WO2004098605A1 - Composition pharmaceutique comprenant un inhibiteur de pde4 et il-1 trap - Google Patents

Composition pharmaceutique comprenant un inhibiteur de pde4 et il-1 trap Download PDF

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Publication number
WO2004098605A1
WO2004098605A1 PCT/EP2004/050747 EP2004050747W WO2004098605A1 WO 2004098605 A1 WO2004098605 A1 WO 2004098605A1 EP 2004050747 W EP2004050747 W EP 2004050747W WO 2004098605 A1 WO2004098605 A1 WO 2004098605A1
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Prior art keywords
tetrahydro
phthalazιn
pιperιdιn
pde4
dιmethoxyphenyl
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PCT/EP2004/050747
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English (en)
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Johannes Barsig
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Altana Pharma Ag
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    • 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
    • A61K31/275—Nitriles; Isonitriles
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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 known active compounds from the PDE inhibitor class and known active compounds from the ⁇ nterleuk ⁇ n-1 (IL-1) antagonist class
  • IL-1 ⁇ nterleuk ⁇ n-1
  • the invention relates to pharmaceutical compositions and methods for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or ⁇ nterleuk ⁇ n-1 (IL-1) activity is detrimental, or treating or reducing the seventy of a disease in which phosphodiesterase 4 (PDE4) and/or ⁇ nterleuk ⁇ n-1 (IL-1) activity is detrimental
  • PDE4 phosphodiesterase 4
  • IL-1 ⁇ nterleuk ⁇ n-1
  • the invention relates in a first aspect to a method for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or ⁇ nterleuk ⁇ n-1 (IL-1 ) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or ⁇ nterleuk ⁇ n-1 (IL-1 ) activity is detrimental by administering to a patient in need thereof simulta neously an effective amount of (1) a PDE 4 inhibitor and (2) IL-1 Trap
  • the invention in a second aspect relates to a method for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE 4 ) and/or ⁇ nterleuk ⁇ n-1 (IL-1) activity is det ⁇ mental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or interleukin- 1 (IL-1) activity is det ⁇ mental by administering to a patient in need thereof in succession, close in time or remote in time, in any order whatever an effective amount of (1 ) a PDE 4 inhibitor and (2) IL-1 Trap
  • the invention also relates to a pharmaceutical composition for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or ⁇ nterleuk ⁇ n-1 (IL-1 ) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE 4 ) and/or ⁇ nterleuk ⁇ n-1 (IL-1 ) activity is detrimental, comprising as a fixed combination an effective amount of
  • the invention furthei relates to a pharmaceutical composition for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or ⁇ nterleuk ⁇ n-1 (IL-1 ) activity is detrimental, or treating or reducing the severity of a disease in which phosphodiesterase 4 (PDE4) and/or ⁇ nterleuk ⁇ n-1 (IL-1 ) activity is detrimental, comprising as a free combination an effective amount of
  • the invention additionally relates to a method for preparing a pharmaceutical composition which is effective for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or ⁇ nterleuk ⁇ n-1 (IL-1) activity is detrimental, or treating or reducing the severity of a dis ease in which phosphodiesterase 4 (PDE4) and/or ⁇ terleuk ⁇ n-1 (IL-1) activity is detrimental, which method comprises mixing an effective amount of a PDE4 inhibitor and IL-1 Trap with a pharmaceutically acceptable carrier
  • the invention furthermore relates to the use of a combination of a PDE4 inhibitor and shulL-1R II for the preparation of a pharmaceutical composition for preventing or reducing the onset of symptoms of a disease in which phosphodiesterase 4 (PDE4) and/or ⁇ nterleuk ⁇ n-1 (IL-1) activity is det ⁇ mental, or treating or reducing the seventy of a disease in which phosphodiesterase 4 (PDE4) and/or mterleukin- 1 (IL-1) activity is detrimental
