WO2004028545A1 - Combinaison d'un agoniste $g(b)2 a action prolongee et d'un glucocorticosteroide dans le traitement de maladies fibrotiques - Google Patents

Combinaison d'un agoniste $g(b)2 a action prolongee et d'un glucocorticosteroide dans le traitement de maladies fibrotiques Download PDF

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Publication number
WO2004028545A1
WO2004028545A1 PCT/SE2003/001486 SE0301486W WO2004028545A1 WO 2004028545 A1 WO2004028545 A1 WO 2004028545A1 SE 0301486 W SE0301486 W SE 0301486W WO 2004028545 A1 WO2004028545 A1 WO 2004028545A1
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WO
WIPO (PCT)
Prior art keywords
hydroxy
use according
agonist
active ingredient
solvate
Prior art date
Application number
PCT/SE2003/001486
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English (en)
Inventor
Jan Trofast
Gunilla Westergren-Thorsson
Original Assignee
Astrazeneca Ab
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
Priority claimed from SE0202837A external-priority patent/SE0202837D0/xx
Priority claimed from SE0300106A external-priority patent/SE0300106D0/xx
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to AU2003263717A priority Critical patent/AU2003263717A1/en
Publication of WO2004028545A1 publication Critical patent/WO2004028545A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the connective tissue consists of extracellular matrix (ECM) molecules and forms the architectural framework of the vertebrate body.
  • ECM extracellular matrix
  • the extracellular matrix molecules are plentiful and play an important role in modulation of the connective tissue.
  • remodelling of connective tissue is due to an increase deposition of ECM components like that of specific types of collagens and proteoglycans.
  • the connective tissue is rich in fibrous proteins, and it is rather the ECM molecules than the cells that bear the mechanical supporty characteristics of the connective tissue.
  • There is an enormous variation in composition and physiological properties of different connective tissues varying from elasticity in fibrous connective tissue to a strength and rigidity in cartilage and bone.
  • the fibrous connective tissue in the lung is crucial for its elasticity.
  • the extracellular matrix forms a complex network of proteins and proteoglycans that embed cells in an interactive environment.
  • This environment provides a surrounding in which cells can migrate and interact with other cells and effector molecules.
  • the ECM constituents are affected during several pathological conditions, and have in many cases been shown to be involved in, and even to directly influence these processes.
  • Major components in the ECM are the collagens, proteoglycans, hyaluronan, fibronectin and laminin, which together with effecter molecules, such as cytokines and proteases, form a dynamic connective tissue.
  • Proteoglycans are a large family of molecules synthesized by a wide variety of cells, and are distributed in many types of tissues. Several deverse biological functions have been ascribed to proteoglycans, such as control of cell differentiation and migration, storage of cytokines, influence of tumor cell growth, regulation of ECM remodelling and tissue reorganization. Proteoglycans are proteins with one or more than a hundred glycosaminoglycan chains covalently attached to the protein core. They are often subdivided into groups according to size, structure and function. The large proteoglycans produced by lung fibroblasts are mainly versican and perlecan and the small proteoglycans are decorin and biglycan.
  • the main cell type found in fibrous connective tissue is the fibroblast.
  • Several diseases are associated with the connective tissue, and there is often an altered composition of ECM molecules over time.
  • the wound healing process is never turned off, resulting in an assembly of connective tissue molecules leading to the formation of fibrotic lesions.
  • This pattern is observed in certain diseases in the lung, for example asthma, systemic sclerosis, alveolitis, sarcoidosis and idiopathic pulmonary fibrosis, but also in chronic obstructive pulmonary disease. Controversy exists as to whether the latter observation involves fibrotic lesions or just emphysema.
