WO1998015280A1 - New combination - Google Patents

New combination Download PDF

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Publication number
WO1998015280A1
WO1998015280A1 PCT/SE1997/001606 SE9701606W WO9815280A1 WO 1998015280 A1 WO1998015280 A1 WO 1998015280A1 SE 9701606 W SE9701606 W SE 9701606W WO 9815280 A1 WO9815280 A1 WO 9815280A1
Authority
WO
WIPO (PCT)
Prior art keywords
active ingredient
solvate
formoterol
budesonide
composition
Prior art date
Application number
PCT/SE1997/001606
Other languages
French (fr)
Inventor
Jan Trofast
Anders Ullman
Original Assignee
Astra Aktiebolag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astra Aktiebolag filed Critical Astra Aktiebolag
Priority to EP97944242A priority Critical patent/EP0871450A1/en
Priority to JP10517442A priority patent/JP2000502365A/en
Priority to KR1019980704266A priority patent/KR19990071975A/en
Priority to AU45782/97A priority patent/AU715319B2/en
Priority to SK751-98A priority patent/SK75198A3/en
Priority to BR9706822A priority patent/BR9706822A/en
Priority to PL97327037A priority patent/PL327037A1/en
Publication of WO1998015280A1 publication Critical patent/WO1998015280A1/en
Priority to NO982414A priority patent/NO982414L/en