  • the combination therapy which is the subject matter of this invention comprises administering a PDE4 inhibitor with IL-1 Trap to prevent onset of a disease in which phosphodiesterase 4 (PDE4) and/or ⁇ nterleuk ⁇ n-1 (IL-1) activity is detrimental or to treat such an existing condition
  • the invention thus relates to the combined use of a PDE4 inhibitor and IL-1 Trap in preventing the symptoms of, or treating a disease in which phosphodiesterase 4 (PDE4) and or ⁇ terleuk ⁇ n-1 (IL-1) activity is detrimental
  • the PDE4 inhibitors useful in this invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which is only or essentially only a PDE4 inhibitor, not compounds which inhibit to a degree of exhibiting a therapeutic effect other members of the PDE family as well as PDE4
  • PDE4 INHIBITORS One group of PDE4 inhibitors that may be usefully employed in the present invention [hereinafter referred to as "SELECTED PDE4 INHIBITORS”] include a compound of formula (1)
  • R1 and R2 are both hydrogen or together form an additional bond
  • R3 represents a benzene derivative of formula (a) or (b)
  • R4 is 1-4C-alkoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine
  • R5 is 1-8C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine
  • R6 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or 1-4C-alkoxy which is completely or predominantly substituted by fluorine, R7 is 1-4C alkyl and R8 is hydrogen or 1 -4C-alkyl, or wherein
  • R7 and R8 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5-, 6- or 7-membered hydrocarbon ring, optionally interrupted by an oxygen or sulphur atom,
  • R9 is 1-4C-Alkyl, -S(O) 2 -R10, -S(0) 2 -(CH 2 ) compassion-R11 , -(CH 2 ) m -S(0) 2 -R12, -C(0)R13, -C(0)-(CH 2 ) n -R14, -(CH 2 ) m -C(0)-R15, Hetaryl, Aryll or Aryl2-(1 -4C)-alkyl, R10 is 1-4C-alkyl, 5-d ⁇ methylam ⁇ nonaphthal ⁇ n-1 -yl, -N(R16)R17, phenyl or phenyl substituted by R18 and/or R19,
  • R13 is 1-4C-alkyl, hydroxycarbonyl-1-4C-alkyl, phenyl, pyndyl, 4ethyl p ⁇ peraz ⁇ n-2,3-d ⁇ on-1-yl or -N(R16)R17,
  • R15 is -N(R16)R17, phenyl, phenyl substituted by R18 and/or R19 and/or R20,
  • R16 and R17 are independent from each other hydrogen, 1-7C-alkyl, 37C-cycloalkyl, 3-7C-cycloalkyI- methyl, phenyl or phenyl substituted by R18 and/or R19 and/or R20, or R16 and R17 together and with inclusion of the nitrogen atom to which they are bonded, form a 4morphol ⁇ nyl-, 1-pyr- rolidinyl-, 1-p ⁇ pe ⁇ d ⁇ nyl-, 1 -hexahydroazep ⁇ no- or a 1-p ⁇ peraz ⁇ nyl ring of formula (c)
  • R21 is pyr ⁇ d-4-yl, py ⁇ d-4-ylmethyl, 1-4C-alkyl-d ⁇ methylam ⁇ o, dimethylaminocarbonylmethyl,
  • R18 is halogen, nitro, cyano, carboxyl, 1-4C-alkyl, tnfluoromethyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, ammo, mono-or d ⁇ -1 -4C-alkylam ⁇ no, aminocarbonyl, 1-4C-alkylcarbonylam ⁇ no or mono-or di-
  • 1-4C-alkylam ⁇ nocarbonyl R19 is halogen, ammo, nitro, 1-4C-alkyl or 1 -4C-alkoxy
  • R20 is halogen
  • Hetaryl is pyr ⁇ m ⁇ d ⁇ n-2-yl, th ⁇ eno-[2,3 d]py ⁇ m ⁇ d ⁇ n-4-yl, 1-methyl-1 H-pyrazolo-[3,4-d]py ⁇ m ⁇ d ⁇ -4-yl, thia- zolyl, i idazolyl or furanyl
  • Aryll is pyndyl, phenyl or phenyl substituted by R18 and/or R19
  • Aryl2 is pyndyl, phenyl, phenyl substituted by R18 and/or R19, 2-oxo-2H-chrome ⁇ -7-yl or 4-(1 ,2,3- th ⁇ ad ⁇ azol-4-yl)phenyl
  • n
  • 1-4C-Alkyl is a straight -chain or branched alkyl radical having 1 to 4 carbon atoms
  • Examples are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals
  • 1-4C-Alkoxy is a radical which, in addition to the oxygen atom, contains a straight chain or branched alkyl radical having 1 to 4 carbon atoms
  • Alkoxy radicals having 1 to 4 carbon atoms which may be mentioned in this context are, for example, the butoxy, isobutoxy, sec butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals
