CA2239308A1 - New combination - Google Patents
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- CA2239308A1 CA2239308A1 CA002239308A CA2239308A CA2239308A1 CA 2239308 A1 CA2239308 A1 CA 2239308A1 CA 002239308 A CA002239308 A CA 002239308A CA 2239308 A CA2239308 A CA 2239308A CA 2239308 A1 CA2239308 A1 CA 2239308A1
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- Prior art keywords
- active ingredient
- solvate
- formoterol
- budesonide
- composition
- Prior art date
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Pulmonology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Otolaryngology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The invention provides a composition or kit having as a first active ingredient formoterol, or a salt or solvate derivative thereof, and having as a second active ingredient budesonide, wherein the molar ratio of the first active ingredient to the second active ingredient is from 1:30 to 1:36, and the use of the composition and kit in the treatment of respiratory disorders.
Description
-W O 98/1~280 - PCT/SE97/01606 ~EW CO M Bn~ATION
Field of the Invention The present invention provides a new combination of ph~rm~re~ltic~lly active substances which is of use in the tre~tment of respiratory disorders, particularly asthma.
Background to the Invention Despite recent advances in the awareness of asthma and the introduction of powerful and effective anti-asthma drugs, asthma remains a poorly understood and frequently poorly o treated (1i~e~ce There have been recent advances in the treatment of the disease which result from the recognition that asthma is a chronic infl~mm~tory ~ e~e Therapy is now aimed at both controlling the symptoms and reducing the infl~mm~tion The symptoms include uncontrolled airway infl~mm~tiQn which may lead to mllcos~ damage and structural changes possibly leading to irreversible n~l~ lg of the airways and fibrosis of the lungs.
The ~y~ Lollls may be controlled by ~2-adrenoreceptor agonists such as salbutamol, s~lmet~rol, terbutaline and formoterol. Forrnoterol is advantageous because the duration of its effect is long; it has a fast onset time and because it gives few nocturnal w~k~nin~
Prophylactic therapy is typically provided by steroids such as beclomethasone diprup~ionate, fluticasone propionate and budesonide. Of these budesonide is advantageous because it may be given in a high inhaled dose (up to 2 mg daily) with very low systemic effects. Long term clinical studies in adults and children have shown that 2s inhaled budesonide has an excellent safety profile.
Description of the Invention According to the invention there is provided a composition comprising, in an ~lmixhlre:
W O 98/15280 PCTtSE97/01606 (a) a first active ingredient which is formoterol, a ph~rm~ceutically acceptable salt or solvate of formoterol, or a solvate of such a salt; and (b) a second active ingredient which is budesonide;
wherein the molar ratio of the first active ingredient to the second active ingredient is from s 1:30 to 1:36, preferably about 1:32.5.
According to the invention there is filr~er provided a kit comprising:
(i) a vessel cont~inin~ the first active ingredient, (ii) a vessel co,.l~ g the second active ingredient; and lO (iii) instructions for the sequential or sepaldle ~riminictration of the first and second active ingredients to a patient in need thereof;
wherein the molar ratio of the first active ingredient to the second active ingredient is from 1:30 to 1:36, preferably about 1:32.5.
s A patient suffering from a ~ ory disorder such as asthma can be treated by 5~rimini~t~rin~ via inh~tion a composition according to the invention. Alternatively such a patient can be treated by ~timini~tering via inhalation, sequentially or separately:
(i) a dose of the first active ingredient; and (ii) a dose of the second active ingredient;
20 wh~,~ehl the molar ratio of the first active ingredient to the second active ingredient is from 1:30 to 1:36, preferably about 1:32.5.
It has been found that the combination of active ingredients according to the invention is advantageous because it gives a significantly improved anti-infl~mm~tory effect compared 2S to known tre~tment~ Tnt~ tional patent publication no. WO 93/1 1773 discloses a combination of budesonide and formoterol having a wide weight ratio range. The closest example of a combination disclosed in this doc-~ment to the system of the invention has a weight ratio of forrnoterol fumarate dihydrate to budesonide of 0.06:1, i.e. a molar ratio of 1:16.3. The combination of active ingredients according to the invention gives surprisingly 30 better results when used to treat patients suffering from asthma compared to this known combination.
W O 98/1~280 PCT/SE97/01606 The first and second active ingredients of the kit can be ~lm;nict~red sequentially or separately to treat rei,~i~dtory disorders. By sequential is meant that the first and second active ingredients are ~-1mini~tered one irnmediately after the other. They still have the s desired effect if they are iq~rninictered separately but less than about 12 hours apart, preferably less than about 2 hours apart, more preferably less than about 30 minlltes apart.
Preferably the first active ingredient is ~-lminietered to provide a daily dose of from 10 to 250nmol (preferably from 15 to 120nmol) and the second active ingredient is ?~1minigtered o to provide a daily dose offrom 0.1 to lO~Lmol (preferably 0.2 to S,umol) or from 39 to 4300~g ofthe second active ingredient (preferably from 86 to 215011g), subject to the molar ratio of the first active ingredient to the second active ingredient being within the range of from 1 :30 to I :36.
