WO2004084894A1 - Combinaison synergetique comprenant du roflumilast et du revatropate destinee au traitement de maladies respiratoires - Google Patents

Combinaison synergetique comprenant du roflumilast et du revatropate destinee au traitement de maladies respiratoires Download PDF

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Publication number
WO2004084894A1
WO2004084894A1 PCT/EP2004/050374 EP2004050374W WO2004084894A1 WO 2004084894 A1 WO2004084894 A1 WO 2004084894A1 EP 2004050374 W EP2004050374 W EP 2004050374W WO 2004084894 A1 WO2004084894 A1 WO 2004084894A1
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WO
WIPO (PCT)
Prior art keywords
roflumilast
revatropate
pharmaceutical composition
respiratory disease
reducing
Prior art date
Application number
PCT/EP2004/050374
Other languages
English (en)
Inventor
Daniela Bundschuh
Stefan-Lutz Wollin
Christian Weimar
Original Assignee
Altana Pharma Ag
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 Altana Pharma Ag filed Critical Altana Pharma Ag
Publication of WO2004084894A1 publication Critical patent/WO2004084894A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof

Definitions

  • the invention relates to the combination of certain known active compounds for therapeutic purposes
  • the substances used in the combination according to the invention are a known active compound from the PDE4 inhibitor class and an active compound from the antichohnergic agent class
  • Their combined use in the sense according to the invention for therapeutic purposes has not jet been described in the prior art
  • the invention relates to pharmaceutical compositions and methods for preventing or reducing the onset of symptoms of respiratory diseases, or treating or reducing the severity of respiratory diseases
  • compositions and methods for treating respiratory diseases mediated by phosphodiesterase 4 (PDE4) by administering a PDE4 inhibitor together with another pharmaceuti- cally active agent, which affects pulmonary function.
  • PDE4 phosphodiesterase 4
  • the invention relates in a first aspect to a method for preventing or reducing the onset of symptoms of a respiratory disease, or treating or reducing the severity of a respiratory disease by administering to a patient in need thereof an effective amount of roflumilast and revatropate.
  • the invention also relates to a pharmaceutical composition for preventing or reducing the onset of symptoms of a respiratory disease, or treating or reducing the severity of a respiratory disease, comprising an effective amount of roflumilast, an effective amount of revatropate and a pharmaceutical acceptable excipient and/or carrier.
  • the invention additionally relates to a method for preparing a composition which is effective for preventing or reducing the onset of symptoms of a respiratory disease, or treating or reducing the severity of a respiratory disease, which method comprises mixing an effective amount of roflumilast and revatropate with a pharmaceutically acceptable excipient and/or carrier.
  • the invention furthermore relates to the use of a combination of roflumilast and the anticholinergic agent revatropate for the preparation of a pharmaceutical composition for preventing or reducing the onset of symptoms of a respiratory disease, or treating or reducing the severity of a respiratory disease.
  • the combination therapy which is the subject matter of this invention comprises administering roflumilast with revatropate to prevent the onset of a respiratory disease event or to treat an existing condition.
  • the two compounds may be administered together in a single dosage form. Or they may be _d- ministered in different dosage forms. They may be administered at the same time. Or they may be administered both close in time or remotely, such as where one active compound is administered in the morning and the second active compound is administered in the evening.
  • the combination may be used prophylactic or after the onset of symptoms has occurred. In some instances the combination may be used to prevent the progression of a respiratory disease or to arrest the decline of a function such as lung function.
  • the invention thus relates to the combined use of roflumilast and revatropate in preventing the symptoms of, or treating a respiratory disease.
  • roflumilast is understood to include the pharmaceutically acceptable salts and the N-oxide of ROFLUIVIILAST, which can likewise be used according to the invention.
  • ROFLUMILAST is the international nonproprietary name (INN) for 3-cyclopropylmethoxy-4-difluoro- methoxy-N-(3,5-dichloropyrid-4-yl)benzamide [structure of formula (1.1)].
  • revatropate is understood to include the pharmaceutically acceptable salts of REVATROPATE, which can likewise be used according to the invention.