  • 1-8C-Alkoxy is a radical which, in addition to the oxygen atom, contains a straight -chain or branched alkyl radical having 1 to 8 carbon atoms
  • Alkoxy radicals having 1 to 8 carbon atoms which may be mentioned in this context are, for example, the octyloxy, heptyloxy, isoheptyloxy (5-methylhexyloxy), hexyloxy, isohexyloxy (4-methylpentyloxy), neohexyloxy (3,3 d ⁇ methylbutoxy), pentyloxy, isopentyloxy (3-methylbutoxy), neopentyloxy (2,2-d ⁇ methylpropoxy), butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals
  • 1-4C-Alkoxy which is completely or predominantly substituted by fluorine is, for example, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1 ,2,2-t ⁇ fluoroethoxy and in particular the 1,1 ,2,2-totrafluoroethoxy, the 2,2,2-t ⁇ fluoroethoxy, the t ⁇ fluoromethoxy and the difluoromethoxy radical, of which the difluoromethoxy radical is preferred "Predominantly" in this connection means that more than half of the hydrogen atoms of the 1-4C-alkoxy group are replaced by fluorine atoms
  • 3-7C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cyclo- heptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred
  • 3-7C-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cy- clohexylmethoxy or cycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy are preferred
  • 3-5C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy and cyclopentyloxy
  • 3-5C-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy
  • Halogen within the meaning of the present invention is bromine, chlorine or fluorine
  • spiro-linked 5-, 6- or 7-memb ⁇ red hydrocarbon rings optionally interrupted by an oxygen or sulphur atom, may be mentioned the cyclopentane, cyclohexane, cycloheptane, tetrahydrofuran, tetrahy- dropyran and the tetrahydrothiophen ring
  • 1-4C-Alkoxycarbonyl is a carbonyl group to which one of the abovementioned 1-4C-alkoxy radicals is bonded Examples are the methoxycarbonyl [CH 3 0-C(0)-] and the ethoxycarbonyl [CH 3 CH 2 0-C(0)-] radical
  • An 1-4C-Alkylcarbo ⁇ ylam ⁇ no radical is, for example, the propionylamino [CyHrCfOJNH-] and the ace- tylammo radical [CH 3 C(0)NH-]
  • Mono- or D ⁇ -1-4C-alkylam ⁇ no radicals contain in addition to the nitrogen atom, one or two of the abovementioned 1-4C-alkyl radicals Preferred are the d ⁇ -1 -4C-alkylam ⁇ no radicals, especially the dimethylamino, the diethylamino and the diisopropylamino radical
  • Mono- or D ⁇ -1-4C-alkylam ⁇ nocarbonyl radicals contain in addition to the carbonyl group one of the abovementioned mono- or d ⁇ -1-4C-alkylam ⁇ no radicals Examples which may be mentioned are the N-methyl- the N,N-d ⁇ methyl-, the N-ethyl-, the N-propyl-, the N,N-d ⁇ ethyl- and the N-isopropylamino- carbonyl radical
  • Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds which are generally prepared by reacting a free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base
  • pharmaceutically acceptable inorganic and organic acids customarily used in pharmacy
  • suitable 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, sulfu ⁇ c acid, acetic acid, citric acid, D gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl) -benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lau ⁇ c acid, malic acid, fuma ⁇ c acid, succinic acid, oxalic acid, tarta ⁇ c acid, embonic acid, stea ⁇ c acid, toluenesulfonic
  • salts with bases are mentioned the lithium, sodium, potassium, calcium, aluminium, magnesium, titanium, ammonium, meglumine or guanidinium salts, here, too, the bases being em ployed in salt preparation in an equimolar quantitative ratio or one differing therefrom
  • 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
  • SELECTED PDE4 INHIBITORS which are to be emphasized include a compound of formula (1), in which
  • R3 represents a benzene derivative of formula (a) or (b)
  • R4 is 1-4C-alkoxy