Suitable physiologically acceptable salts of formoterol include acid addition salts derived from inorganic and organic acids, for example the chloride, bromide, sl-lph~te, phosphate, maleate, rulll~dLe, tartrate, citrate, ben7n~te, 4-methoxyben7-~te, 2- or 4-hydroxyben70~qt~, 4-chloroben7O~te p-tol-l~n(?s-llphonate, methanesulphonate, ascorbate, acetate, succinate, lactate, glu~LLd~e, gluconate, tricarballylate, hydroxyn~phth~lene-carboxylate or oleate salts or solvates thereof. l~e first active ingredient is preferably formoterol fumarate, especially the dihydrate.
When the first active ingredient is formoterol fumarate dihydrate, the preferred daily dose of the first active ingredient is from 4 to l OO~lg, more preferably from 6 to 50~g (subject to the molar ratio of the first actlve ingredient to the second active ingredient being within the range of from 1 :30 to 1 :36).
Most preferably the composition or kit of the invention comprises 6~g of formoterol ruul~dle dihydrate and 200~1g of budesonide, or 4.5~Lg of formoterol fumarate dihydrate and 160~1g of budesonide, either of ~vhich is ~-lmini~t~red up to four times a day.
W 098/lS280 PCT~E97/01606 tPrn~tively the composition or kit of the invention comprises 12,ug of formoterol fumarate dihydrate and 400~1g of budesonide, or 9,ug of formoterol fumarate dihydrate and 320,ug of budesonide, either of which is arlminict~red once or twice a day.
s Preferably the active ingredient(s~ are used in ~lmixtllre with one or more ph~rm~entically acceptable additives, ~ nt~ or carriers, preferably in an amount of from 50~1g to 25mg per dose, more preferably in an amount of from 50~1g to l Omg, most preferably in an amount of from l 00 to 2000,ug. Examples of suitable diluents or carriers include 1~rtose, dextran, m~nnitol and glucose. Preferably lactose is used, especially as the 10 monohydrate.
It should be understood that where reference is made to the amounts of each active ingredient that these are metered amounts. When the active ingredients are ~minietered, the amount of each ingredient inhaled by the patient can differ from the metered amount, e.g. due to retention of the active ingredient in the inhalation device. Furthermore when the active ingredients are fo~m~ te~l sep~ualely~ the ~rlminict~red arnourlt of each is not nec~s~ri1y reduced proportionately. Thus the ~-lmini~t~red ratio of the active ingredients could differ from the metered ratio. Preferably the ~lmini~t~red ratio is within the metered ratio specified above.
One or more of the active ingredients used in the invention is preferably in the forrn of a dry powder, more preferably a finely divided, e.g. a micronised, dry powder, e.g. having a mass median diameter of less than l0~1m, for exarnple from I to 5~m, most preferably an agglomerated micronised dry powder. As an alternative to agglomeration the finely 2S divided active ingredients may be in the form of an ordered mixture with the one or more ph~ ceutically acceptable additives, diluents or carriers. An ordered mixture is the combination of finely divided active ingredient with coarse particles of ph~ eutically acceptable additive, diluent or carrier. The ingredients used in the invention can be obtained in these ~L.,rel~ed forms using methods known to those of skill in the art.
-W O 98/lS280 PCT/SE97tO1606 s According to the invention there is further provided the use of a composition or kit according to the invention in the manufacture of a medicament for use in the tr~tment of a hdl~ly disorder, e.g. ~ethm~ The invention also provides the use of budesonide or of formoterol in the m~nllf~cture of a kit or of a composition according to the invention for use in the tre~tment of a ~e;~uhcLLoly disorder, e.g. ~cthm~
~clmini~tration may be by inh~l~t;on orally or intr~n~lly. The ingredients are preferably adapted to be ~iminictered from a dry powder inhaler, a ~lc;,~ul;sed metered dose inhaler, or a nebuliser.
When the ingredients of the composition or kit are adapted to be ~mini~t~red from a pre;,~lllised inhaler, they are preferably in micronised form. They are dissolved or, preferably, suspended in a liquid propellant ~ Lu~t. The propellants which can be used include chlorofluorocarbons, hydrocarbons or hydrofluoro~lk~n~c Especially plerell..d propellants are P 1 34a (tetrafluoroethane) and P227 (h~La~luolupr(,~le) 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 s-lrf~-~t~nt~ and/or one or more other excipients, for example ethanol, a lubricant, an anti-oxidant and/or a stabilising agent.
20 When the ingredients of the composition or kit of the invention are adapted to be ~riminict~red via a nebuliser they may be in the form of a nebulised aqueous ~u~ension or solution, with or without a suitable pH or tonicity adJustment, either as a unit dose or multidose device.
