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WO2006123125A1 - Combinaisons de statines avec des glucocorticosteroides - Google Patents

Combinaisons de statines avec des glucocorticosteroides Download PDF

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Publication number
WO2006123125A1
WO2006123125A1 PCT/GB2006/001791 GB2006001791W WO2006123125A1 WO 2006123125 A1 WO2006123125 A1 WO 2006123125A1 GB 2006001791 W GB2006001791 W GB 2006001791W WO 2006123125 A1 WO2006123125 A1 WO 2006123125A1
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WO
WIPO (PCT)
Prior art keywords
solvate
copd
statin
salt
pharmaceutically acceptable
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/GB2006/001791
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English (en)
Inventor
Bertil Lindmark
Anders Thoren
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca UK Ltd
AstraZeneca AB
Original Assignee
AstraZeneca UK Ltd
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
Application filed by AstraZeneca UK Ltd, AstraZeneca AB filed Critical AstraZeneca UK Ltd
Publication of WO2006123125A1 publication Critical patent/WO2006123125A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • 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
    • 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
    • A61P11/08—Bronchodilators

Definitions

  • the invention provides medicaments comprising combinations of glucocorticosteroids and HMG-CoA reductase inhibitors in the treatment of respiratory disorders such as chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • COPD ulcerative colitis
  • a systemic inflammation continues to be active also long after smoking cessation.
  • Patients with COPD are numerous and the disease is difficult to treat. Treatments exist that have effect on bronchospasm, symptoms, quality of life and exacerbations, however there is none that is able to slow down the progressive and accelerated loss of lung function.
  • One of the primary objectives of treatment is to reduce the progression of the disease and to obtain this smoking cessation is the most important step. However, far from all COPD patients can or even wish to give up smoking and even if the patients stop smoking the airway obstruction will most often not disappear. In these cases pharmacological therapy may provide some relief.
  • bronchodilating agents consists mainly of short and long-acting anticholinergics and ⁇ 2 -agonists.
  • the glucocorticosteroid treatment approach is more questioned, but with the introduction of combination therapies using the long-acting ⁇ 2 -agonists such as formoterol and salmeterol together with glucocorticosteroids such as budesonide and fluticasone propionate, a new pharmacological tool has become available.
  • inflammatory mediators are likely to be involved in COPD as many inflammatory cells are activated.
  • the influence on a single mediator has been unsuccessful in the development of new therapies.
  • mediators involved in COPD compared to asthma and therefore it is necessary to develop different drugs.
  • targets for COPD have been mentioned leukotriene B 4 inhibitors, chemokine antagonists, neutrophil elastase, phosphodiesterase-4 inhibitors, cathepsins, matrix metallo-proteinases (MMPs), protease inhibitors and many others. Compelling evidence suggests that the lung damage associated with COPD results from an imbalance between proteases.
  • Matrix metalloproteinases are capable of degrading all of the components of the extracellular matrix of lung parenchyma including elastin, collagen, proteoglycans, laminin and fibronectin (FASEB J, 12 1075 (1998)). It has been developed some nonselective MMP inhibitors, but the side effects may be a problem in long-term use. More selective inhibitors of individual MMPs, such as MMP-9 and MMP-12 are now in development.
  • Statins are increasingly being recognized as anti-inflammatory agents.
  • Schonbeck and Libby (Circulation, 109 (suppl. II), 11-18-26 (2004)) are addressing this by reviewing in vitro and in vivo evidence regarding statins (3 -hydroxy-3 -methyl glutaryl coenzyme A (HMG- CoA) reductase inhibitors) as antiinflammatory agents.
  • statins 3 -hydroxy-3 -methyl glutaryl coenzyme A (HMG- CoA) reductase inhibitors
  • Statins are the most commonly used lipid-lowering compounds. Examples are lovastatin, rosuvastatin (CrestorTM, AstraZeneca), pravastatin, simvastatin, itavastatin, cerivastatin, fluvastatin, atorvastatin (Lipitor , Pfizer) and mevastatin.
  • WO 00/48626 (Univ. of Washington) provides a composition comprising a HMG-CoA reductase inhibitor (statin) at a concentration of less than 0.1 mg and a method of treating a pulmonary disease including COPD with an aerosol formulation of statins.
  • EP 1 275 388 provides a TNF- ⁇ inhibitor (statins) for the prevention and treatment of TNF- ⁇ - associated diseases such as inflammatory diseases including asthma and COPD.
  • the statin cerivastatin has been shown to reduce inflammatory activity in alveolar macrophages derived from chronic bronchitis patients (Circulation 101 (2000), 1760). In a study with patients receiving statins it was shown that initiation of statin therapy was associated with a significant improvement (certain patient inclusion criteria were used) in the rate of FEV 1 decline that was unrelated to cigarette use factors.
  • the prestatin baseline FEV 1 slope was -109.2 ml/yr and following statin therapy the slope was -46.7 ml/yr (Chest, 120 (4), suppl, p291S (2001)).
  • a combination of a HMG-CoA reductase inhibitor (preferably a statin) and a glucocorticosteroid given separately, sequentially or simultaneously may potentiate the effect of either component and also produce a better effect than conventional COPD treatments.