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Classifications

    • 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

Definitions

  • the present invention provides a new combination of pharmaceutically active substances which is of use in the treatment of respiratory disorders, particularly asthma.
  • asthma 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 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 include uncontrolled airway inflammation which may lead to mucosal damage and structural changes possibly leading to irreversible narrowing of the airways and fibrosis of the lungs.
  • the symptoms may be controlled by ⁇ 2 -adrenoreceptor agonists such as salbutamol, salmeterol, terbutaline and formoterol.
  • Formoterol is advantageous because the duration of its effect is long; it has a fast onset time and because it gives few nocturnal wakenings.
  • Prophylactic therapy is typically provided by steroids such as beclomethasone diproprionate, fluticasone propionate and budesonide.
  • steroids such as beclomethasone diproprionate, fluticasone propionate and budesonide.
  • 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 inhaled budesonide has an excellent safety profile.
  • composition comprising, in an admixture: (a) a first active ingredient which is formoterol, a pharmaceutically acceptable salt or solvate of formoterol, or a solvate of such a salt; and
  • a second active ingredient which is budesonide 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.
  • kits comprising: (i) a vessel containing the first active ingredient; (ii) a vessel containing the second active ingredient; and (iii) 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, preferably about 1 :32.5.
  • a patient suffering from a respiratory disorder such as asthma can be treated by administering via inhalation a composition according to the invention.
  • a patient can be treated by administering via inhalation, sequentially or separately: (i) a dose of the first active ingredient; and (ii) a dose of the second active ingredient; 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.
  • the combination of active ingredients according to the invention is advantageous because it gives a significantly improved anti-inflammatory effect compared to known treatments.
  • International patent publication no. WO 93/11773 discloses a combination of budesonide and formoterol having a wide weight ratio range.
  • the closest example of a combination disclosed in this document to the system of the invention has a weight ratio of formoterol 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 better results when used to treat patients suffering from asthma compared to this known combination.
  • the first and second active ingredients of the kit can be administered sequentially or separately to treat respiratory disorders. By sequential is meant that the first and second active ingredients are administered one immediately after the other. They still have the desired effect if they are administered separately but less than about 12 hours apart, preferably less than about 2 hours apart, more preferably less than about 30 minutes apart.
  • the first active ingredient is administered to provide a daily dose of from 10 to 250nmol (preferably from 15 to 120nmol) and the second active ingredient is administered to provide a daily dose of from 0.1 to lO ⁇ mol (preferably 0.2 to 5 ⁇ mol) or from 39 to 4300 ⁇ g of the second active ingredient (preferably from 86 to 2150 ⁇ g), subject to the molar ratio of the first active ingredient to the second active ingredient being within the range of from 1:30 to 1 :36.
  • Suitable physiologically acceptable salts of formoterol include acid addition salts derived from inorganic and organic acids, for example the chloride, bromide, sulphate, phosphate, maleate, fumarate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate, p-toluenesulphonate, methanesulphonate, ascorbate, acetate, succinate, lactate, glutarate, gluconate, tricarballylate, hydroxynaphthalene-carboxylate or oleate salts or solvates thereof.
  • the first active ingredient is preferably formoterol fumarate, especially the dihydrate.
  • the preferred daily dose of the first active ingredient is from 4 to lOO ⁇ g, more preferably from 6 to 50 ⁇ g (subject to the molar ratio of the first active ingredient to the second active ingredient being within the range of from 1:30 to 1:36).
  • composition or kit of the invention comprises 6 ⁇ g of formoterol fumarate dihydrate and 200 ⁇ g of budesonide, or 4.5 ⁇ g of formoterol fumarate dihydrate and 160 ⁇ g of budesonide, either of which is administered up to four times a day.
  • composition or kit of the invention comprises 12 ⁇ g of formoterol fumarate dihydrate and 400 ⁇ g of budesonide, or 9 ⁇ g of formoterol fumarate dihydrate and 320 ⁇ g of budesonide, either of which is administered once or twice a day.
  • the active ingredient(s) are used in admixture with one or more pharmaceutically acceptable additives, diluents or carriers, preferably in an amount of from 50 ⁇ g to 25mg per dose, more preferably in an amount of from 50 ⁇ g to lOmg, most preferably in an amount of from 100 to 2000 ⁇ g.
  • suitable diluents or carriers include lactose, dextran, mannitol and glucose.
  • lactose is used, especially as the monohydrate.
  • the amounts of each active ingredient that these are metered amounts.
  • 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.
  • the administered amount of each is not necessarily reduced proportionately.
  • the administered ratio of the active ingredients could differ from the metered ratio.
  • the administered ratio is within the metered ratio specified above.
  • One or more of the active ingredients used in the invention is preferably in the form 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 lO ⁇ m, for example from 1 to 5 ⁇ m, most preferably an agglomerated micronised dry powder.
  • the finely divided active ingredients may be in the form of an ordered mixture with the one or more pharmaceutically acceptable additives, diluents or carriers.
  • An ordered mixture is the combination of finely divided active ingredient with coarse particles of pharmaceutically acceptable additive, diluent or carrier.
  • the ingredients used in the invention can be obtained in these preferred forms using methods known to those of skill in the art.
  • compositions or kit according to the invention in the manufacture of a medicament for use in the treatment of a respiratory disorder, e.g. asthma.
  • the invention also provides the use of budesonide or of formoterol in the manufacture of a kit or of a composition according to the invention for use in the treatment of a respiratory disorder, e.g. asthma.
  • Administration may be by inhalation orally or intranasally.
  • the ingredients are preferably adapted to be administered from a dry powder inhaler, a pressurised metered dose inhaler, or a nebuliser.
  • ingredients of the composition or kit are adapted to be administered from a pressurised inhaler, they are preferably in micronised form. They are dissolved or, preferably, suspended in a liquid propellant mixture.
  • the propellants which can be used include chlorofluorocarbons, hydrocarbons or hydrofluoroalkanes.
  • Especially preferred propellants are PI 34a (tetrafluoroethane) and P227 (heptafluoropropane) 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 excipients, for example ethanol, a lubricant, an anti-oxidant and/or a stabilising agent.
  • ingredients of the composition or kit of the invention are adapted to be administered via a nebuliser they may be in the form of a nebulised aqueous suspension or solution, with or without a suitable pH or tonicity adjustment, either as a unit dose or multidose device.
  • composition or kit may optionally be administered as divided doses from 1 to 4, and preferably once or twice a day.
  • 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 pressure 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 mixture was then spheronised using the process of EP-A-721 331 and filled into the storage compartment of a Turbuhaler.
  • Example 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 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 compartment of a Turbuhaler.
  • micronised budesonide 200 Parts by weight of micronised budesonide was mixed with 800 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 compartment of a Turbuhaler.
  • Example 5 4.5 Parts by weight of formoterol fumarate 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 compartment of a Turbuhaler.
  • micronised budesonide 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 mixture was then spheronised using the process of EP-A-721 331 and filled into the storage compartment 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 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 compartment of a Turbuhaler.
  • micronised budesonide 400 Parts by weight of micronised budesonide was mixed with 600 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 compartment of a Turbuhaler.