  • the treatment of asthma generally consists of inhaled corticosteroids and inhaled ⁇ 2 agonists. Both beneficial and deleterious effects have been described when glucocorticosteroids and ⁇ -agonists are administered simultanously.
  • the invention therefore provides the use of a glucocorticosteroid and a long-acting ⁇ 2 -agonist for the treatment of fibrotic diseases mediated by the proteoglycan production of human embryonic lung fibroblasts.
  • the combination has more than an additive effect on a parameter like the decorin, which dominates the fibrotic type of matrix.
  • idiopathic pulmonary fibrosis also called cryptogenic or idopathic fibrosing alveolitis
  • pulmonary fibrosis in association with systemic sclerosis, systemic lupus erythernatosus, rheumatoid arthritis, dermatomyositis and polymyositis, Goodpasture's syndrome, and other immunologically mediated systemic diseases, and furthermore allergic alvelolitis (also called hypersensitivity pneumonitis), silicosis, asbestosis and other pulmonary granulomatoses, bronchiliotis, pulmonary vasculitis, drug-induced pneumonites, histiocytosis X, chronic eosinophilic pneumonia, pulmonary hemo
  • a preferred disease that can be treated is idiopathic pulmonary fibrosis.
  • a futher preferred disease that can be treated is allergic alveolitis.
  • a further preferred disease that can be treated is cystic fibrosis.
  • a further preferred disease that can be treated is rheumatoid arthritis.
  • glucocorticosteroids such as: budesonide, fluticasone (e.g. as propionate ester), mometasone (e.g. as furoate ester), beclomethasone (e.g. as 17-propionate or 17,21- dipropionate esters), ciclesonide, triamcinolone (e.g. as acetonide), flunisolide, zoticasone, flumoxonide, rofleponide, butixocort (e.g.
  • Long-acting ⁇ 2 agonists include: salmeterol, formoterol, bambuterol, TA 2005 (chemically identified as 2(lH)-Quinolone, 8-hydroxy-5-[l- hydroxy-2- [ [2-(4-methoxy-phenyl)- 1 -methylethyl] amino] ethyl] -monohydrochloride, [R- (R*,R*)] also identified by Chemical Abstract Service Registry Number 137888-11-0 and disclosed in U.S. Patent No 4.579.854, formanilide derivatives (HI) e.g.
  • the preferred pharmacologically active long-acting ⁇ 2 -agonist is salmeterol xinafoate, formanilide derivatives (III), benzenesulfonamide derivatives (IV) and formoterol (e.g. as fumarate dihydrate) and even more preferred is formoterol fumarate dihydrate.
  • the preferred combinations include fluticasone propionate/salmeterol xinafoate, ciclesonide/formoterol fumarate dihydrate, mometasone furoate/formoterol fumarate dihydrate, fluticasone propionate/formoterol fumarate dihydrate, and budesonide/formoterol fumarate dihydrate.
  • steroids from WO 2002/88167 /formanilide derivatives from WO 2002/76933 steroids from WO 2002/88167/benzenesulfonamide derivatives from WO 2002/88167, steroids from DE 4129535/formoterol fumarate dihydrate, zoticasone/benzenesulfonamide derivatives from WO 2002/88167 and zoticasone/formanilide derivative.
  • the most preferred combination is budesonide/formoterol fumarate dihydrate.
  • composition comprising, in admixture or separately:
  • a first active ingredient which is a long-acting ⁇ 2 -agonist, a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt
  • a second active ingredient which is a glucocorticosteroid. in the manufacture of a medicament for use in the prevention and/or treatment of fibrotic diseases.
  • the invention also provides a method of preventing and/or treating a fibrotic disease in patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a composition comprising, in admixture or separately:
  • a first active ingredient which is a long-acting ⁇ 2 -agonist, a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt
  • a second active ingredient which is a glucocorticosteroid.
  • the molar ratio of the first active ingredient to the second active ingredient is from 1:2500 to 12:1.
  • the molar ratio of the first active ingredient to the second active ingredient is preferably from 1:555 to 2: 1 and more preferably from 1:150 to 1:1.
  • the molar ratio of the first active ingredient to the second active ingredient is more preferably from 1:133 to 1:6.
  • the molar ratio of the first active ingredient to the second active ingredient is most preferably 1:70 to 1:4.