  • R5 is 1-4C-alkoxy
  • R6 is 1-2C-alkoxy
  • R7 is methyl
  • R8 is hydrogen, R9 is 1-4C-alkyl, -S(O) 2 -R10, -C(0)R13, -C(0)-(CH 2 ) n -R14, -(CH 2 ) m -C(0)-R15, Hetaryl, Aryll or
  • Aryl2 (1-2C-)alkyl R10 is 1 4C-alkyl, 5 d ⁇ methylam ⁇ nonaphthal ⁇ n-1 -yl, phenyl or phenyl substituted by R18, R13 is 1-40-alkyl, hydroxycarbonyl-1-4C-alkyl, pyndyl, 4-ethyl-p ⁇ peraz ⁇ n-2,3-d ⁇ on 1-yl or
  • R15 is -N(R16)R17, phenyl or phenyl substituted by R18 and/or R19 and/or R20, R16 and R17 are independent from each other hydrogen, 1-4C-alkyl, phenyl or phenyl substituted by
  • R21 is d ⁇ methylam ⁇ no-1 -4C-alkyl
  • R18 is halogen, nitro, 1-4C alkyl or 1-4C-alkoxycarbonyl
  • R19 is ammo
  • R20 is halogen
  • Hetaryl is py ⁇ m ⁇ d ⁇ n-2-yl, th ⁇ eno-[2,3-d]py ⁇ m ⁇ d ⁇ n-4-yl or 1-methyl-1 H-pyrazolo-[3,4-d]pyr ⁇ m ⁇ d ⁇ n-4-yl,
  • Aryll is phenyl or phenyl substituted by R18,
  • Aryl2 is pyndyl, phenyl, 2-oxo-2H-chromen-7-yl or 4-(1 ,2,3-th ⁇ ad ⁇ azol-4-yl)phenyl, m is 1 or 2, or a pharmaceutically acceptable salt or a N-oxide thereof or a pharmaceutically acceptable salt of the latter
  • SELECTED PDE4 INHIBITORS which are preferred include a compound selected from
  • SELECTED PDE4 INHIBITORS which are particularly preferred include a compound selected from
  • PDE4 inhibitors that may be usefully employed in the present invention include a compound selected from
  • IL-1 Trap is understood to represent the IL-1 Trap of Regeneron Pharmaceuticals Inc
  • the IL-1 Trap is an Fc fusion protein consisting of both the IL 1 Type I Receptor and the IL-1 Receptor Accessory Protein
  • U S Patents Nos 5,844,099 and 6,472,179 methods of making and using the lnterleuk ⁇ n-1 (IL-1) Trap of Regeneron Pharmaceuticals Inc are disclosed
  • phosphodiesterase 4 PDE4
  • IL-1 ⁇ nterleuk ⁇ ns-1
  • bronchitis in particular acute and chronic (in particular inflammatory and allergen- induced) airway disorders of varying origin
  • dermatoses especially of proliferative, inflammatory and allergic type
  • psoriasis vulga ⁇ s
  • toxic and allergic contact eczema atopic eczema
  • seborrhoeic eczema Lichen simplex, sunburn, pruritus in the anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, fol
  • combined use (or 'combination ) embraces the administration of a PDE4 inhibitor and IL-1 Trap as part of a specific treatment regimen intended to provide a beneficial effect from the co- action of these therapeutic agents
  • Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually, minutes, hours, days or weeks depending upon the combination selected)
  • Combined use' generally is not intended to encompass the administration of two of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention
  • 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 more or less simultaneously, respectively in succession (from separate pack units -free combination, directly in succession or else alternatively at a relatively large time interval)
  • one therapeutic agent could be taken in the morning and one later in the day
  • one therapeutic agent could be taken once daily and the other once weekly or only once in a 2 weeks time interval
  • Simultaneous administration preferably is accomplished by administering to the subject in need thereof, for example, a single intravenous injection having a fixed ratio of each therapeutic agent
  • More or less simultaneous administration or administration in succession of each therapeutic agent can be effected by any appropriate route, including, but not limited to, oral routes, intravenous routes, intramuscular routes, and by infusion techniques
  • the therapeutic agents can be administered by the same route or by different routes
  • a first therapeutic agent of the combination selected may be administered by intravenous or subcutaneous injection while the other therapeutic agent of the combination may be administered orally
