EP1791538A1 - Inhibiteur de roflumilast et de syk combine et procedes d'utilisation associes - Google Patents

Inhibiteur de roflumilast et de syk combine et procedes d'utilisation associes

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Publication number
EP1791538A1
EP1791538A1 EP05787069A EP05787069A EP1791538A1 EP 1791538 A1 EP1791538 A1 EP 1791538A1 EP 05787069 A EP05787069 A EP 05787069A EP 05787069 A EP05787069 A EP 05787069A EP 1791538 A1 EP1791538 A1 EP 1791538A1
Authority
EP
European Patent Office
Prior art keywords
fluoro
pyrimidinediamine
hydroxyphenyl
pyrimidine
carbonylmethyleneoxyphenyl
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.)
Withdrawn
Application number
EP05787069A
Other languages
German (de)
English (en)
Inventor
Tushar P. Shah
Shahin Sanjar
Pamela Weir
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.)
Takeda GmbH
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 EP1791538A1 publication Critical patent/EP1791538A1/fr
Withdrawn legal-status Critical Current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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • 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
    • 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
    • A61P11/16—Central respiratory analeptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • This invention relates to the combination of roflumilast with syk inhibitors, in particular to pharmaceuti ⁇ cal formulations containing combinations of roflumilast and syk inhibitors, or the combined administra ⁇ tion of roflumilast and syk inhibitors, in particular in the prophylaxis and treatment of respiratory dis ⁇ ease.
  • a number of PDE 4 inhibitors are currently undergo ⁇ ing advanced clinical testing, including the compound N-(3,5-dichloropyrid-4-yl)-3- cyclopropylmethoxy-4-difluoromethoxybenzamide (INN: roflumilast).
  • NNN N-(3,5-dichloropyrid-4-yl)-3- cyclopropylmethoxy-4-difluoromethoxybenzamide
  • This and other compounds with a benzamide structure and their use as cyclic nucleotide phosphodiesterase (PDE) inhibitors are de ⁇ scribed in U.S. Patent 5,712,298.
  • compositions of the invention which have a rapid onset and a long duration of action may be prepared.
  • combination therapy ac ⁇ cording to the inventions permits the establishment of a twice daily, in particular once daily dosing regimen with consequent substantial benefits in, for example the treatment of obstructive or inflamma ⁇ tory airways diseases (e.g. higher patient compliance, less side effects).
  • the present invention relates to a syk inhibitor in combination with an active phar ⁇ maceutical ingredient being a compound selected from the group consisting of roflumilast, pharma- ceutically acceptable salts of roflumilast, solvates or physiologically functional derivative thereof and a pharmaceutically acceptable carrier and/or one or more excipients, and optionally one or more other therapeutic ingredients.
  • an active phar ⁇ maceutical ingredient being a compound selected from the group consisting of roflumilast, pharma- ceutically acceptable salts of roflumilast, solvates or physiologically functional derivative thereof and a pharmaceutically acceptable carrier and/or one or more excipients, and optionally one or more other therapeutic ingredients.
  • Syk inhibitors include those compounds disclosed in U.S. Pat ⁇ ent No. 6,432,963, which patent is hereby incorporated by reference in its entirety; emphasized may be those compounds encompassed by the definition set out between column 3, line 45 to column 6, line 22, and in particular a compound selected from the group consisting of 2-(2-aminoethylamino)-4- (3-methylanilino)pyrimidine-5-carboxamide, 2-(2-aminoethylamino)-4-(3- trifluoromethylanilino)pyrimidine-5-carboxamide, 2-(4-aminobutylamino)-4-(3- trifluoromethylanilino)pyrimidine-5-carboxamide , 2-(2-aminoethylamino)-4-(3- bromoanilino)pyrimidine-5-carboxamide, 2-(2-aminoethylamino)-4-(3-nitroanilino)pyrimidine-5- carbox
  • Syk inhibitors as employed in the present invention, also include those compounds disclosed in U.S.
  • Patent Application Publication No. US2004/0029902 A1 published on February 12, 2004, inventors R.
  • Such compounds can be synthesized, e.g., by methods set out between paragraphs 0218 and 0260 of U.S. Patent Application Publication No. US2004/0029902.
  • Roflumilast (hereinafter also referred to as active ingredient) is the INN for a compound of the formula I
  • R1 is difluoromethoxy
  • R2 is cyclopropylmethoxy
  • R3 is 3,5-dichloropyrid-4-yl.
  • This compound has the chemical name N- ⁇ .S-dichloropyrid ⁇ -yO-S-cyclopropylmethoxy ⁇ -difluoro- methoxybenzamide (INN: roflumilast).
  • physiologically functional derivative is meant a chemical derivative of roflumilast having the same physiological function as roflumilast, for example, by being convertible in the body thereto or by being an active metabolite of roflumilast.
  • Physiological functional derivatives of roflumilast which may be mentioned in connection with the invention are for example the N-oxide of roflumilast, and its salts and solvates.
  • the N-oxide of roflumilast has the chemical name 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl 1 -oxide)benzamide.
  • This compound of the formula I, its salts, the N-oxide, its salts and the use of these compounds as phosphodiesterase (PDE) 4 inhibitors are described in U.S. Patent No. 5,712,298.
  • Salts suitable for compounds of the formula I - depending on the substitution - can be acid or base addition salts. Particular mention may be made of the pharmacologically acceptable salts of the inorganic and organic acids and bases normally used in pharmaceutical technology. Pharmacologically unacceptable salts, which, for example, may be the initial products of the process for preparing the compounds of the invention on the industrial scale are converted into pharmacologically acceptable salts by processes known to the skilled worker.