  • the components of the invention can be administered in admixture, i.e. together, or separately.
  • the components can be administered as a single pharmaceutical composition such as a fixed combination.
  • the components can be administered separately, i.e. one after the other.
  • the time interval for separate administration can be anything from sequential administration to administration several hours apart.
  • intestinal bowel diseases e.g. Crohn's disease
  • the daily dosage of the first active ingredient may be in the range of from 0.001 mg to 30 mg, in the case of the preferred formoterol (as fumarate dihydrate) from 0.001 mg to 0.100 mg.
  • the daily dosage of the second active ingredient may be in the range of from 0.01 mg to 30 mg, in the case of the preferred budesonide from 0.01 mg to 10 mg.
  • the invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing
  • a second active ingredient which is a glucocorticosteroid; with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the therapeutically active ingredients may be administered prophylactically as a preventive treatment or during the course of a medical condition as a treatment of cure.
  • compositions may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, fluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or foams or transdermally.
  • composition used in the invention optionally additionally comprises one or more pharmaceutically acceptable additives (e.g. pH or tonicity adjustment), diluents and/or carriers.
  • the composition is preferably in the form of a dry powder for inhalation, wherein the particles of the pharmaceutically active ingredients have a mass median diameter of less than 10 ⁇ m.
  • Suitable physiologically acceptable include acid addition salts derived from inorganic and organic acids, for example the chloride, bromide, sulphate, phosphate, maleate, fumarate, citrate, tartrate, benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate, p-toluenesulphonate, methane-sulphonate, ascorbate, acetate, succinate, lactate, glutarate, tricarballylate, hydroxynaphthalene-carboxylate (xinafoate) or oleate salts or solvates thereof.
  • the first active ingredient is preferably formoterol fumarate dihydrate or salmeterol xinafoate.
  • HFL-1 Human Embryonic Lung Fibroblast (HFL-1) cultures were incubated with BUD 10 "8 M, FORM 10 "8 - 10 "10 M and combinations thereof like BUD 10 "8 M + FORM 10 "8 M and BUD 10 "8 M + FORM 10 "10 M. Controls were used as described above. After 2h incubation the cells were labeled with 100 ⁇ Ci/ml 35 S-sulphate (ARC St. Louis, MO, USA) for 24 h in sulfate-low EMEM supplemented with 10 % fetal calf serum. The culture medium was then harvested and analyzed for amounts and type of secreted proteoglycans.
  • the total amount of proteoglycans was determined by ion exchange chromatography as previously described (Westergren Thorsson et al (Eur. J. Biochem. 205 (1992), 277-286)). Briefly, the cell medium was applied to a DEAE-cellulose DE-52 column (0.7 x 4 cm: Whatman, Maidstone, UK), which had been equilibrated with 6 M urea, 50 mM acetic acid, pH 5.8, 5 mM N-ethylmaleimide, 1 mM EDTA and 5 ⁇ g/ml of ovalbumin. To remove unincorporated radioactive precursors, the columns were washed with 60 bed volumes of the same solution.
  • Hyaluronan was eluted with 6 bed volumes of 6 M urea, 500 mM acetic acid, and 5 ⁇ g/ml of ovalbumin. Finally, proteoglycans were eluted twice with 3 bed volumes of 4 M guanidium chloride, 50 mM sodium acetate, pH 5.8, and 5 ⁇ g/ml of ovalbumin.
  • BUD (10 "8 M) Treatment with BUD (10 "8 M) alone selectively decreased the production of some proteoglycans such as versican and biglycan. Both versican and biglycan production decreased by 34-36 %. However no effect was seen on the production of either perlecan or decorin.
  • the combination of BUD (10 "8 M) +FORM (10 "10 M) decreased the production of all four types of proteoglycans like versican, perlecan, biglycan and decorin by 62-68% and the combination of BUD (10 "8 M) + FORM (10 "10 M) was even more potent, decreasing the production all four types of proteoglycans by 80-88%. This clearly shows that the combination also has effect on the more fibrotic type of matrix, where decorin is known to be a marker.