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

NEW COMBINATION
Field of the Invention
The present invention provides a new combination of pharmaceutically active substances which is of use in the treatment 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 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 include uncontrolled airway inflammation which may lead to mucosal damage and structural changes possibly leading to irreversible narrowing of the airways and fibrosis of the lungs.
The symptoms may be controlled by β2-adrenoreceptor agonists such as salbutamol, salmeterol, terbutaline and formoterol. Formoterol is advantageous because the duration of its effect is long; it has a fast onset time and because it gives few nocturnal wakenings.
Prophylactic therapy is typically provided by steroids such as beclomethasone diproprionate, 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 inhaled budesonide has an excellent safety profile.
Description of the Invention
According to the invention there is provided a composition comprising, in an admixture: (a) a first active ingredient which is formoterol, a pharmaceutically 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 1 :30 to 1 :36, preferably about 1 :32.5.
According to the invention there is further provided a kit comprising: (i) a vessel containing the first active ingredient; (ii) a vessel containing the second active ingredient; and (iii) 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, preferably about 1 :32.5.
A patient suffering from a respiratory disorder such as asthma can be treated by administering via inhalation a composition according to the invention. Alternatively such a patient can be treated by administering via inhalation, sequentially or separately: (i) a dose of the first active ingredient; and (ii) a dose of the second active ingredient; 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.
It has been found that the combination of active ingredients according to the invention is advantageous because it gives a significantly improved anti-inflammatory effect compared to known treatments. International patent publication no. WO 93/11773 discloses a combination of budesonide and formoterol having a wide weight ratio range. The closest example of a combination disclosed in this document to the system of the invention has a weight ratio of formoterol 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 better results when used to treat patients suffering from asthma compared to this known combination. The first and second active ingredients of the kit can be administered sequentially or separately to treat respiratory disorders. By sequential is meant that the first and second active ingredients are administered one immediately after the other. They still have the desired effect if they are administered separately but less than about 12 hours apart, preferably less than about 2 hours apart, more preferably less than about 30 minutes apart.
Preferably the first active ingredient is administered to provide a daily dose of from 10 to 250nmol (preferably from 15 to 120nmol) and the second active ingredient is administered to provide a daily dose of from 0.1 to lOμmol (preferably 0.2 to 5μmol) or from 39 to 4300μg of the second active ingredient (preferably from 86 to 2150μg), subject to the molar ratio of the first active ingredient to the second active ingredient being within the range of from 1:30 to 1 :36.
Suitable physiologically acceptable salts of formoterol include acid addition salts derived from inorganic and organic acids, for example the chloride, bromide, sulphate, phosphate, maleate, fumarate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate, p-toluenesulphonate, methanesulphonate, ascorbate, acetate, succinate, lactate, glutarate, gluconate, tricarballylate, hydroxynaphthalene-carboxylate or oleate salts or solvates thereof. The 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 lOOμg, more preferably from 6 to 50μg (subject to the molar ratio of the first active 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 6μg of formoterol fumarate dihydrate and 200μg of budesonide, or 4.5μg of formoterol fumarate dihydrate and 160μg of budesonide, either of which is administered up to four times a day. Alternatively the composition or kit of the invention comprises 12μg of formoterol fumarate dihydrate and 400μg of budesonide, or 9μg of formoterol fumarate dihydrate and 320μg of budesonide, either of which is administered once or twice a day.
Preferably the active ingredient(s) are used in admixture with one or more pharmaceutically acceptable additives, diluents or carriers, preferably in an amount of from 50μg to 25mg per dose, more preferably in an amount of from 50μg to lOmg, most preferably in an amount of from 100 to 2000μg. Examples of suitable diluents or carriers include lactose, dextran, mannitol and glucose. Preferably lactose is used, especially as the 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 administered, 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 formulated separately, the administered amount of each is not necessarily reduced proportionately. Thus the administered ratio of the active ingredients could differ from the metered ratio. Preferably the administered ratio is within the metered ratio specified above.
One or more of the active ingredients used in the invention is preferably in the form 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 lOμm, for example from 1 to 5μm, most preferably an agglomerated micronised dry powder. As an alternative to agglomeration the finely divided active ingredients may be in the form of an ordered mixture with the one or more pharmaceutically acceptable additives, diluents or carriers. An ordered mixture is the combination of finely divided active ingredient with coarse particles of pharmaceutically acceptable additive, diluent or carrier. The ingredients used in the invention can be obtained in these preferred forms using methods known to those of skill in the art. 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 treatment of a respiratory disorder, e.g. asthma. The invention also provides the use of budesonide or of formoterol in the manufacture of a kit or of a composition according to the invention for use in the treatment of a respiratory disorder, e.g. asthma.
Administration may be by inhalation orally or intranasally. The ingredients are preferably adapted to be administered from a dry powder inhaler, a pressurised metered dose inhaler, or a nebuliser.
When the ingredients of the composition or kit are adapted to be administered from a pressurised inhaler, they are preferably in micronised form. They are dissolved or, preferably, suspended in a liquid propellant mixture. The propellants which can be used include chlorofluorocarbons, hydrocarbons or hydrofluoroalkanes. Especially preferred propellants are PI 34a (tetrafluoroethane) and P227 (heptafluoropropane) 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 excipients, for example ethanol, a lubricant, an anti-oxidant and/or a stabilising agent.
When the ingredients of the composition or kit of the invention are adapted to be administered via a nebuliser they may be in the form of a nebulised aqueous suspension or solution, with or without a suitable pH or tonicity adjustment, either as a unit dose or multidose device.
The composition or kit may optionally be administered as divided doses from 1 to 4, and preferably once or twice a day.
The invention is illustrated by the following Examples which are not intended to limit the scope of the application. In the Examples micronisation is carried out in a conventional manner such that the particle size range for each component is suitable for administration 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 pressure 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 mixture was then spheronised using the process of EP-A-721 331 and filled into the storage compartment of a Turbuhaler.
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-717 616. 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-721 331 and filled into the storage compartment of a Turbuhaler.
Example 3 12 Parts by weight of formoterol fumarate dihydrate was mixed with 588 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. 400 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-721 331 and filled into the storage compartment of a Turbuhaler.
Example 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 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 compartment of a Turbuhaler.
200 Parts by weight of micronised budesonide was mixed with 800 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 compartment of a Turbuhaler.
Example 5 4.5 Parts by weight of formoterol fumarate 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 compartment 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 mixture was then spheronised using the process of EP-A-721 331 and filled into the storage compartment 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 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 compartment 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 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 compartment of a Turbuhaler.