  • 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, sulphosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulphonic acid, methanesulphonic acid, or 3-hydroxy-2-naphthoic acid, the acids being employed to prepare the salts in the equimolar ratio of amounts, or one differing therefrom - depending on whether the acid is monobasic or polybasic and depending on which salt is desired.
  • acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid,
  • salts with bases are also particularly suitable.
  • basic salts which may be mentioned are lithium, sodium, potassium, calcium, aluminium, magnesium, titanium, ammonium, meglumine or guanidinium salts, once again the bases being employed to prepare the salts in the equimolar ratio of amounts or one differing therefrom.
  • both drugs may be provided separately as oral formulations, or one may be an oral prepara ⁇ tion and the other an inhalant, or both may be provided in a form suitable for inhalation.
  • Administration may be at the same time. Or they may be administered either close in time or remotely, such as where one drug is administered in the morning and the second drug is administered in the evening.
  • syk inhibitors and roflumilast and their pharmaceutically acceptable salts, solvates, and physiologically functional derivatives have been described for use in the treatment of respiratory diseases. Therefore, formulations of syk inhibitors and roflumilast pharmaceutically ac ⁇ ceptable salts, solvates, and physiologically functional derivatives have use in the prophylaxis and treatment of clinical conditions for which a PDE 4 inhibitor and/or a syk inhibitor is indicated.
  • diseases associated with reversible airways obstruction such as asthma, nocturnal asthma, exercise-induced asthma, chronic obstructive pulmonary diseases (COPD) (e. g.
  • rhinitis chronic and whez bronchitis, emphysema
  • respiratory tract infection e. g. rhinitis, such as allergic and seasonal rhinitis
  • the combination may be administered prophylactically or after onset of symptoms.
  • the present invention also provides a method for the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which a PDE 4 inhibitor and/or syk inhibitor is indicated, which comprises administration of a therapeutically effective amount of a pharmaceutical formulation comprising roflumilast or a pharmaceutical acceptable salt, solvate, or physiologically functional de ⁇ rivative thereof and a syk inhibitor, and a pharmaceutical acceptable carrier and/or one or more ex- cipients.
  • a method which comprises administration of a therapeutically effective amount of a combination comprising roflumilast and a syk inhibitor, and a pharmaceutical acceptable carrier and/or one or more excipients.
  • the present invention provides such a method for the prophylaxis or treatment of a disease associated with reversible air ⁇ ways obstruction such as asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection or upper respiratory tract disease.
  • COPD chronic obstructive pulmonary disease
  • roflumilast or a pharmaceutical acceptable salt, solvate or physiologically functional derivative thereof and a syk inhibitor which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment, and the particular disorder or disease being treated.
  • the dosage of roflumilast is of the order of magnitude customary for PDE4 inhibitors, it being possible to administer the daily dose in one or more dosage units.
  • the normal dose on systemic therapy is between 0.001 mg and 3mg per kilogram and day.
  • Oral dosage forms according to the invention contain from 0.01 mg to 5mg of roflumilast, preferably from 0.05mg to 2.5mg, particularly preferably 0.1 mg to 0.5mg of roflumilast per dosage unit.
  • Examples of oral dosage forms (tablets) contain 0.1 mg, 0.125mg, 0.25mg and 0.5mg of roflumilast per dosage unit. Normally, one or more than one dosage unit of the invention is administered once a day.
  • dosage units of the invention may be administered more than once a day.
  • Dosage forms for inhalation according to the invention contain from 0.01 mg to 5mg of roflumilast, preferably from 0.05mg to 2.5mg, particu ⁇ larly preferably 0.1 mg to 0.5mg of roflumilast per dosage unit.
  • inhalative dosage units e.g. inhalation capsules
  • the dosage of the pharmaceutically acceptable salt of a syk inhibitor is in the order of magnitude cus ⁇ tomary for a syk inhibitor for the treatment of respiratory diseases for example in doses between about 0.0001 and 100 mg/kg per day, e.g., 0.0001 mg/kg/day, 0.001 mg/kg/day, 0.01 mg/kg/day, 0.1 mg/kg/day, 1 mg/kg/day, 10 mg/kg/day and 100 mg/kg/day.
  • Doses of syk inhibitor can of course be higher or lower depending on the age of the patient, condition, bioavailability of the inhibitor, and mode of administration. It is preferred in connection with the present invention to have a twice daily and particularly preferred to have a once daily dosing regimen.
  • the pharmaceutical formulations for inhalation according to the invention comprise the active ingredients in amounts such that in case of administration by inhalation from inhalers each actuation provides a therapeutically effective dose, for example, a dose of roflumilast in a range of 0.01 mg up to 2.0 mg , preferably of 10 ⁇ g to 500 ⁇ g, 50 ⁇ g to 350 ⁇ g or 100 ⁇ g to 250 ⁇ g and a dose of a syk inhibitor or a pharmaceutically acceptable salt thereof in a range between about 0.0001 and 100 mg/kg per day. It is particularly preferred that each actuation provide a dose therapeutically effective for a twice daily dosing regimen or more particularly preferred for a once daily dosing regimen.