Abstract

L'invention concerne de nouvelles applications de glucocorticostéroïdes et d'agonistes β2 à action prolongée dans le traitement de diverses maladies fibrotiques, p. ex. la fibrose pulmonaire idiopathique, l'alvéolite allergique et la mucoviscidose. La combinaison préférée de principes actifs associe budesonide et dihydrate de fumarate de formoterol.
PCT/SE2003/001486 2002-09-25 2003-09-24 Combinaison d'un agoniste $g(b)2 a action prolongee et d'un glucocorticosteroide dans le traitement de maladies fibrotiques WO2004028545A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003263717A AU2003263717A1 (en) 2002-09-25 2003-09-24 A COMBINATION OF A LONG-ACTING Beta2-AGONIST AND A GLUCOCORTICOSTEROID IN THE TREATMENT OF FIBROTIC DISEASES

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
SE0202837-1 2002-09-25
SE0202837A SE0202837D0 (sv) 2002-09-25 2002-09-25 New use
SE0300106-2 2003-01-16
SE0300106A SE0300106D0 (sv) 2003-01-16 2003-01-16 New use

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WO2004028545A1 true WO2004028545A1 (fr) 2004-04-08

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005013945A2 (fr) * 2003-08-05 2005-02-17 Boehringer Ingelheim International Gmbh Medicament pour inhalation comprenant des steroides et un betamimetique
WO2008048770A1 (fr) 2006-10-17 2008-04-24 Lipothera, Inc. Procédés, compositions, et formulations pour le traitement de la maladie de l'oeil liée à la thyroïde
EP1921919A2 (fr) * 2005-07-14 2008-05-21 Lipothera, Inc. Preparation lipolytique amelioree a liberation prolongee pour traitement de tissu adipeux localise
CN102247380A (zh) * 2011-08-19 2011-11-23 北京阜康仁生物制药科技有限公司 一种以布地奈德与茚达特罗为活性成分的复方制剂
WO2012007729A2 (fr) 2010-07-16 2012-01-19 Cipla Limited Compositions pharmaceutiques
WO2012049444A1 (fr) 2010-10-12 2012-04-19 Cipla Limited Composition pharmaceutique
US8404750B2 (en) 2009-05-27 2013-03-26 Lithera, Inc. Methods for administration and formulations for the treatment of regional adipose tissue
US9402854B2 (en) 2012-04-11 2016-08-02 Cipla Limited Pharmaceutical composition
WO2016149756A1 (fr) * 2015-03-23 2016-09-29 The University Of Melbourne Traitement de maladies respiratoires
US9597531B2 (en) 2010-11-24 2017-03-21 Neothetics, Inc. Selective, lipophilic, and long-acting beta agonist monotherapeutic formulations and methods for the cosmetic treatment of adiposity and contour bulging

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WO2002017894A2 (fr) * 2000-08-31 2002-03-07 Glaxo Group Limited Utilisation d'une combinaison de salmeterol et de propionate de fluticasone