  • REVATROPATE is the international nonproprietary name (INN) for (R)-3-quinuclidinyl-(S)-beta-hy- droxy-alpha-[2-(R)-methylsulfinyl]- ⁇ thyl]hydratropate [structure of formula (1.3)].
  • INN international nonproprietary name
  • the preparation of (R)-3-quinuclidinyl-(S)- ⁇ -hydroxy- -[2-(R)-methylsulfinyl]-ethyl]hydratropate and its pharmaceutically acceptable salts as well as the use of these compounds as anticholinergic/antimuscarinic agents is described in WO93/06098.
  • Suitable pharmaceutically acceptable salts of ROFLUMILAST and REVATROPATE are in particular water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)-benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 1-hydroxy-2-naphthoic acid, the acids being employed in salt preparation - depending on whether it is a mono- or polybasic acid and depending on which salt is desired - in an equi molar quantitative ratio or one differing therefrom.
  • acids such as,
  • active compounds and their pharmaceutically acceptable salts mentioned can also be present, for example, in the form of their pharmaceutically acceptable solvates, in particular In the form of their hydrates.
  • Respiratory diseases which may be mentioned are in particular allergen- and inflammation-induced bronchial disorders (bronchitis, obstructive bronchitis, spastic bronchitis, allergic bronchitis, allergic asthma, bronchial asthma, COPD), which can be treated by the combination according to the invention also in the sense of a long-term therapy (if desired with appropriate adjustment of the dose of the individual components to the needs at the time, for example needs subject to seasonally related variations).
  • the combination is particularly useful in the treatment of COPD.
  • Combined use or “combination” within the meaning of the present invention is to be understood as meaning that the individual components can be administered simultaneously (in the form of a combination medicament - fixed combination) or in succession (from separate pack units -free combination), close in time or remote in time, in any order whatever.
  • one active compound could be taken in the morning and one later in the day.
  • one active compound could be taken twice daily and the other once daily, either at the same time as one of the twice-a-day dosing occurred, or separately.
  • the anticholinergic agent is administered first and roflumilast thereafter.
  • Combined use or “combination” within the meaning of the present invention is particularly to be understood as meaning that the two active compounds act together in a synergistic manner.
  • Roflumilast and revatropate may be administered to a subject in need of treatment by a variety of conventional routes of admmstration, including oral, mtranasal or intravenous administration as well as administration by inhalation
  • This invention contemplates either co-administering both active compounds in one delivery form such as an inhaler, which is putting both active compounds in the same inhaler Alternatively one can put roflumilast into pills and package them in a medicament pack with an inhaler that contains revatropate Preferred is the administration of both active compounds in one delivery form, such as a fixed oral combination or - as indicated above - putting both active compounds in the same inhaler
  • the selective PDE4 inhibitors and the anticholinergic agents of the present invention may be conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrodynamics to produce a fine mist) or nebulizer, with or without the use of a suitable propellant, e g dichlorodifluorometha ⁇ e, t ⁇ - chlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1 ,1 ,2,2-tetrafluoroethane (HFA 134A [trade mark]) or, 1,1,1 ,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide, a further perfluo ⁇ nated hydrocarbon such as Perfiubon [trade mark] or other suitable gas
  • the dosage unit may be determined by providing
  • the selective PDE4 inhibitors and the anticholinergic agents of the invention will be micronised to a size suitable for delivery by inhalation (typically considered as less than 5 microns) Micronisation could be achieved by a range of methods, for example spiral jet milling, fluid bed jet milling or use of supercritical fluid crystallization
  • a suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine- mist may contain from 1 ⁇ g to 10 mg of an anticholinergic agent of the invention and the actuation volume may vary from 1 to 100 ⁇ l
  • a typical formulation may comprise an anticholinergic agent of the invention, propylene glycol, sterile water, ethanol and sodium chloride
  • Aerosol or dry powder formulations are preferably arranged so that each metered dose or "puff' contains from 1 to 4000 ⁇ g of an anticholinergic agent of the invention for delivery to the patient
  • the overall daily dose with an aerosol will be in the range from 1 ⁇ g to 20 mg which may be administered in a single dose or, alternatively, in divided doses throughout the day