25 The composition or kit may optionally be ~imini.~t~red as divided doses from 1 to 4, and preferably once or twice a day.
The invention is illustrated by the following Exarnples which are not intended to limit the scope of the application. In the Examples micronisation is carried out in a conventional 30 manner such that the particle size range for each component is suitable for ~lminic~tiQn by inhalation. Turbuhaler is a trademark of Astra AB.
Example I
6 Parts by weight of formoterol fumarate dihydrate was mixed with 794 parts by weight of lactose monohydrate. The blend was micronised using a high ples~ air jet mill and then conditioned using the process of EP-A-717 616. 200 Parts by weight of micronised- budesonide was added to the conditioned product by mixing and homogenising with a low pressure jet mill. The llliiCLlllG was then spheronised using the process of EP-A-72 1 331 and filled into the storage C(J11~ llen:t of a Turbuhaler.
0 Example 2 4.5 Parts by weight of formoterol fumarate dihydrate was mixed with 835 parts by weight of lactose monohydrate. The blend was micronised using a high pressure air jet mill and then conditioned using the process of EP-A-7 17 616. 160 Parts by weight of micronised budesonide was added to the conditioned product by mixing and homogenising with a low pressure jet mill. The mixture was then spheronised using the process of EP-A-72 1 331 and filled into the storage co~ lent of a Turbuhaler.
I~xample 3 12 Parts by weight of forrnoterol furnarate dihydrate was mixed with 588 parts by weight of lactose monohydrate. The blend was rnicronised using a high pressure air jet mill and then conditioned using the process of EP-A-7 17 616. 400 Parts by weight of micronised budesonide was added to tne conditioned product by mixing and homogenising with a low ~)leSSulc jet mill. The mixture was then spheronised using the process of EP-A-721 331 and filled into the storage COlll~ nent of a Turbuhaler.
Eicample 4 6 Parts by weight of formoterol fumarate dihydrate was mixed with 994 parts by weight of lactose monohydrate. The blend was micronised using a high pressure air jet rnill and then conditioned using the process of EP-A-717 616. The mixture was then spheronised using the process of EP-A-721 331 and filled into the storage compartment of a Turbuhaler.
200 Parts by weight of micronised budesonide was mixed with 800 parts by weight of s lactose monohydrate. The blend was micronised using a high ~les~llle air jet mill and then conditioned using the process of EP-A-717 616. The mixture was then spheronised using the process of EP-A-721 331 and filled into the storage CO~ u Llllent of a Turbuhaler.
Example S
o 4.5 Parts by weight of formoterol rulll~d~ dihydrate was mixed with 995 parts by weight of lactose monohydrate. The blend was micronised using a high pressure air jet mill and then conditioned using the process of EP-A-717 616. The mixture was then spheronised using the process of EP-A-721 331 and filled into the storage co~ llent of a Turbuhaler.
160 Parts by weight of micronised budesonide was mixed with 840 parts by weight of lactose monohydrate. The blend was micronised using a high pressure air jet mill and then conditioned using the process of EP-A-717 616. The llli~LuL~ was then spheronised using the process of EP-A-721 331 and filled into the storage colll~ L~llent of a Turbuhaler.
Example 6 12 Parts by weight of formoterol fumarate dihydrate was mixed with 988 parts by weight of lactose monohydrate. The blend was micronised using a high ~r~,s~uLc air jet mill and then conditioned using the process of EP-A-717 616. The mixture was then spheronised using the process of EP-A-721 331 and filled into the storage COlLl~d~ Illlent of a Turbuhaler.
400 Parts by weight of micronised budesonide was mixed with 600 parts by weight of lactose monohydrate. The blend was micronised using a high ~L~S~U1G air jet mill and then conditioned using the process of EP-A-717 616. The ll~Lule was then spheronised using the process of EP-A-721 331 and filled into the storage c~m~ Llllc~lL of a Turbuhaler.
-
Field of the Invention The present invention provides a new combination of ph~rm~re~ltic~lly active substances which is of use in the tre~tment of respiratory disorders, particularly asthma.
Background to the Invention Despite recent advances in the awareness of asthma and the introduction of powerful and effective anti-asthma drugs, asthma remains a poorly understood and frequently poorly o treated (1i~e~ce There have been recent advances in the treatment of the disease which result from the recognition that asthma is a chronic infl~mm~tory ~ e~e Therapy is now aimed at both controlling the symptoms and reducing the infl~mm~tion The symptoms include uncontrolled airway infl~mm~tiQn which may lead to mllcos~ damage and structural changes possibly leading to irreversible n~l~ lg of the airways and fibrosis of the lungs.