  • the sequence in which the therapeutic agents are administered is not narrowly critical
  • the therapeutic agent(s) according to the invention may be administered in a variety of forms These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e g , inject- able and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes or suppo- sito ⁇ es
  • liquid solutions e g , inject- able and infusible solutions
  • dispersions or suspensions tablets, pills, powders, liposomes or suppo- sito ⁇ es
  • the preferred form depends on the intended mode of administration and therapeutic applica ⁇
  • PDE4 inhibitor is oral
  • PDE4 inhibitor is administered by intravenous infusion or injection
  • PDE4 inhibitor is administered by intramuscular or subcutaneous injection
  • Other routes of administration are also contemplated, including intranasal and transdermal routes, and by inhalation
  • compositions for use according to the invention include the IL-1 Trap in a pharmacologically acceptable liquid, solid or semi-solid carrier, linked to a carrier or targeting molecule (e g , antibody, hormone, growth factor, etc ) and/or incorporated into liposomes, microcapsules, and controlled release preparation (including antagonist expressing cells) prior to administration in vivo
  • the pharmaceutical composition comprise the IL-1 Trap in an aqueous solution, such as sterile water, saline, phosphate buffer or dextrose solution
  • IL-1 Trap may be comprised in a solid (e g wax) or semi-solid (e g gelatinous) formulation that may be implanted into a patient in need of such treatment
  • the administration route may be any mode of administration known in the art, including but not limited to intravenously, intrathecally, subcutaneously, by injection into involved tissue, intraarte ⁇ ally, intranasally, orally, or via an implanted device
  • the therapeutic agent(s) according to the invention will be administered in the form of a composition comprising the therapeutic agent in conjunction with pharmaceutically acceptable earners
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial, and aitifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible
  • pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof
  • isotonic agents for example sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition
  • Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life and the effectiveness of the therapeutic agent(s)
  • compositions typically must be sterile and stable under the condition of manufacture and storage
  • the composition can be formulated, for example, as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high drug concentration
  • Sterile injectable solutions can be prepared by incorporating the therapeutic agent(s) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization
  • dispersions are prepared by incorporating the therapeutic agent(s) into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above
  • the preferred methods of preparation are vacuum drying and freeze-drying that yields a powder of the therapeutic agent(s) plus any additional desired ingredient from the previously sterile filtered solution thereof
  • the proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants
  • Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, mono- stearate salts and gelatin
  • the therapeutic agent(s) of the present invention can be administered by a variety of methods known in the art, although for many therapeutic applications, the preferred route of administration for a fixed combination of a PDE4 inhibitor and the IL 1 Trap according to the invention is intravenous injection or infusion
  • the therapeutic agent(s) may be prepared with a carrier that will protect the agent against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems
  • a controlled release formulation including implants, transdermal patches, and microencapsulated delivery systems