  • the active ingredients roflumilast and/or revatropate are formulated to give medicaments according to processes known per se and familiar to the person skilled in the art.
  • the active ingredients are employed as medicament, preferably in combination with suitable pharmaceutical excipients or vehicles, in the form of tablets, coated tablets, capsules, caplets, emulsions, suspensions or solutions, the active compound content advantageously being between 0.1 and 95% and, by the appropriate choice of the excipients and vehicles, it being possible to achieve a pharmaceutical administration form precisely tailored to the active compound(s) and/or to the desired onset of action (e.g. a sustained-release form or an enteric form).
  • excipients or vehicles are suitable for the desired pharmaceutical formulations.
  • solvents for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, colorants or permeation promoters and complexing agents (e.g. cyclodextrins).
  • Typical formulations for intranasal administration include those mentioned above for inhalation and further include non-pressurized formulations in form of a solution or suspension in an inert vehicle such as water optionally in combination with conventional excipients such as buffers, anti-microbials, tonicity modifying agents and viscosity modifying agents, which may be administered by a nasal pump.
  • the dosages administered will, of course vary with the first and second active compound employed, the treatment desired and the disorder indicated.
  • the active compounds are dosed in an order of magnitude customary for the individual dose, it more likely being possible, on account of the individual actions, which are mutually positively influencing and reinforcing, to reduce the respective doses on the combined administration of the active compounds compared with the norm.
  • the daily dose is likely to range from 0.01 to 1 mg/kg body weight of the subject to be treated, preferably 0.1 to 0.5 mg/kg.
  • 3-cyclopropylmethoxy-4-difluorome.hoxy-N-(3,5-dichloropyrid-4-yl)benzamide is administered in a daily dose of 1 to 15 ⁇ g/Kg body weight of the subject to be treated, preferably 3 to 7 ⁇ g/kg, preferably by once daily administration.
  • the daily dose is in the range 1 to 7 ⁇ g/kg body weight of the subject to be treated, preferably by once daily administration.
  • the daily dose is in the range from 50 to 500 ⁇ g per day, preferably in the range from 150 to 300 ⁇ g.
  • Example 1 Dry Powder Inhaler (mono dose system based on capsule for inhalation)
  • Example 2 Dry Powder Inhaler ( ulti dose system)
  • micronized ROFLUMILAST and 33.4 g of deagglomerated lactose monohydrate are screened (0.5 mm sieve) and mixed in a turbula mixer until homogenous.
  • 10.67 g of micronized revatropate and 53.4 g of deagglomerated lactose monohydrate are screened (0.5 mm sieve) and mixed in a turbula mixer until homogenous.
  • the ROFLUMILAST and the REVATROPATE pre-blends obtained are screened (0.5 mm sieve) and filled into a stainless steel container together with 295.9 g of deagglomerated lactose monohydrate. The powders are blended in a turbula mixer until homogenous.
  • Such dry powder inhaler may contain 120 individual doses of 7.5 mg powder each containing 125 ⁇ g of ROFLUMILAST and 200 ⁇ g of REVATROPATE.
  • ROFLUMILAST is mixed with corn starch and, subsequently, triturated in a planetary mill.
  • the tritura- tion is screened (1.0 mm sieve) and transferred into the product container of a fluidised bed granula- tor.
  • REVATROPATE, microcrystalline cellulose and sodium carboxymethylstarch (type A) are added to the product container.
  • a solution of povidone in purified water is sprayed onto the powders under suitable process conditions until granules of a suitable size range are obtained.
  • the granules are dried to the moisture content specified.
  • Magnesium stearate is added to the dried granules using a suitable mixer.
  • the blend is compressed into tablets having an average weight of approx. 80 mg using a standard rotary tablet press. Each tablet contains 250 ⁇ g of ROFLUMILAST and 10 mg of REVATROPATE.
  • COM and CON were determined up to 120 s after methacholine-induced bronchospasm. AUCs for 0 to 120s were determined. Inhibition was calculated based on the AUC data. Data are shown as mean + SEM. Results were taken to be significant if p ⁇ 0.05 versus placebo (ANOVA and Dunnett's multiple comparison test).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne l'administration de roflumilast et de revatropate pour le traitement de maladies respiratoires.
PCT/EP2004/050374 2003-03-28 2004-03-26 Combinaison synergetique comprenant du roflumilast et du revatropate destinee au traitement de maladies respiratoires WO2004084894A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP03007099.9 2003-03-28
EP03007099 2003-03-28