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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005013945A3 (fr) * 2003-08-05 2005-06-23 Boehringer Ingelheim Int Medicament pour inhalation comprenant des steroides et un betamimetique
WO2005013945A2 (fr) * 2003-08-05 2005-02-17 Boehringer Ingelheim International Gmbh Medicament pour inhalation comprenant des steroides et un betamimetique
EP2397034A1 (fr) * 2005-07-14 2011-12-21 Lithera, Inc. Formulation lipolytique améliorée à libération prolongée pour le traitement régional des tissus adipeux
US9707192B2 (en) 2005-07-14 2017-07-18 Neothetics, Inc. Lipolytic methods
EP1921919A2 (fr) * 2005-07-14 2008-05-21 Lipothera, Inc. Preparation lipolytique amelioree a liberation prolongee pour traitement de tissu adipeux localise
US9452147B2 (en) 2005-07-14 2016-09-27 Neothetics, Inc. Lipolytic methods
US9370498B2 (en) 2005-07-14 2016-06-21 Neothetics, Inc. Methods of using lipolytic formulations for regional adipose tissue treatment
EP1921919A4 (fr) * 2005-07-14 2010-04-14 Lithera Inc Preparation lipolytique amelioree a liberation prolongee pour traitement de tissu adipeux localise
US9198885B2 (en) 2005-07-14 2015-12-01 Neothetics, Inc. Lipolytic methods for regional adiposity comprising salmeterol or formoterol
US7829554B2 (en) 2005-07-14 2010-11-09 Lithera, Inc. Sustained release enhanced lipolytic formulation for regional adipose tissue treatment
US8420625B2 (en) 2005-07-14 2013-04-16 Lithera, Inc Lipolytic methods for regional adiposity
EP2077830A4 (fr) * 2006-10-17 2010-04-14 Lithera Inc Procédés, compositions, et formulations pour le traitement de la maladie de l'oeil liée à la thyroïde
EP2076269A4 (fr) * 2006-10-17 2010-05-19 Lithera Inc Formulations pour le traitement de troubles des tissus adipeux, cutanés et musculaires
WO2008048770A1 (fr) 2006-10-17 2008-04-24 Lipothera, Inc. Procédés, compositions, et formulations pour le traitement de la maladie de l'oeil liée à la thyroïde
EP2076269A2 (fr) * 2006-10-17 2009-07-08 Lithera, Inc. Formulations pour le traitement de troubles des tissus adipeux, cutanés et musculaires
EP2077830A1 (fr) * 2006-10-17 2009-07-15 Lithera, Inc. Procédés, compositions, et formulations pour le traitement de la maladie de l'oeil liée à la thyroïde
US9132084B2 (en) 2009-05-27 2015-09-15 Neothetics, Inc. Methods for administration and formulations for the treatment of regional adipose tissue
US9452132B2 (en) 2009-05-27 2016-09-27 Neothetics, Inc. Methods for administration and formulations for the treatment of regional adipose tissue
US8404750B2 (en) 2009-05-27 2013-03-26 Lithera, Inc. Methods for administration and formulations for the treatment of regional adipose tissue
WO2012007729A2 (fr) 2010-07-16 2012-01-19 Cipla Limited Compositions pharmaceutiques
EP3871676A1 (fr) 2010-07-16 2021-09-01 Cipla Limited Compositions pharmaceutiques comprenant r(+) budesonide et arformoterol
WO2012049444A1 (fr) 2010-10-12 2012-04-19 Cipla Limited Composition pharmaceutique
US9597531B2 (en) 2010-11-24 2017-03-21 Neothetics, Inc. Selective, lipophilic, and long-acting beta agonist monotherapeutic formulations and methods for the cosmetic treatment of adiposity and contour bulging
CN102247380A (zh) * 2011-08-19 2011-11-23 北京阜康仁生物制药科技有限公司 一种以布地奈德与茚达特罗为活性成分的复方制剂
US9402854B2 (en) 2012-04-11 2016-08-02 Cipla Limited Pharmaceutical composition
WO2016149756A1 (fr) * 2015-03-23 2016-09-29 The University Of Melbourne Traitement de maladies respiratoires
US10722513B2 (en) 2015-03-23 2020-07-28 The University Of Melbourne Treatment of respiratory diseases
US11564925B2 (en) 2015-03-23 2023-01-31 The University Of Melbourne Treatment of respiratory diseases

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