The ~y~ Lollls may be controlled by ~2-adrenoreceptor agonists such as salbutamol, s~lmet~rol, terbutaline and formoterol. Forrnoterol is advantageous because the duration of its effect is long; it has a fast onset time and because it gives few nocturnal w~k~nin~
Prophylactic therapy is typically provided by steroids such as beclomethasone diprup~ionate, fluticasone propionate and budesonide. Of these budesonide is advantageous because it may be given in a high inhaled dose (up to 2 mg daily) with very low systemic effects. Long term clinical studies in adults and children have shown that 2s inhaled budesonide has an excellent safety profile.
Description of the Invention According to the invention there is provided a composition comprising, in an ~lmixhlre:
W O 98/15280 PCTtSE97/01606 (a) a first active ingredient which is formoterol, a ph~rm~ceutically acceptable salt or solvate of formoterol, or a solvate of such a salt; and (b) a second active ingredient which is budesonide;
wherein the molar ratio of the first active ingredient to the second active ingredient is from s 1:30 to 1:36, preferably about 1:32.5.
According to the invention there is filr~er provided a kit comprising:
(i) a vessel cont~inin~ the first active ingredient, (ii) a vessel co,.l~ g the second active ingredient; and lO (iii) instructions for the sequential or sepaldle ~riminictration of the first and second active ingredients to a patient in need thereof;
wherein the molar ratio of the first active ingredient to the second active ingredient is from 1:30 to 1:36, preferably about 1:32.5.
s A patient suffering from a ~ ory disorder such as asthma can be treated by 5~rimini~t~rin~ via inh~tion a composition according to the invention. Alternatively such a patient can be treated by ~timini~tering via inhalation, sequentially or separately:
(i) a dose of the first active ingredient; and (ii) a dose of the second active ingredient;
20 wh~,~ehl the molar ratio of the first active ingredient to the second active ingredient is from 1:30 to 1:36, preferably about 1:32.5.
It has been found that the combination of active ingredients according to the invention is advantageous because it gives a significantly improved anti-infl~mm~tory effect compared 2S to known tre~tment~ Tnt~ tional patent publication no. WO 93/1 1773 discloses a combination of budesonide and formoterol having a wide weight ratio range. The closest example of a combination disclosed in this doc-~ment to the system of the invention has a weight ratio of forrnoterol fumarate dihydrate to budesonide of 0.06:1, i.e. a molar ratio of 1:16.3. The combination of active ingredients according to the invention gives surprisingly 30 better results when used to treat patients suffering from asthma compared to this known combination.
W O 98/1~280 PCT/SE97/01606 The first and second active ingredients of the kit can be ~lm;nict~red sequentially or separately to treat rei,~i~dtory disorders. By sequential is meant that the first and second active ingredients are ~-1mini~tered one irnmediately after the other. They still have the s desired effect if they are iq~rninictered separately but less than about 12 hours apart, preferably less than about 2 hours apart, more preferably less than about 30 minlltes apart.
Preferably the first active ingredient is ~-lminietered to provide a daily dose of from 10 to 250nmol (preferably from 15 to 120nmol) and the second active ingredient is ?~1minigtered o to provide a daily dose offrom 0.1 to lO~Lmol (preferably 0.2 to S,umol) or from 39 to 4300~g ofthe second active ingredient (preferably from 86 to 215011g), subject to the molar ratio of the first active ingredient to the second active ingredient being within the range of from 1 :30 to I :36.
Suitable physiologically acceptable salts of formoterol include acid addition salts derived from inorganic and organic acids, for example the chloride, bromide, sl-lph~te, phosphate, maleate, rulll~dLe, tartrate, citrate, ben7n~te, 4-methoxyben7-~te, 2- or 4-hydroxyben70~qt~, 4-chloroben7O~te p-tol-l~n(?s-llphonate, methanesulphonate, ascorbate, acetate, succinate, lactate, glu~LLd~e, gluconate, tricarballylate, hydroxyn~phth~lene-carboxylate or oleate salts or solvates thereof. l~e first active ingredient is preferably formoterol fumarate, especially the dihydrate.
When the first active ingredient is formoterol fumarate dihydrate, the preferred daily dose of the first active ingredient is from 4 to l OO~lg, more preferably from 6 to 50~g (subject to the molar ratio of the first actlve ingredient to the second active ingredient being within the range of from 1 :30 to 1 :36).
Most preferably the composition or kit of the invention comprises 6~g of formoterol ruul~dle dihydrate and 200~1g of budesonide, or 4.5~Lg of formoterol fumarate dihydrate and 160~1g of budesonide, either of ~vhich is ~-lmini~t~red up to four times a day.
W 098/lS280 PCT~E97/01606 tPrn~tively the composition or kit of the invention comprises 12,ug of formoterol fumarate dihydrate and 400~1g of budesonide, or 9,ug of formoterol fumarate dihydrate and 320,ug of budesonide, either of which is arlminict~red once or twice a day.
s Preferably the active ingredient(s~ are used in ~lmixtllre with one or more ph~rm~entically acceptable additives, ~ nt~ or carriers, preferably in an amount of from 50~1g to 25mg per dose, more preferably in an amount of from 50~1g to l Omg, most preferably in an amount of from l 00 to 2000,ug. Examples of suitable diluents or carriers include 1~rtose, dextran, m~nnitol and glucose. Preferably lactose is used, especially as the 10 monohydrate.