  • the pharmaceutical formulations for inhalation according to the invention provide therapeuti ⁇ cally effective doses that permit the establishment of a twice daily (bis in diem - b. i. d) dosing regi ⁇ men and in particular a once daily dosing regimen.
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, in ⁇ tramuscular, intravenous and intraarticular, intranasal, inhalation (including fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulisers, liquid-based inhalers equipped with appropriate aerolization technologies/apparatus or insufflators), rectal and topical (including dermal, buccal, sublingual and intraocular administration) although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • All methods include the step of bringing the active ingredients into association with the carrier, which constitutes one or more accessory ingredi- ents/excipients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • roflumilast is provided as oral administration form and the syk inhibitor is provided as either an intranasal administration form or an inhalation administration form.
  • roflumilast is provided in tablet form when given as oral administration form.
  • the syk inhibitor and roflumilast are provided in form suitable for inhalation. Both active ingredients may be provided in separate dosage forms (free combination) and preferably in a fixed combination.
  • Formulations for inhalation include powder compositions, which will preferably contain lactose, and spray compositions which may be formulated, for example, as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, with the use of a suitable propellant, e. g. 1 , 1 , 1 , 2-tera- fluorethane, 1 , 1 , 1 , 2, 3, 3, 3-heptafluoropropane, carbon dioxide or other suitable gas.
  • a suitable propellant e. g. 1 , 1 , 1 , 2-tera- fluorethane, 1 , 1 , 1 , 2, 3, 3, 3-heptafluoropropane, carbon dioxide or other suitable gas.
  • a class of propellants which are believed to have minimal ozone-depleting effects in comparison to conventional chlorofluorocarbons comprise hydrofluorocarbons and a number of medicinal aerosol formulations using such propellant systems are disclosed in, for example, EP 0372777, W091/04011 , W091/11173, W091/11495, W091/14422, W093/11743, and EP-0553298. These applications are all concerned with the preparation of pressurised aerosols for the administration of medicaments and seek to overcome problems associated with the use of this new class of propellants, in particular the problems of stability associated with the pharmaceutical formulations prepared.
  • the applications propose, for example, the addition of one or more of excipients such as polar cosolvents or wetting agents (e.g. alcohols such as ethanol), alkanes, dimethyl ether, surfactants (including fluorinated and non-fluorinated surfactants, carboxylic acids such as oleic acid, polyethoxylates etc.) or bulking agents such as a sugar (see for example WO02/30394) and amino acids and vehicles such as cromoglicic acid and/or nedocromil which are contained at concentrations, which are not therapeutically and prophylactically active (see WO00/07567).
  • excipients such as polar cosolvents or wetting agents (e.g. alcohols such as ethanol), alkanes, dimethyl ether, surfactants (including fluorinated and non-fluorinated surfactants, carboxylic acids such as oleic acid, polyethoxylates etc.) or bulking agents such as a sugar (
  • the active ingredients should be micronised so as to permit inhalation of substantially all of the active ingredients into the lungs upon administration of the aerosol formulation, thus the active ingredients will have a mean particle size of less than 100 microns, de ⁇ sirably less than 20 microns, and preferably in the range 0.7 to 10 microns, for example, 1 to 5 mi ⁇ crons.
  • Canisters generally comprise a container capable of withstanding the vapour pressure of the propel ⁇ lant, such as plastic or plastic-coated glass bottle or a metal can, for example an aluminium can which may optionally be anodised, lacquer-coated and/or plastic-coated, which container is closed with a metering valve.
  • Canisters may be coated with a fluorocarbon polymer as described in WO 96/32150, for example, a co-polymer of polyethersulphone (PES) and polytetrafluoroethylene (PTFE).
  • PES polyethersulphone
  • PTFE polytetrafluoroethylene
  • FEP fluorinated ethylene propylene
  • the metering valves are designed to deliver a metered amount of the formulation per actuation and incorporate a gasket to prevent leakage of propellant through the valve.
  • the gasket may comprise any suitable elastomeric material such as for example low density polyethylene, chlorobutyl, black and white butadiene-acrylonitrile rubbers, butyl rubber and neoprene.
  • Thermoplastic elastomer valves as described in W092/11190 and valves containing EPDM rubber as described in W095/02650 may be suitable. Suitable valves are commercially available from manufacturers well known in the aerosol industry, for example, from Valois, France (eg. DF10, DF30, DF60), Bespak pic, UK (eg. BK300, BK356, BK357) and 3M-Neotechnic Ltd, UK (eg. Spraymiser).
  • Valve seals can be manufactured of a material, which is inert to and resists extraction into the contents of the formulation, especially when the contents include ethanol.
  • Valve materials especially the material of manufacture of the metering chamber, can be manufac ⁇ tured of a material which is inert to and resists distortion by contents of the formulation, especially when the contents include ethanol.
  • Particularly suitable materials for use in manufacture of the meter ⁇ ing chamber include polyesters eg polybutyleneterephthalate (PBT) and acetals, especially PBT.
