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.

Landscapes

• Health & Medical Sciences (AREA)
• 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)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Pulmonology (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)
• Medicines Containing Plant Substances (AREA)
• Medicinal Preparation (AREA)

Applications Claiming Priority (3)

Publications (1)

Family

ID=20404167

Family Applications (1)

Country Status (18)

Families Citing this family (32)

Family Cites Families (1)

• 1996
  • 1996-10-08 SE SE9603669A patent/SE9603669D0/xx unknown
• 1997
  • 1997-09-24 EP EP97944242A patent/EP0871450A1/en not_active Withdrawn
  • 1997-09-24 AU AU45782/97A patent/AU715319B2/en not_active Ceased
  • 1997-09-24 BR BR9706822A patent/BR9706822A/pt not_active IP Right Cessation
  • 1997-09-24 NZ NZ330482A patent/NZ330482A/xx unknown
  • 1997-09-24 JP JP10517442A patent/JP2000502365A/ja active Pending
  • 1997-09-24 PL PL97327037A patent/PL327037A1/xx unknown
  • 1997-09-24 WO PCT/SE1997/001606 patent/WO1998015280A1/en not_active Application Discontinuation
  • 1997-09-24 KR KR1019980704266A patent/KR19990071975A/ko not_active Application Discontinuation
  • 1997-09-24 HU HU9901674A patent/HUP9901674A3/hu unknown
  • 1997-09-24 CZ CZ981761A patent/CZ176198A3/cs unknown
  • 1997-09-24 CA CA002239308A patent/CA2239308A1/en not_active Abandoned
  • 1997-09-24 SK SK751-98A patent/SK75198A3/sk unknown
  • 1997-10-02 TW TW086114371A patent/TW470647B/zh not_active IP Right Cessation
  • 1997-10-03 ZA ZA9708889A patent/ZA978889B/xx unknown
  • 1997-10-07 AR ARP970104615A patent/AR013614A1/es not_active Application Discontinuation
  • 1997-10-07 MY MYPI97004698A patent/MY128337A/en unknown
• 1998
  • 1998-05-27 NO NO982414A patent/NO982414D0/no not_active Application Discontinuation

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events