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
  • 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 relates to compositions and methods useful 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, bambuterol, clenbuterol, fenoterol, procaterol, bitolterol, broxaterol, salmeterol, terbutaline and formoterol.
• ⁇ 2 -adrenoreceptor agonists such as salbutamol, bambuterol, clenbuterol, fenoterol, procaterol, bitolterol, broxaterol, salmeterol, terbutaline and formoterol.
• Prophylactic therapy is typically provided by steroids such as beclomethasone dipropionate (BDP), beclomethasone monopropionate (BMP), flunisolide, triamcinolone acetonide, dexamethasone, tipredane, ciclesonid, momethasone, RPR 106541, fluticasone or fluticasone propionate and budesonide or by way of sodium cromoglycate or nedocromil sodium.
• steroids such as beclomethasone dipropionate (BDP), beclomethasone monopropionate (BMP), flunisolide, triamcinolone acetonide, dexamethasone, tipredane, ciclesonid, momethasone, RPR 106541, fluticasone or fluticasone propionate and budesonide or by way of sodium cromoglycate or nedocromil sodium.
• the invention is based on the discovery that formeterol and rofleponide esters, or their salts or solvates, when administered to a patient either concurrently or sequentially, are unexpectedly effective in treating respiratory disorders involving inflammation, such as asthma.
• the invention features a composition having, 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 rofleponide or a fatty acid ester of rofleponide.
• the molar ratio of (a) to (b) is from 1:1 to 1 :100, preferably from 1 : 1 to 1 :60, more preferably from 1 : 1 to 1 :35, and most preferably from 1 :16.
• the first active ingredient (a) of the composition can be, for example, formoterol fumarate dihydrate, and the second active ingredient (b) of the composition can be, for example, rofleponide palmitate.
• the composition can be provided in the form of a dry powder, the particles of which may have a mass median diameter of less than lO ⁇ m.
• the invention also includes a kit containing: (a) a vessel containing a first active ingredient that is formoterol, a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt; (b) a vessel containing a second active ingredient that is either rofleponide or a fatty acid ester of rofleponide; and (c) instructions for the sequential or simultaneous admimstration of the first and second active ingredients to a patient in need thereof.
• a patient suffering from a respiratory disorder such as asthma can be treated by administering (e.g., via inhalation), simultaneously or sequentially, (a) a dose of 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 dose of a second active ingredient selected from the group consisting of rofleponide and a fatty acid ester of rofleponide.
• the active ingredients can be provided to the patient for inhalation in dry powder form.
• the active ingredients can be administered in either order, and within a two-hour time period.
• the first active ingredient can be administered to the patient less than about 30 minutes after the second active ingredient, or the second active ingredient can be administered to the patient less than about 30 minutes after the first active ingredient.
• the combination according to the invention has the advantage that the toal dose of each active ingredient can be decreased and is more likely to provide patient compliance then would be extected from the properties of the individual active ingredients.
• the invention provides a composition having (a) a first active ingredient selected from the group consisting of formoterol, a pharmaceutically acceptable salt or solvate of formoterol, and a solvate of such a salt; (b) a second active ingredient selected from the group consisting of rofleponide and a fatty acid ester of rofleponide; and, optionally, (c) one or more pharmaceutically acceptable additives, diluents or carriers.
• the first and second active ingredients of the composition can be administered simultaneously or sequentially to treat respiratory disorders.
• simultaneous is meant that the first and second active ingredients (a) and (b) are administered concomitantly, for example as an admixture.
• Sequential administration generally comprises administering one immediately after the other. They still have the desired effect if they are administered separately but not more than about two hours apart, for example no more than 30 minutes and preferably no more than 5 minutes apart.
• the composition is administered to provide a daily dose of from 0.5 to 200 nmol (preferably from 4 to 100 nmol) of (a) and from 0.5 to 1140 nmol (preferably 14 to 285 nmol and more preferably from 14 to 285 nmol) of (b) (subject to the molar ratio of (a) to (b) being from 1 :1 to 1 :100).
• the preferred daily dose is from 0.2 to 84 ⁇ g (preferably from 2 to 42 ⁇ g) of (a), and from 0.4 to 800 ⁇ g (preferably from 10 to 400 ⁇ g, more preferably from 10 to 200 ⁇ g) of (b) where (b) is rofleponide pa nitate (subject to the molar ratio of (a) to (b) being within the range of from 1 : 1 to 1 : 100).
• 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.
• Active ingredient (a) is preferably formoterol fumarate, especially as the dihydrate.
• Rofleponide is preferably esterified by a palmitoyl group.
• each of the active ingredients comprises one or more pharmaceutically acceptable additives, diluents or carriers, more preferably in an amount of from 50 to 2000 ⁇ g in a daily dose, most preferably in an amount of from 100 to 1000 ⁇ g.
