhalation of e?ective amounts of formoterol
`(and/or a physiologically acceptable salt and/or solvate
`thereof) and budesonide.
`Suitable physiologically salts of formoterol include acid
`addition salts derived from inorganic and organic acids. such
`as the hydrochloride. hydrobromide. sulphate. phosphate.
`maleate. fumarate. tartrate. citrate. benzoate.
`4-methoxybenzoate. 2- or 4-hydroxybenzoate.
`4»chlorobenzoate. p-toluenesulphonate. methanesulphonate.
`ascorbate. salicylate. acetate succinate. lactate. glutarate.
`gluconate. tricarballylate. hydroxynaphthalenecarboxylate
`or oleate. Formoterol is preferably used in the form of its
`furnarate salt and as a dihydrate.
`The ratio of formoterol to budesonide used according to
`the invention is preferably within the range of 1:4 to 1:70.
`The two drugs may be administered separately in the same
`ratio.
`The intended dose regimen is a twice daily
`administration. where the suitable daily dose of formoterol
`is in the range of 6 to 100 pg with a preferred dose of 6-43
`pg and the suitable daily dose for budesonide is 50 to 4800
`pg with a preferred dose of 100-1600 pg. The particular dose
`used will strongly depend on the patient (age. weight etc)
`and the severity of the disease (mild. moderate. severe
`asthma etc).
`For administration. the combination is suitably inhaled
`from a nebulizer. from a pressurized metered dose inhaler or
`as a dry powder from a dry powder inhaler (e.g. as sold
`under the trade mark Turbuhaler) or from a dry powder
`inhaler utilizing gelatin. plastic or other capsules. cartridges
`or blister packs.
`A diluent or carrier. generally non-toxic and chemically
`inert to the medicament e.g. lactose. dextran. mannitol or
`glucose or any additives that will give the medicament a
`desired taste. can be added to the powdered medicament.
`Examples of the preparation of suitable dosage forms
`according to the invention include the following: Formoterol
`fumarate dihydrate and budesonide (optionally
`premicronized) are mixed in the proportions given above.
`The agglomerated. free-?owing micronized mixture may be
`?lled into a dry powder inhaler such as sold under the trade
`mark 'Ittrbuhaler. When a capsule system is used. it is
`desirable to include a ?ller in the mixture.
`
`20
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`
`ECAMPLE 1
`
`Dry Powder Inhaler (Turbuhaler)
`
`Active ingredient
`
`Formoterol (as fumarate dihydrate)
`Budesonide
`
`Per dose
`
`12 pg
`Z10 pg
`
`The storage unit of the inhaler is ?lled with sui?cient
`matm'al for at least 200 doses.
`
`Active ingedient
`
`Formoterol (as fumarate dihydrate)
`Budesonide
`
`Per dose
`
`24 pg
`200 pg
`
`The storage unit is ?lled with su?icient material for at
`least 200 doses.
`
`Active iugredimt
`
`Formoterol (as fumarate diltydrate)
`Budesonide
`
`Per dose
`
`12 pg
`100 pg
`
`The storage unit is ?lled with su?icient material for at
`least 200 doses.
`
`EXAMPLE 2
`
`Metered Dose Inhaler
`
`55
`
`Active in‘ gredien' t
`
`Formoterol (as fumarate dihydrate)
`Budcsonide
`Stabilizer
`Propellant
`Fomoterol (as fumarate dihydmte)
`Budesonide
`Stabilizer
`Propellmt
`Formoterol (as fumarate dihydrate)
`Butbsonink
`Stabilizer
`Propellant
`
`65
`
`Per dose
`
`12 pg
`200 pg
`0.1-0.7 mg
`75-100 pl
`24 pg
`200 pg
`0.1-0.7 mg
`25400 pl
`12 pg
`200 pg
`0.1-0.7 mg
`25-100 pl
`
`3
`
`

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`5,674,860
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`5
`EXAMPLE3
`Metered Dose Dry Powder Formulation
`
`Active ingredient
`
`Per dose
`
`Formoterol (as futnarate dihydrate)
`Budesonide
`Lactose
`Formoterol (as fumarate dihydrate)
`Budesonide
`Lactose
`Formoterol (as fumarate dihydrate)
`Budesonide
`Lactose
`
`12 pg
`200 pg
`up to 5, 12.5 or 25 mg
`24 pg
`230 pg
`up to 5, 12.5 or 25 mg
`12 pg
`100 pg
`up to 5, 12.5 or 25 mg
`
`We claim:
`1. Amedicament containing as active ingredients effective
`amounts of a physiologically acceptable salt of formoterol or
`a solvate thereof. and budesonide wherein the molar ratio of
`the formoterol component to the budesonide component is in
`the range from 1:4 to 1:60.
`2. The medicament of claim 1 wherein the active ingre
`dients are in dry powder form.
`3. The medicament of claim 1 or 2 wherein the formoterol
`is in the form of the fumarate dihydrate.
`4. A pharmaceutical composition which comprises effec
`tive amounts of a physiologically acceptable salt of formot
`erol or a solvate thereof. and budesonide wherein the molar
`ratio of the formoterol component to the budesonide com
`ponent is in the range from 1:4 to 1:60. together with a
`pharmaceutically acceptable carrier.