It should be understood that where reference is made to the amounts of each active ingredient that these are metered amounts. When the active ingredients are ~minietered, the amount of each ingredient inhaled by the patient can differ from the metered amount, e.g. due to retention of the active ingredient in the inhalation device. Furthermore when the active ingredients are fo~m~ te~l sep~ualely~ the ~rlminict~red arnourlt of each is not nec~s~ri1y reduced proportionately. Thus the ~-lmini~t~red ratio of the active ingredients could differ from the metered ratio. Preferably the ~lmini~t~red ratio is within the metered ratio specified above.
One or more of the active ingredients used in the invention is preferably in the forrn of a dry powder, more preferably a finely divided, e.g. a micronised, dry powder, e.g. having a mass median diameter of less than l0~1m, for exarnple from I to 5~m, most preferably an agglomerated micronised dry powder. As an alternative to agglomeration the finely 2S divided active ingredients may be in the form of an ordered mixture with the one or more ph~ ceutically acceptable additives, diluents or carriers. An ordered mixture is the combination of finely divided active ingredient with coarse particles of ph~ eutically acceptable additive, diluent or carrier. The ingredients used in the invention can be obtained in these ~L.,rel~ed forms using methods known to those of skill in the art.
-W O 98/lS280 PCT/SE97tO1606 s According to the invention there is further provided the use of a composition or kit according to the invention in the manufacture of a medicament for use in the tr~tment of a hdl~ly disorder, e.g. ~ethm~ The invention also provides the use of budesonide or of formoterol in the m~nllf~cture of a kit or of a composition according to the invention for use in the tre~tment of a ~e;~uhcLLoly disorder, e.g. ~cthm~
~clmini~tration may be by inh~l~t;on orally or intr~n~lly. The ingredients are preferably adapted to be ~iminictered from a dry powder inhaler, a ~lc;,~ul;sed metered dose inhaler, or a nebuliser.
When the ingredients of the composition or kit are adapted to be ~mini~t~red from a pre;,~lllised inhaler, they are preferably in micronised form. They are dissolved or, preferably, suspended in a liquid propellant ~ Lu~t. The propellants which can be used include chlorofluorocarbons, hydrocarbons or hydrofluoro~lk~n~c Especially plerell..d propellants are P 1 34a (tetrafluoroethane) and P227 (h~La~luolupr(,~le) 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 s-lrf~-~t~nt~ and/or one or more other excipients, for example ethanol, a lubricant, an anti-oxidant and/or a stabilising agent.
20 When the ingredients of the composition or kit of the invention are adapted to be ~riminict~red via a nebuliser they may be in the form of a nebulised aqueous ~u~ension or solution, with or without a suitable pH or tonicity adJustment, either as a unit dose or multidose device.
25 The composition or kit may optionally be ~imini.~t~red as divided doses from 1 to 4, and preferably once or twice a day.
The invention is illustrated by the following Exarnples which are not intended to limit the scope of the application. In the Examples micronisation is carried out in a conventional 30 manner such that the particle size range for each component is suitable for ~lminic~tiQn by inhalation. Turbuhaler is a trademark of Astra AB.
Example I
6 Parts by weight of formoterol fumarate dihydrate was mixed with 794 parts by weight of lactose monohydrate. The blend was micronised using a high ples~ air jet mill and then conditioned using the process of EP-A-717 616. 200 Parts by weight of micronised- budesonide was added to the conditioned product by mixing and homogenising with a low pressure jet mill. The llliiCLlllG was then spheronised using the process of EP-A-72 1 331 and filled into the storage C(J11~ llen:t of a Turbuhaler.
0 Example 2 4.5 Parts by weight of formoterol fumarate dihydrate was mixed with 835 parts by weight of lactose monohydrate. The blend was micronised using a high pressure air jet mill and then conditioned using the process of EP-A-7 17 616. 160 Parts by weight of micronised budesonide was added to the conditioned product by mixing and homogenising with a low pressure jet mill. The mixture was then spheronised using the process of EP-A-72 1 331 and filled into the storage co~ lent of a Turbuhaler.
I~xample 3 12 Parts by weight of forrnoterol furnarate dihydrate was mixed with 588 parts by weight of lactose monohydrate. The blend was rnicronised using a high pressure air jet mill and then conditioned using the process of EP-A-7 17 616. 400 Parts by weight of micronised budesonide was added to tne conditioned product by mixing and homogenising with a low ~)leSSulc jet mill. The mixture was then spheronised using the process of EP-A-721 331 and filled into the storage COlll~ nent of a Turbuhaler.