• suitable diluents or carriers include lactose, dextran, mannitol and glucose.
• lactose is used.
• active ingredient (b) is preferably a fatty acid ester
• formulations containing it are desirably liposomal or proliposomal if they are dry powder formulations.
• Suitable proliposomal formulations of fatty acid esters of rofleponide are described in WO
• the formulation may comprise tocopherol, especially ⁇ - tocopherol.
• Active ingredients (a) and (b) may optionally be formulated together to be administered simultaneously.
• they may be formulated in admixture as a proliposomal powder, for example of the general type described in WO 96/19199
• One or more of the active ingredients according to the invention are preferably in the form of a dry powder, more preferably 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.
• active ingredient (a) may be in the form of an ordered mixture with ingredient (c).
• the ingredients used in the invention can be obtained in these preferred forms using methods known to those of skill in the art.
• the invention further provides a method of treating a respiratory disorder, which is preferably asthma, chronic obstructive pulmonary disease (COPD) and/or rhinitis, which method comprises applying to a patient suffering from, or liable to suffer from, such a disorder a therapeutically effective amount of a combination according to the invention.
• a respiratory disorder which is preferably asthma, chronic obstructive pulmonary disease (COPD) and/or rhinitis
• COPD chronic obstructive pulmonary disease
• rhinitis which method comprises applying to a patient suffering from, or liable to suffer from, such a disorder a therapeutically effective amount of a combination according to the invention.
• an admixture or kit according to the invention in the manufacture of a medicament for simultaneous, separate or sequential use in therapy, preferably in the treatment of a respiratory disorder, e.g. asthma, chronic obstructive pulmonary disease (COPD) and/or rhinitis.
• a respiratory disorder e.g. asthma, chronic obstructive pulmonary disease (COPD) and/or rhinitis.
• COPD chronic obstructive pulmonary disease
• Administration may be by inhalation orally or intranasally.
• the ingredients are preferably adapted to be administered from a dry powder inhaler.
• the combination may optionally be administered as divided doses from 1 to 4, and preferably once or twice a day, which means unit doses from 0.05 ⁇ g to 84 ⁇ g (preferably from 0.5 ⁇ g to 42 ⁇ g) of formoterol fumarate dihydrate and from 0.1 ⁇ g to 800 ⁇ g (preferably from 2.5 ⁇ g to 400 ⁇ g) of rofleponide pahnitate.
• Example 1 Rofleponide pahnitate (10 parts by weight), dipalmitoylphosphatidylcholine (63 parts), dimyristoylphosphatidylcholine (24 parts), sodium dipalmitoylphosphatidylglycerol (3 parts) and racemic ⁇ -tocopherol (0.1 part) were dissolved in tertiary butanol (1300 parts) at 80°C. The solution was poured onto the shelves of a freeze-dryer cooled to -35°C. The solution had reached this temperature after about 30 minutes, the pressure in the freeze- dryer was then reduced in order to induce sublimation of the solvent.

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• Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical & Material Sciences (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pulmonology (AREA)
• General Chemical & Material Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Epidemiology (AREA)
• Organic Chemistry (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1998
  • 1998-06-08 CA CA002295076A patent/CA2295076A1/en not_active Abandoned
  • 1998-06-08 IL IL13359798A patent/IL133597A0/xx unknown
  • 1998-06-08 SK SK1847-99A patent/SK184799A3/sk unknown
  • 1998-06-08 PL PL98337722A patent/PL337722A1/xx unknown
  • 1998-06-08 AU AU81350/98A patent/AU8135098A/en not_active Abandoned
  • 1998-06-08 ID IDW991684A patent/ID24063A/id unknown
  • 1998-06-08 EE EEP199900594A patent/EE9900594A/xx unknown
  • 1998-06-08 TR TR1999/03272T patent/TR199903272T2/xx unknown
  • 1998-06-08 EP EP98931163A patent/EP1009408A1/de not_active Withdrawn
  • 1998-06-08 JP JP50547999A patent/JP2002510310A/ja active Pending
  • 1998-06-08 KR KR1019997012233A patent/KR20010014162A/ko not_active Application Discontinuation
  • 1998-06-08 WO PCT/SE1998/001089 patent/WO1999000134A1/en not_active Application Discontinuation
  • 1998-06-08 HU HU0002533A patent/HUP0002533A3/hu unknown
  • 1998-06-08 BR BR9810452-7A patent/BR9810452A/pt not_active IP Right Cessation
• 1999
  • 1999-12-15 IS IS5303A patent/IS5303A/is unknown
  • 1999-12-23 NO NO996438A patent/NO996438L/no not_active Application Discontinuation

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