  • the therapeutic effect may be observed with regard to the fast decline in 5 lung function that is a hallmark of COPD, and effects may be observed regarding the systemic inflammation that is also characteristic of COPD.
  • the long-term effect of a combination according to the invention will be conservation of lung function and putatively less comorbidity (based on effects on the systemic inflammation).
  • the invention provides a pharmaceutical combination comprising, in o admixture or separately:
  • a second active ingredient which is a glucocorticosteroid, a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt s
  • respiratory diseases such as asthma and COPD and fibrolytic diseases like systemic sclerosis, alveolitis, sarcoidosis and idiopathic pulmonary fibrosis, particularly COPD.
  • the pharmacologically active agents in accordance with the present invention include statins like lovastatin, rosuvastatin (CrestorTM, AstraZeneca), pravastatin, simvastatin, 0 itavastatin, cerivastatin, fluvastatin, atorvastatin (LipitorTM, Pfizer) and mevastatin.
  • statins like lovastatin, rosuvastatin (CrestorTM, AstraZeneca), pravastatin, simvastatin, 0 itavastatin, cerivastatin, fluvastatin, atorvastatin (LipitorTM, Pfizer) and mevastatin.
  • Suitable glucocorticosteroids include budesonide, fluticasone (e.g. as propionate ester), mometasone (e.g. as furoate ester), beclomethasone (e.g. as 17-propionate or 17,21- dipropionate esters), loteprednol (e.g. as etabonate), etiprednol (e.g. as dicloacetate), ciclesonide, triamcinolone (e.g. as acetonide), flunisolide, zoticasone, flumoxonide, 5 rofleponide, butixocort (e.g.
  • esters such as hydrates, or solvates of such esters or salts, if any.
  • Suitable physiologically acceptable salts 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.
  • 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
  • the preferred pharmacologically active statins for use in accordance with the present invention include rosuvastatin and atorvastatin.
  • the preferred glucocorticosteroid agents include mometasone furoate, ciclesonide, zoticasone, flumoxonide, steroid (I), steroid (II) , steroid (III), steroid (IV), fluticasone propionate and budesonide, and even more preferred is budesonide.
  • the preferred combinations include: atorvastatin/budesonide rosuvastatin/budesonide simvastatin/budesonide rosuvastatin/ciclesonide atorvastatin/fluticasone propionate atorvastatin/ciclesonide rosuvastatin/mometasone furoate and rosuvastatin/fluticasone propionate
  • the most preferred combinations are atorvastatin/budesonide and rosuvastatin/budesonide.
  • a combination comprising, in admixture or separately: (a) a first active ingredient which is a statin, a pharmacetucally acceptable salt or solvate thereof, or a solvate of such a salt, and
  • the invention also provides a method of treating a respiratory disease which comprises administering to the patient a therapeutically effective amount of a combination comprising, in admixture or separately:
  • the effective dose of the components will strongly depend on the particular compound used and the mode of administration, as well as the weight and disease state of the individual s being treated.
  • An orally administered dose of the statins will generally range from about 0.01 mg to about 200 mg, preferably from 10 to 80 mg, more preferably from 5 to 40 mg; for inhalation a dose range of 0.001 mg to about 25 mg is preferred, even more preferably is a dose from 0.1 to 25 mg.
  • the suitable daily dose for the glucocorticosteroids is in the range of 50 ⁇ g to 2000 ⁇ g, 0 where e.g. for budesonide the daily dose is in the range of 50 ⁇ g to 1600 ⁇ g.
  • 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 given by e.g. inhalation.
  • the components can be administered separately, i.e. one after the other e.g. the s statin orally and the remaining component by inhalation.
  • the time interval for separate administration can be anything from direct sequential (one after the other) administration to administration several hours apart.
  • respiratory diseases examples include asthma, chronic obstructive pulmonary disease (COPD), systemic sclerosis, alveolitis, 0 sarcoidosis, cystic fibrosis, fibrinous and pseudomembraneous rhinitis and idiopathic pulmonary fibrosis.
  • COPD chronic obstructive pulmonary disease
  • systemic sclerosis alveolitis
  • 0 sarcoidosis cystic fibrosis
  • fibrinous and pseudomembraneous rhinitis examples of respiratory diseases that can be treated according to the invention.
  • idiopathic pulmonary fibrosis examples include asthma, chronic obstructive pulmonary disease (COPD), systemic sclerosis, alveolitis, 0 sarcoidosis, cystic fibrosis, fibrinous and pseudomembraneous rhinitis and idiopathic pulmonary fibrosis.
  • COPD chronic obstructive pulmonary disease
  • systemic sclerosis alveolitis
  • a first active ingredient which is a statin, a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt
  • a second active ingredient which is a glucocorticosteroid, a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt 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
  • the pharmaceutical 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, 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.
  • mice are exporesed to tobacco smoke once or twice daily for 1-9 days.
  • Read-outs in the model include cell infiltration and inflammatory mediators in broncho-alveolar lavage and tissue histopathology.
  • the model can also be applied to guinea pigs.
  • effects of compounds on chronic pathologic changes to lungs over 3-6 months can be determined.
  • statin treatment vs other placebo treated patient was further amplified if the patients received the combination of s statins and ICS.
  • statin treatment on FEV 1 decline in COPD is potentiated by inhaled corticosteroids.