Eicample 4 6 Parts by weight of formoterol fumarate dihydrate was mixed with 994 parts by weight of lactose monohydrate. The blend was micronised using a high pressure air jet rnill and then conditioned using the process of EP-A-717 616. The mixture was then spheronised using the process of EP-A-721 331 and filled into the storage compartment of a Turbuhaler.
200 Parts by weight of micronised budesonide was mixed with 800 parts by weight of s lactose monohydrate. The blend was micronised using a high ~les~llle air jet mill and then conditioned using the process of EP-A-717 616. The mixture was then spheronised using the process of EP-A-721 331 and filled into the storage CO~ u Llllent of a Turbuhaler.
Example S
o 4.5 Parts by weight of formoterol rulll~d~ dihydrate was mixed with 995 parts by weight of lactose monohydrate. The blend was micronised using a high pressure air jet mill and then conditioned using the process of EP-A-717 616. The mixture was then spheronised using the process of EP-A-721 331 and filled into the storage co~ llent of a Turbuhaler.
160 Parts by weight of micronised budesonide was mixed with 840 parts by weight of lactose monohydrate. The blend was micronised using a high pressure air jet mill and then conditioned using the process of EP-A-717 616. The llli~LuL~ was then spheronised using the process of EP-A-721 331 and filled into the storage colll~ L~llent of a Turbuhaler.
Example 6 12 Parts by weight of formoterol fumarate dihydrate was mixed with 988 parts by weight of lactose monohydrate. The blend was micronised using a high ~r~,s~uLc air jet mill and then conditioned using the process of EP-A-717 616. The mixture was then spheronised using the process of EP-A-721 331 and filled into the storage COlLl~d~ Illlent of a Turbuhaler.
400 Parts by weight of micronised budesonide was mixed with 600 parts by weight of lactose monohydrate. The blend was micronised using a high ~L~S~U1G air jet mill and then conditioned using the process of EP-A-717 616. The ll~Lule was then spheronised using the process of EP-A-721 331 and filled into the storage c~m~ Llllc~lL of a Turbuhaler.
-
Claims (16)
1. A composition comprising, in admixture:
(a) a first active ingredient selected which is formoterol, a pharmaceutically acceptable salt or solvate thereof, and a solvate of such a salt; and (b) a second active ingredient which is budesonide;
wherein the molar ratio of (a) to (b) in the composition is from 1:30 to 1:36.
(a) a first active ingredient selected which is formoterol, a pharmaceutically acceptable salt or solvate thereof, and a solvate of such a salt; and (b) a second active ingredient which is budesonide;
wherein the molar ratio of (a) to (b) in the composition is from 1:30 to 1:36.
2. A composition according to claim 1, wherein the molar ratio is about 1:32.5.
3. A composition according to claim 1 or 2, wherein the first active ingredient is formoterol fumarate dihydrate.
4. A composition according to claim 1, 2 or 3, additionally comprising a pharmaceutically acceptable additive, diluent or carrier.
5. A composition according to any one of the preceding claims for use in the treatment of a respiratory disorder.
6. A kit comprising (a) a vessel containing a first active ingredient selected from the group consisting of formoterol, a pharmaceutically acceptable salt or solvate thereof, and a solvate of such a salt; and (b) a vessel containing a second active ingredient which is budesonide;
(c) instructions for the sequential or separate administration of the first and second active ingredients to a patient in need thereof;
wherein the molar ratio of the first active ingredient to the second active ingredient is from 1:30 to 1:36.
(c) instructions for the sequential or separate administration of the first and second active ingredients to a patient in need thereof;
wherein the molar ratio of the first active ingredient to the second active ingredient is from 1:30 to 1:36.
7. A kit according to claim 6, wherein the molar ratio is about 1:32.5.
8. A kit according to claim 6 or 7, wherein the first active ingredient is formoterol fumarate dihydrate.
9. A kit according to claim 6, 7 or 8, additionally comprising a pharmaceutically acceptable additive, diluent or carrier suitable for inhalation.
10. A kit according to any one of claims 6 to 9, wherein each ingredient is in the form of a finely divided dry powder and each vessel is a dry powder inhaler.
11. A method of treating a respiratory disorder, which method comprises administering via inhalation to a patient suffering from the disorder a therapeutically effective amount of a composition as defined in any one of claims 1 to 4.
12. A method of treating a respiratory disorder, which method comprises sequentially or separately administering via inhalation to a patient suffering from the disorder(a) a dose of a first active ingredient which is formoterol, a pharmaceutically acceptable salt or solvate thereof, and a solvate of such a salt; and (b) a dose of a second active ingredient which is budesonide;
wherein the molar ratio of (a) to (b) is from 1:30 to 1:36.
wherein the molar ratio of (a) to (b) is from 1:30 to 1:36.
13. Use of a composition according to any one of claims 1 to 4 in the manufacture of a medicament for use in the treatment of a respiratory disorder.