  • Materials of manufacture of the metering chamber and/or the valve stem may desirably be fluorinated, partially fluorinated or impregnated with fluorine containing substances in order to resist drug deposi ⁇ tion.
  • Valves which are entirely or substantially composed of metal components (eg Spraymiser, 3M-Neo- technic), are especially preferred for use according to the invention.
  • Intranasal sprays or nasal drops may be formulated with aqueous or non-aqueous vehicles with or without the addition of agents such as thickening agents, buffer salts or acid or alkali to adjust the pH, isotonicity adjusting agents, preservatives or anti-oxidants.
  • agents such as thickening agents, buffer salts or acid or alkali to adjust the pH, isotonicity adjusting agents, preservatives or anti-oxidants.
  • the pharmaceutical formulation comprising the syk inhibitor in combination with roflumilast is a dry powder, i.e. roflumilast and the syk inhibitor are present in a dry powder comprising finely divided pharmaceutical acceptable salt of a syk inhibitor and roflumilast op ⁇ tionally together with a finely divided pharmaceutically acceptable carrier, which is preferably present and may be one or more materials known as carriers in dry powder inhalation compositions, for exam ⁇ ple saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches, dex- tran or mannitol.
  • a finely divided pharmaceutically acceptable carrier which is preferably present and may be one or more materials known as carriers in dry powder inhalation compositions, for exam ⁇ ple saccharides, including monosaccharides, dis
  • the dry powder may be in capsules of gelatine or plastic, or in blisters, for use in a dry powder inhala ⁇ tion device, preferably in dosage units of the mixture of a syk inhibitor and roflumilast together with the carrier in amounts to bring the total weight of powder in each capsule to from 5mg to 50mg.
  • the dry powder may be contained in a reservoir of a multi-dose dry powder inhalation device.
  • Capsules and cartridges of for example gelatin, or blisters of for example laminated aluminium foil, for use in an inhaler or insulator may be formulated containing a powder mix of the active ingredients and a suitable powder base such as lactose or starch, preferably lactose.
  • the active ingredi ⁇ ents are suitably micronised so as to permit inhalation of substantially all of the active ingredients into the lungs upon administration of the dry powder formulation, thus the active ingredients will have a particle size of less than 100 ⁇ m, desirably less than 20 ⁇ m, and preferably in the range 1 to 10 ⁇ m.
  • the solid carrier where present, generally has a maximum particle diameter of 300 ⁇ m, preferably 200 ⁇ m, and conveniently has a mean particle diameter of 40 to 100 ⁇ m, preferably 50 to 75 ⁇ m.
  • the particle size of the active ingredients and that of a solid carrier where present in dry powder compositions can be reduced to the desired level by conventional methods, for example by grinding in an air-jet mill, ball mill or vibrator mill, microprecipitation, spray drying, lyophilisation or recrystallisation from super ⁇ critical media.
  • the inhalation device may be, for example a dry powder inhalation device adapted to deliver dry powder from a capsule or blister containing a dosage unit of the dry powder or a multi-dose dry powder inhala ⁇ tion device.
  • dry powder inhalation devices are known in the art. Examples which may be men ⁇ tioned are Cyclohaler®, Diskhaler® Rotadisk®, Turbohaler®, Novolizer® or the dry powder inhalation devices disclosed EP 0 505 321 , EP 407028, EP 650410, EP 691865 or EP 725725 (Ultrahaler®).
  • Formulations for inhalation by nebulization may be formulated with an aqueous vehicle with the addi ⁇ tion of agents such as acid or alkali, buffer salts, isotonicity adjusting agents or antimicrobials. They may be sterilised by filtration or heating in an autoclave. Suitable technologies for this type of admini ⁇ stration are known in the art. As an example the Mystic® technology is to be mentioned (see for ex ⁇ ample US6397838, US6454193 and US6302331) as well as the Respimat® technology or e-flow tech ⁇ nology by Pari.
  • Preferred unit dosage formulations are those containing a pharmaceutical effective dose, as hereinbe ⁇ fore recited, or an appropriate fraction thereof, of the active ingredient.
  • a pharmaceutical effective dose as hereinbe ⁇ fore recited, or an appropriate fraction thereof, of the active ingredient.
  • one actuation of the aerosol may deliver half of the therapeutical effective amount such that two actuations are necessary to deliver the therapeutically effective dose.
  • the formula ⁇ tions of this invention may include other agents conventional in the art having regard to the type of formulation in question.
  • the claimed formulations include bioequivalents as defined by the US Food and Drug Administration.
  • Example 1 Combination of Roflumilast Tablet and Nasal or Inhalation Formulation of Svk Inhibitor
  • intranasal and inhalation formulations of syk inhibitors can be administered in combina ⁇ tion with tablets containing roflumilast with the compositions set out below.
  • (1) is mixed with part of (3), and a trituration is produced in a planetary mill.
  • the trituration is put together with (2), (5) and the remaining amount of (3) in the product container of a fluidized bed granulation system, and a 5% granulation solution of (4) in purified water is sprayed on and dried un ⁇ der suitable conditions.
  • (6) is added to the granules, and the mixture obtained after mixing is com ⁇ pressed in a tablet press to tablets having an average weight of 59.5 mg.