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

Abstract

L’invention concerne des médicaments comprenant des combinaisons de glucocorticostéroïdes et d'inhibiteurs de la HMG-CoA réductase dans le traitement de troubles respiratoires tels que la bronchopneumopathie chronique obstructive (BPCO).
PCT/GB2006/001791 2005-05-19 2006-05-16 Combinaisons de statines avec des glucocorticosteroides Ceased WO2006123125A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0510207.4A GB0510207D0 (en) 2005-05-19 2005-05-19 Novel combination
GB0510207.4 2005-05-19

Publications (1)

Publication Number Publication Date
WO2006123125A1 true WO2006123125A1 (fr) 2006-11-23

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Application Number Title Priority Date Filing Date
PCT/GB2006/001791 Ceased WO2006123125A1 (fr) 2005-05-19 2006-05-16 Combinaisons de statines avec des glucocorticosteroides

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GB (1) GB0510207D0 (fr)
WO (1) WO2006123125A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9713614B2 (en) 2006-07-05 2017-07-25 Astrazeneca Ab Combination of HMG-CoA reductase inhibitors with phosphodiesterase 4 inhibitors for the treatment of inflammatory pulmonary diseases
EP3406245A4 (fr) * 2016-01-20 2019-09-04 Zhang, Jianning Application conjointe de statine et d'hormone corticosurrénale pour traiter un hématome sous-dural chronique
CN116744934A (zh) * 2020-05-07 2023-09-12 加利福尼亚大学董事会 用于治疗病毒性呼吸疾病的吸入性他汀类药物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000048626A2 (fr) * 1999-02-17 2000-08-24 University Of Washington Compositions aerosol d'inhibiteurs de hmg-coa reductase permettant d'inhiber l'inflammation associee a une maladie pulmonaire
EP1275388A1 (fr) * 2000-02-10 2003-01-15 Takeda Chemical Industries, Ltd. Inhibiteurs de tnf-alpha

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000048626A2 (fr) * 1999-02-17 2000-08-24 University Of Washington Compositions aerosol d'inhibiteurs de hmg-coa reductase permettant d'inhiber l'inflammation associee a une maladie pulmonaire
EP1275388A1 (fr) * 2000-02-10 2003-01-15 Takeda Chemical Industries, Ltd. Inhibiteurs de tnf-alpha

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9713614B2 (en) 2006-07-05 2017-07-25 Astrazeneca Ab Combination of HMG-CoA reductase inhibitors with phosphodiesterase 4 inhibitors for the treatment of inflammatory pulmonary diseases
EP3406245A4 (fr) * 2016-01-20 2019-09-04 Zhang, Jianning Application conjointe de statine et d'hormone corticosurrénale pour traiter un hématome sous-dural chronique
AU2016387192B2 (en) * 2016-01-20 2021-10-28 Rongcai JIANG Joint application of statin and adrenocortical hormone for treating chronic subdural hematoma
CN116744934A (zh) * 2020-05-07 2023-09-12 加利福尼亚大学董事会 用于治疗病毒性呼吸疾病的吸入性他汀类药物

Also Published As

Publication number Publication date
GB0510207D0 (en) 2005-06-22

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