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydndes, polyglycolic acid, collagen, polyorthoesters, and poylactic acid
  • ethylene vinyl acetate, polyanhydndes, polyglycolic acid, collagen, polyorthoesters, and poylactic acid Many methods for the preparation of such formulations are generally known to those skilled in the art
  • the therapeutic agent(s) of the invention may be orally administered, for example, with an inert diluent or an assimilable edible carrier
  • the therapeutic agent(s) may also be en closed in a hard or soft shell gelatine capsule or compressed into tablets
  • the therapeutic age ⁇ t(s) may be incorporated with excipients and used in the form of ingesta- ble tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like
  • the therapeutic agent(s) 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 therapeutic agent(s) with the norm
  • the daily dose will be in the range from 0 001 to 3 mg/kg body weight of the subject to be treated, preferably by once daily administration
  • the daily dose will be in the range from 0001 to 3 mg/kg body weight of the subject to be treated, preferably by once daily administration
  • the adult dose of Cilomilast is between 5 mg and 20 mg twice a day, preferably between 10 mg and 15 mg twice a day
  • An exemplary, non-limiting range for the IL-1 Trap is 50-800 ⁇ g/kg body weight of the subject to be treated by a once weekly administration
  • the adult dose of the IL-1 Trap is 25-100 mg administered by a once weekly subcutaneous injection

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Abstract

L'invention concerne l'administration combinée d'un inhibiteur de PDE4 et IL-1 Trap afin de traiter une maladie dans laquelle l'activité de la phosphodiestérase 4 (PDE4) eu/ou de l'interleukine1 (IL-1 ) est nocive.
PCT/EP2004/050747 2003-05-12 2004-05-10 Composition pharmaceutique comprenant un inhibiteur de pde4 et il-1 trap WO2004098605A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP03010631 2003-05-12
EP03010631.4 2003-05-12

Publications (1)

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WO2004098605A1 true WO2004098605A1 (fr) 2004-11-18

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001058441A1 (fr) * 2000-02-08 2001-08-16 Smithkline Beecham Corporation Methode et compositions de traitement d'une maladie inflammatoire
WO2002064584A1 (fr) * 2001-02-15 2002-08-22 Altana Pharma Ag Derives de phtalazinone-piperidine en tant qu'inhibiteurs de pde4

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001058441A1 (fr) * 2000-02-08 2001-08-16 Smithkline Beecham Corporation Methode et compositions de traitement d'une maladie inflammatoire
WO2002064584A1 (fr) * 2001-02-15 2002-08-22 Altana Pharma Ag Derives de phtalazinone-piperidine en tant qu'inhibiteurs de pde4

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
COMPTON C H ET AL: "Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study", LANCET, XX, XX, vol. 358, no. 9278, 28 July 2001 (2001-07-28), pages 265 - 270, XP004297349, ISSN: 0140-6736 *
ECONOMIDES A N ET AL: "Cytokine traps: multi-component, high-affinity blockers of cytokine action", NATURE MEDICINE, NATURE PUBLISHING, CO, US, vol. 9, no. 1, January 2003 (2003-01-01), pages 47 - 52, XP002256034, ISSN: 1078-8956 *
EHINGER A M ET AL: "STUDIES WITH AWD 12281 IN THE SKIN OF SENSITIZED MICE", NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY, SPRINGER, BERLIN, DE, vol. 363, no. 4, SUPPLEMENT, 13 March 2001 (2001-03-13), pages R85, XP009019486, ISSN: 0028-1298 *
GABAY C: "IL-1 TRAP", CURRENT OPINION IN INVESTIGATIONAL DRUGS, CURRENT DRUGS, LONDON, GB, vol. 4, no. 5, May 2003 (2003-05-01), pages 593 - 597, XP009017868, ISSN: 0967-8298 *
WOLDA S L: "PDE4 INHIBITORS AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE", EMERGING DRUGS, ASHLEY PUBLICATIONS, LONDON, GB, vol. 5, no. 3, 2000, pages 309 - 319, XP008016335, ISSN: 1361-9195 *

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