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

Abstract

L'invention porte sur des formulations pharmaceutiques contenant des combinaisons d'inhibiteur de roflumilast et de syk, ainsi que sur l'utilisation de ces compositions pharmaceutiques en médecine, notamment pour la prophylaxie et le traitement de maladies respiratoires.
EP05787069A 2004-09-10 2005-09-08 Inhibiteur de roflumilast et de syk combine et procedes d'utilisation associes Withdrawn EP1791538A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US60854304P 2004-09-10 2004-09-10
PCT/EP2005/054470 WO2006027378A1 (fr) 2004-09-10 2005-09-08 Inhibiteur de roflumilast et de syk combine et procedes d'utilisation associes

Publications (1)

Publication Number Publication Date
EP1791538A1 true EP1791538A1 (fr) 2007-06-06

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EP05787069A Withdrawn EP1791538A1 (fr) 2004-09-10 2005-09-08 Inhibiteur de roflumilast et de syk combine et procedes d'utilisation associes

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EA019973B1 (ru) 2008-04-16 2014-07-30 Портола Фармасьютиклз, Инк. ИНГИБИТОРЫ Syk ПРОТЕИНКИНАЗ
US8138339B2 (en) 2008-04-16 2012-03-20 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
TWI681952B (zh) 2011-04-22 2020-01-11 美商標誌製藥公司 經取代之二胺基甲醯胺及二胺基甲腈嘧啶、其組合物、及以該等治療之方法
IN2014CN04065A (fr) 2011-11-23 2015-09-04 Portola Pharm Inc
CN104955805B (zh) 2012-10-19 2018-11-09 霍夫曼-拉罗奇有限公司 Syk的抑制剂
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AU2005281736A1 (en) 2006-03-16
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WO2006027378A1 (fr) 2006-03-16

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