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WO2004084894A1 true WO2004084894A1 (fr) 2004-10-07

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103536582A (zh) * 2013-10-12 2014-01-29 云南龙海天然植物药业有限公司 罗氟司特干粉吸入剂
WO2014115127A1 (fr) * 2013-01-28 2014-07-31 Incozen Therapeutics Pvt. Ltd. Procédés de traitement de troubles auto-immuns, respiratoires et inflammatoires par inhalation de n-oxyde de roflumilast
CN104800192A (zh) * 2014-01-27 2015-07-29 成都英诺新科技有限公司 一种罗氟司特吸入粉雾剂及制备方法

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US20020052312A1 (en) * 2000-05-30 2002-05-02 Reiss Theodore F. Combination therapy of chronic obstructive pulmonary disease using muscarinic receptor antagonists
WO2002069945A2 (fr) * 2001-03-07 2002-09-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelles preparations de medicaments a base d'anticholinergiques et d'inhibiteurs pde-iv

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WO2002069945A2 (fr) * 2001-03-07 2002-09-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelles preparations de medicaments a base d'anticholinergiques et d'inhibiteurs pde-iv

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CAMPILLO N ET AL: "NOVEL BRONCHODILATORS IN THE TREATMENT OF ASTHMA AND COPD", EXPERT OPINION ON THERAPEUTIC PATENTS, ASHLEY PUBLICATIONS, GB, vol. 1, no. 12, 2002, pages 53 - 63, XP008002080, ISSN: 1354-3776 *
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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20200006630A (ko) * 2013-01-28 2020-01-20 인코젠 쎄라퓨틱스 프라이빗 리미티드 로플루밀라스트 n- 옥사이드의 흡입에 의한 자가면역, 호흡 및 염증성 장애의 치료방법
IL272701A (en) * 2013-01-28 2020-04-30 Incozen Therapeutics Pvt Ltd Means and methods for treating autoimmune, respiratory, and inflammatory diseases by inhaling roflumilast N-oxide
IL272701B2 (en) * 2013-01-28 2023-05-01 Incozen Therapeutics Pvt Ltd Means and methods for treating autoimmune, respiratory, and inflammatory diseases by inhaling roflomilast n-oxide
US9649302B2 (en) 2013-01-28 2017-05-16 Incozen Therapeutics Pvt. Ltd. Methods of treating autoimmune, respiratory and inflammatory disorders by inhalation of roflumilast N-oxide
AU2014208359B2 (en) * 2013-01-28 2018-04-26 Incozen Therapeutics Pvt. Ltd. Methods of treating autoimmune, respiratory and inflammatory disorders by inhalation of roflumilast N-oxide
EA033113B1 (ru) * 2013-01-28 2019-08-30 Инкозен Терапьютикс Пвт. Лтд. Способы лечения аутоиммунных, респираторных и воспалительных расстройств ингаляцией n-оксида рофлумиласта
WO2014115127A1 (fr) * 2013-01-28 2014-07-31 Incozen Therapeutics Pvt. Ltd. Procédés de traitement de troubles auto-immuns, respiratoires et inflammatoires par inhalation de n-oxyde de roflumilast
AU2018205077B2 (en) * 2013-01-28 2020-02-20 Incozen Therapeutics Pvt. Ltd. Methods of treating autoimmune, respiratory and inflammatory disorders by inhalation of roflumilast N-oxide
JP7015331B2 (ja) 2013-01-28 2022-02-02 インコゼン・セラピューティクス・プライベート・リミテッド ロフルミラストｎ－酸化物の吸入によって自己免疫、呼吸器性および炎症性の障害を処置する方法
JP2020079295A (ja) * 2013-01-28 2020-05-28 インコゼン・セラピューティクス・プライベート・リミテッド ロフルミラストｎ−酸化物の吸入によって自己免疫、呼吸器性および炎症性の障害を処置する方法
KR102154104B1 (ko) * 2013-01-28 2020-09-09 인코젠 쎄라퓨틱스 프라이빗 리미티드 로플루밀라스트 n- 옥사이드의 흡입에 의한 자가면역, 호흡 및 염증성 장애의 치료방법
EP3763366A1 (fr) * 2013-01-28 2021-01-13 Incozen Therapeutics Pvt. Ltd. N-oxyde de roflumilast pour l'utilisation dans le traitement de troubles auto-immuns, respiratoires et inflammatoires par inhalation
US11103488B2 (en) 2013-01-28 2021-08-31 Incozen Therapeutics Pvt. Ltd. Methods of treating autoimmune, respiratory and inflammatory disorders by inhalation of roflumilast N-oxide
CN103536582A (zh) * 2013-10-12 2014-01-29 云南龙海天然植物药业有限公司 罗氟司特干粉吸入剂
CN104800192A (zh) * 2014-01-27 2015-07-29 成都英诺新科技有限公司 一种罗氟司特吸入粉雾剂及制备方法

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