Claims

Claims
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.
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.
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.
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.
PCT/SE1997/001606 1996-10-08 1997-09-24 New combination WO1998015280A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
EP97944242A EP0871450A1 (en) 1996-10-08 1997-09-24 New combination
JP10517442A JP2000502365A (en) 1996-10-08 1997-09-24 New combinations
KR1019980704266A KR19990071975A (en) 1996-10-08 1997-09-24 New complex composition
AU45782/97A AU715319B2 (en) 1996-10-08 1997-09-24 New combination
SK751-98A SK75198A3 (en) 1996-10-08 1997-09-24 Pharmaceutical composition
BR9706822A BR9706822A (en) 1996-10-08 1997-09-24 Process kit composition for treatment of a respiratory disorder and use of the formoterol kit composition of a pharmaceutically acceptable salt or solvate of it and budesonide
PL97327037A PL327037A1 (en) 1996-10-08 1997-09-24 Novel combination
NO982414A NO982414L (en) 1996-10-08 1998-05-27 New combination

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US5980949A (en) * 1994-10-03 1999-11-09 Astra Aktiebolag Formulation for inhalation
US5983956A (en) * 1994-10-03 1999-11-16 Astra Aktiebolag Formulation for inhalation
US6027714A (en) * 1997-01-20 2000-02-22 Astra Aktiebolag Formulation for inhalation
US6030604A (en) * 1997-01-20 2000-02-29 Astra Aktiebolag Formulation for inhalation
WO2000035441A2 (en) * 1998-12-18 2000-06-22 Baker Norton Pharmaceuticals, Inc. Pharmaceutical aerosol formulations containing fluoroalkanes, budesonide and formoterol
WO2000053188A1 (en) * 1999-03-09 2000-09-14 Astrazeneca Ab New combination of r,r-formoterol and budesonide in a pharmaceutical composition useful for treating respiratory disorders, such as asthma, rhinitis and copd
ES2149083A1 (en) * 1997-01-20 2000-10-16 Astra Ab New formulation for inhalation having a poured bulk density of from 0.28 to 0.38 g/ml, comprising terbutaline sulphate, a process for preparing the formulation and the use thereof
US6290930B1 (en) 1998-12-18 2001-09-18 Baker Norton Pharmaceuticals, Inc. Pharmaceutical solution aerosol formulations containing fluoroalkanes and budesonide
WO2001078737A1 (en) * 2000-04-18 2001-10-25 Glaxo Group Limited Medical combinations comprising formoterol and budesonide
WO2002028378A1 (en) 2000-10-06 2002-04-11 Orion Corporation Combination particles for the treatment of asthma
US6451285B2 (en) 1998-06-19 2002-09-17 Baker Norton Pharmaceuticals, Inc. Suspension aerosol formulations containing formoterol fumarate and a fluoroalkane propellant
EP1316311A1 (en) * 1998-06-11 2003-06-04 AstraZeneca AB Therapeutic use on-demand of formoterol and budesonide
US6667344B2 (en) 2001-04-17 2003-12-23 Dey, L.P. Bronchodilating compositions and methods
EP1462100A1 (en) * 2000-05-19 2004-09-29 AstraZeneca AB Composition comprising formoterol and a glucosorticosteroid
WO2004110539A1 (en) 2003-06-19 2004-12-23 Microdrug Ag Administration of medicinal dry powders
US7348362B2 (en) 2003-07-10 2008-03-25 Dey, L.P. Bronchodilating β-agonist compositions and methods
EP2124915A2 (en) 2007-02-19 2009-12-02 Cipla Limited Pharmaceutical combinations of at least two bronchodilators or of a bronchodilator with a corticosteroid
US7759328B2 (en) 2002-02-01 2010-07-20 Astrazeneca Ab Composition for inhalation