`5. The pharmaceutical composition of claim 4 wherein the
`formoterol is in the form of the fumarate dihydrate.
`6. A pharmaceutical composition according to claim 4
`wherein the pharmaceutically acceptable carrier is lactose.
`7. A pharmaceutical composition according to claim 6 in
`dosage unit form.
`8. A pharmaceutical composition according to claim 7
`comprising 12 pg formoterol fumarate dihydrate. 200 pg
`budesonide and up to 25 mg lactose.
`9. A medicament containing as active ingredients effective
`amounts of a physiologically acceptable salt of formoterol or
`a solvate thereof. and budesonide wherein the molar ratio of
`the formoterol component to the budesonide component is in
`the range from 1:1 to 1:60.
`10. The medicament of claim 9 wherein the active ingre
`dients are in dry powder form.
`11. The medicament of claim 9 or 10 wherein the for
`moterol is in the form of the fumarate dihydrate.
`12. A pharmaceutical composition which comprises effec
`tive amounts of a physiologically acceptable salt of formot
`erol or a solvate thereof. and budesonide wherein the molar
`ratio of the formoterol component to the budesonide com
`ponent is in the range from 1:1 to 1:60. together with a
`pharmaceutically acceptable carrier.
`13. The pharmaceutical composition of claim 12 wherein
`the formoterol is in the form of the fumarate dihydrate.
`14. A pharmaceutical composition according to claim 12
`wherein the pharmaceutically acceptable carrier is lactose.
`15. A pharmaceutical composition according to claim 14
`in dosage unit form.
`16. A pharmaceutical composition according to claim 15
`comprising 12 pg formoterol fumarate dihydrate. 200 pg
`budesonide and up to 25 mg lactose.
`17. A method for the treatment of asthma and other
`in?ammatory respiratory disorders which comprises admin
`istering by inhalation to a host in need of such treatment
`e?‘ective amounts of a physiologically acceptable salt of
`
`10
`
`20
`
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`
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`
`6
`formoterol or a solvate thereof. and budesonide wherein the
`molar ratio of the formoterol component to the budesonide
`component is in the range from 1:4 to 1:60.
`18. The method according to claim 17. wherein the
`effective amount of the physiologically acceptable salt of
`formoterol or solvate thereof is 6-100 pg per day. and the
`effective amount of budesonide is 50-4800 pg per day.
`19. The method according to claim 18 wherein the eifec~
`tive amount of the physiologically acceptable salt of for
`moterol or solvate thereof is 6-48 pg per day. and the
`effective amount of budesonide is 100-1600 pg per day.
`20. The method according to any one of claims 17. 18 and
`19 wherein the administration is performed from a dry
`powder inhaler.
`21. The method according to claim 20 wherein the inhaler
`is a 'I‘urbuhalerm.
`22. The method according to any one of claims 17. 18 and
`19 wherein the administration is performed from a metered
`dose inhaler.
`23. The method according to any one of claims 17. 18 and
`19 wherein the formoterol is in the form of the fumarate
`dihydrate.
`24. The method according to any one of claims 17. 18 and
`19 wherein the administration is performed with a nebulizer.
`25. A method according to any one of claims 17. 18 and
`19 wherein the formoterol component and the budesonide
`component are administered simultaneously.
`26. The method according to any one of claims 17. 18 and
`19. wherein the physiologically acceptable salt of formoterol
`or the solvate thereof is administered in admixture with the
`budesonide.
`27. A method for the treatment of asthma and othm'
`in?ammatory respiratory disorders which comprises admin
`istering by inhalation to a host in need of such treatment
`effective amounts of a physiologically acceptable salt of
`formoterol or a solvate thereof. and budesonide wherein the
`molar ratio of the formoterol component to the budesonide
`component is in the range from 1:1 to 1:60.
`28. The method according to claim 27. wherein the
`effective amount of the physiologically acceptable salt of
`formoterol or solvate thereof is 6-100 pg per day. and the
`effective amount of budesonide is 50-4800 pg per day.
`29. The method according to claim 28 wherein the effec
`tive amount of the physiologically acceptable salt of for
`moterol or solvate thereof is 6-48 pg per day. and the
`etfective amount of budesonide is 100-1600 pg per day.
`30. The method according to any one of claims 27. 28 and
`29 wherein the administration is performed from a dry
`powder inhaler.
`31. The method according to claim 30 wherein the inhaler
`is a Turbuhalerm.
`32. The method according to any one of claims 27. 28 and
`29 wherein the administration is performed from a metered
`dose inhaler.
`33. The method according to any one of claims 27 . 28 and
`29 wherein the formoterol is in the form of the fumarate
`dihydrate.
`34. The method according to any one of claims 27. 28 and
`29 wherein the administration is perfonned with a nebulizer.
`35. The method according to any one of claims 27. 28 and
`29 wherein the formoterol component and the budesonide
`component are administered simultaneously.
`36. The method according to any one of claims 27. 28 and
`29. wherein the physiologically acceptable salt of formoterol
`or the solvate thereof is administered in admixture with the
`budesonide.
`
`4