14. Use of a kit according to any one of claims 6 to 10 in the manufacture of a medicament for use in the treatment of a respiratory disorder.
15. Use of formoterol, a pharmaceutically acceptable salt or solvate thereof, and a solvate of such a salt in the manufacture of a composition according to any one of claims 1 to 4 or of a kit according to any one of claims 6 to 10 for use in the treatment of a respiratory disorder.
16. Use of budesonide in the manufacture of a composition according to any one of claims 1 to 4 or of a kit according to any one of claims 6 to 10 for use in the treatment of a respiratory disorder.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9603669A SE9603669D0 (en) | 1996-10-08 | 1996-10-08 | New combination |
| SE9603669-4 | 1996-10-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2239308A1 true CA2239308A1 (en) | 1998-04-16 |
Family
ID=20404167
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002239308A Abandoned CA2239308A1 (en) | 1996-10-08 | 1997-09-24 | New combination |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP0871450A1 (en) |
| JP (1) | JP2000502365A (en) |
| KR (1) | KR19990071975A (en) |
| AR (1) | AR013614A1 (en) |
| AU (1) | AU715319B2 (en) |
| BR (1) | BR9706822A (en) |
| CA (1) | CA2239308A1 (en) |
| CZ (1) | CZ176198A3 (en) |
| HU (1) | HUP9901674A3 (en) |
| MY (1) | MY128337A (en) |
| NO (1) | NO982414D0 (en) |
| NZ (1) | NZ330482A (en) |
| PL (1) | PL327037A1 (en) |
| SE (1) | SE9603669D0 (en) |
| SK (1) | SK75198A3 (en) |
| TW (1) | TW470647B (en) |
| WO (1) | WO1998015280A1 (en) |
| ZA (1) | ZA978889B (en) |
Families Citing this family (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9700136D0 (en) * | 1997-01-20 | 1997-01-20 | Astra Ab | New formulation |
| SE9700134D0 (en) * | 1997-01-20 | 1997-01-20 | Astra Ab | New formulation |
| US5983956A (en) | 1994-10-03 | 1999-11-16 | Astra Aktiebolag | Formulation for inhalation |
| US5980949A (en) * | 1994-10-03 | 1999-11-09 | Astra Aktiebolag | Formulation for inhalation |
| SE9700133D0 (en) * | 1997-01-20 | 1997-01-20 | Astra Ab | New formulation |
| SE9700135D0 (en) | 1997-01-20 | 1997-01-20 | Astra Ab | New formulation |
| TR199903272T2 (en) * | 1997-06-27 | 2000-08-21 | Astra Aktiebolag | New knowledge of asthma prescription drugs. |
| SE9703407D0 (en) | 1997-09-19 | 1997-09-19 | Astra Ab | New use |
| SE9802073D0 (en) * | 1998-06-11 | 1998-06-11 | Astra Ab | New use |
| US6451285B2 (en) | 1998-06-19 | 2002-09-17 | Baker Norton Pharmaceuticals, Inc. | Suspension aerosol formulations containing formoterol fumarate and a fluoroalkane propellant |
| US6290930B1 (en) | 1998-12-18 | 2001-09-18 | Baker Norton Pharmaceuticals, Inc. | Pharmaceutical solution aerosol formulations containing fluoroalkanes and budesonide |
| US6004537A (en) * | 1998-12-18 | 1999-12-21 | Baker Norton Pharmaceuticals, Inc. | Pharmaceutical solution aerosol formulations containing fluoroalkanes, budesonide and formoterol |
| SE9900834D0 (en) * | 1999-03-09 | 1999-03-09 | Astra Ab | Novel combination |
| DE19921693A1 (en) * | 1999-05-12 | 2000-11-16 | Boehringer Ingelheim Pharma | Pharmaceutical composition for treating respiratory disorders, e.g. asthma, comprises combination of anticholinergic and beta-mimetic agents having synergistic bronchospasmolytic activity and reduced side-effects |
| ES2165768B1 (en) | 1999-07-14 | 2003-04-01 | Almirall Prodesfarma Sa | NEW DERIVATIVES OF QUINUCLIDINE AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM. |
| GB0009584D0 (en) * | 2000-04-18 | 2000-06-07 | Glaxo Group Ltd | Pharmaceutical compositions |
| GB0012260D0 (en) | 2000-05-19 | 2000-07-12 | Astrazeneca Ab | Novel composition |
| FI20002216A0 (en) | 2000-10-06 | 2000-10-06 | Orion Yhtymae Oyj | Combination particles for asthma therapy |
| US6667344B2 (en) | 2001-04-17 | 2003-12-23 | Dey, L.P. | Bronchodilating compositions and methods |