JP2011021036A (en) * 1999-05-12 2011-02-03 Boehringer Ingelheim Pharma Gmbh & Co Kg NEW MEDICAMENT COMPOSITIONS BASED ON ANTI-CHOLINERGICALLY-EFFECTIVE COMPOUNDS AND beta-MIMETICS
US20110038806A1 (en) * 2003-07-29 2011-02-17 Boehringer Ingelheim International Gmbh Medicaments for inhalation comprising an anticholinergic and a steroid
US7897646B2 (en) 1997-09-19 2011-03-01 Astrazeneca Ab Use for budesonide and formoterol
WO2013128283A3 (en) * 2012-02-28 2013-10-31 Iceutica Holdings Inc. Bvi Inhalable pharmaceutical compositions
US8623851B2 (en) 2001-04-17 2014-01-07 Mylan Specialty L.P. Formoterol/steroid bronchodilating compositions and methods of use thereof
US9333195B2 (en) 1999-07-14 2016-05-10 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US9737520B2 (en) 2011-04-15 2017-08-22 Almirall, S.A. Aclidinium for use in improving the quality of sleep in respiratory patients
US10085974B2 (en) 2008-03-13 2018-10-02 Almirall, S.A. Dosage and formulation
US10226421B2 (en) 2013-04-10 2019-03-12 Zambon S.P.A. Pharmaceutical composition containing budesonide and formoterol
US10716753B2 (en) 2009-05-29 2020-07-21 Pearl Therapeutics, Inc. Compositions for pulmonary delivery of long-acting muscarinic antagonists or long-acting B2 adrenergic receptor agonists and associated methods and systems
US11103516B2 (en) 2011-11-23 2021-08-31 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
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GR980100022A (en) * 1997-01-20 1998-09-30 Astra Aktiebolag New formulation for inhalation
US6027714A (en) * 1997-01-20 2000-02-22 Astra Aktiebolag Formulation for inhalation
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US6199607B1 (en) 1997-01-20 2001-03-13 Astra Aktiebolag Formulation for inhalation
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WO1999000134A1 (en) * 1997-06-27 1999-01-07 Astra Aktiebolag (Publ) New combination of antiasthma medicaments
US8461211B2 (en) 1997-09-19 2013-06-11 Astrazeneca Ab Use for budesonide and formoterol
US7897646B2 (en) 1997-09-19 2011-03-01 Astrazeneca Ab Use for budesonide and formoterol
US9295644B2 (en) 1998-06-11 2016-03-29 Astrazeneca Ab Methods and compositions for treating asthma
EP2266574A1 (en) 1998-06-11 2010-12-29 AstraZeneca AB (Publ) Therapeutic use on-demand of formoterol and budesonide
EP1316311A1 (en) * 1998-06-11 2003-06-04 AstraZeneca AB Therapeutic use on-demand of formoterol and budesonide
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
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WO2000035441A2 (en) * 1998-12-18 2000-06-22 Baker Norton Pharmaceuticals, Inc. Pharmaceutical aerosol formulations containing fluoroalkanes, budesonide and formoterol
JP2002532418A (en) * 1998-12-18 2002-10-02 ベーカー ノートン ファーマシューティカルズ インコーポレイテッド Pharmaceutical aerosol formulation containing fluoroalkane, budesonide and formoterol
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EP0871450A1 (en) 1998-10-21
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NO982414D0 (en) 1998-05-27
HUP9901674A2 (en) 1999-09-28
SK75198A3 (en) 1998-11-04
BR9706822A (en) 1999-03-23
CZ176198A3 (en) 1998-09-16
NZ330482A (en) 1999-11-29
KR19990071975A (en) 1999-09-27
SE9603669D0 (en) 1996-10-08
CA2239308A1 (en) 1998-04-16
HUP9901674A3 (en) 2001-04-28
NO982414L (en) 1998-05-27
JP2000502365A (en) 2000-02-29
AR013614A1 (en) 2001-01-10
ZA978889B (en) 1998-04-08
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MY128337A (en) 2007-01-31

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