| US20030055026A1 (en) | 2001-04-17 | 2003-03-20 | Dey L.P. | Formoterol/steroid bronchodilating compositions and methods of use thereof |
| SE0200312D0 (en) | 2002-02-01 | 2002-02-01 | Astrazeneca Ab | Novel composition |
| SE527069C2 (en) | 2003-06-19 | 2005-12-13 | Mederio Ag | Method and apparatus for administering drug powder |
| TWI359675B (en) | 2003-07-10 | 2012-03-11 | Dey L P | Bronchodilating β-agonist compositions |
| US20050026887A1 (en) * | 2003-07-29 | 2005-02-03 | Boehringer Ingelheim International Gmbh | Medicaments for inhalation comprising an anticholinergic and a steroid |
| IN2014MN00380A (en) | 2006-06-30 | 2015-06-19 | Iceutica Pty Ltd | |
| KR20090121338A (en) | 2007-02-19 | 2009-11-25 | 씨아이피엘에이 엘티디. | Pharmaceutical combinations of at least two bronchodilators or of a bronchodilator with a corticosteroid |
| EP2100599A1 (en) | 2008-03-13 | 2009-09-16 | Laboratorios Almirall, S.A. | Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease |
| CA2763939A1 (en) | 2009-05-29 | 2010-12-02 | Pearl Therapeutics, Inc. | Compositions for pulmonary delivery of long-acting muscarinic antagonists and long-acting b2 adrenergic receptor agonists and associated methods and systems |
| EP2510928A1 (en) | 2011-04-15 | 2012-10-17 | Almirall, S.A. | Aclidinium for use in improving the quality of sleep in respiratory patients |
| CA2856520C (en) | 2011-11-23 | 2021-04-06 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
| CA2865702C (en) | 2012-02-28 | 2020-04-28 | Iceutica Holdings Inc. Bvi | Inhalable pharmaceutical compositions |
| ITMI20130571A1 (en) | 2013-04-10 | 2014-10-11 | Zambon Spa | PHARMACEUTICAL COMPOSITION CONTAINING BUDESONIDE AND FORMOTEROL |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2356145A1 (en) * | 1991-12-18 | 1993-06-24 | Aktiebolaget Astra | New combination of formoterol and budesonide |
-
1996
- 1996-10-08 SE SE9603669A patent/SE9603669D0/en unknown
-
1997
- 1997-09-24 CZ CZ981761A patent/CZ176198A3/en unknown
- 1997-09-24 PL PL97327037A patent/PL327037A1/en unknown
- 1997-09-24 JP JP10517442A patent/JP2000502365A/en active Pending
- 1997-09-24 EP EP97944242A patent/EP0871450A1/en not_active Withdrawn
- 1997-09-24 KR KR1019980704266A patent/KR19990071975A/en not_active Application Discontinuation
- 1997-09-24 CA CA002239308A patent/CA2239308A1/en not_active Abandoned
- 1997-09-24 BR BR9706822A patent/BR9706822A/en not_active IP Right Cessation
- 1997-09-24 AU AU45782/97A patent/AU715319B2/en not_active Ceased
- 1997-09-24 NZ NZ330482A patent/NZ330482A/en unknown
- 1997-09-24 HU HU9901674A patent/HUP9901674A3/en unknown
- 1997-09-24 WO PCT/SE1997/001606 patent/WO1998015280A1/en not_active Application Discontinuation
- 1997-09-24 SK SK751-98A patent/SK75198A3/en unknown
- 1997-10-02 TW TW086114371A patent/TW470647B/en not_active IP Right Cessation
- 1997-10-03 ZA ZA9708889A patent/ZA978889B/en unknown
- 1997-10-07 AR ARP970104615A patent/AR013614A1/en not_active Application Discontinuation
- 1997-10-07 MY MYPI97004698A patent/MY128337A/en unknown
-
1998
- 1998-05-27 NO NO982414A patent/NO982414D0/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| JP2000502365A (en) | 2000-02-29 |
| BR9706822A (en) | 1999-03-23 |
| EP0871450A1 (en) | 1998-10-21 |
| HUP9901674A2 (en) | 1999-09-28 |
| TW470647B (en) | 2002-01-01 |
| MY128337A (en) | 2007-01-31 |
| NO982414L (en) | 1998-05-27 |
| ZA978889B (en) | 1998-04-08 |
| NZ330482A (en) | 1999-11-29 |
| WO1998015280A1 (en) | 1998-04-16 |
| PL327037A1 (en) | 1998-11-09 |
| NO982414D0 (en) | 1998-05-27 |
| CZ176198A3 (en) | 1998-09-16 |
| KR19990071975A (en) | 1999-09-27 |
| AU715319B2 (en) | 2000-01-20 |
| HUP9901674A3 (en) | 2001-04-28 |
| SE9603669D0 (en) | 1996-10-08 |
| AR013614A1 (en) | 2001-01-10 |
| AU4578297A (en) | 1998-05-05 |
| SK75198A3 (en) | 1998-11-04 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |