WO2005089748A1 - Combinaison pour traitement de maladies inflammatoires - Google Patents

Combinaison pour traitement de maladies inflammatoires Download PDF

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Publication number
WO2005089748A1
WO2005089748A1 PCT/IB2005/000594 IB2005000594W WO2005089748A1 WO 2005089748 A1 WO2005089748 A1 WO 2005089748A1 IB 2005000594 W IB2005000594 W IB 2005000594W WO 2005089748 A1 WO2005089748 A1 WO 2005089748A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
receptor antagonist
histamine
pharmaceutical composition
leukotriene
Prior art date
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PCT/IB2005/000594
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English (en)
Inventor
Michael Yeadon
Original Assignee
Pfizer Limited
Pfizer Inc.
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Filing date
Publication date
Priority claimed from GB0405995A external-priority patent/GB0405995D0/en
Application filed by Pfizer Limited, Pfizer Inc. filed Critical Pfizer Limited
Publication of WO2005089748A1 publication Critical patent/WO2005089748A1/fr

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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
    • A61K31/33—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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to a pharmaceutical composition containing a combination of a leukotriene antagonist and a histamine H 4 receptor antagonist.
  • the composition can be used in the treatment of inflammatory and/or allergic conditions.
  • Leukotrienes are mediators which belong to the group of eicosanoids. They are derivatives of arachidonic acid, a fatty acid which is a constituent of membrane phospholipids. The leukotrienes are formed from arachidonic acid via 5-lipoxygenase (5- OX). At the present time, only the pathogenetically relevant role of the so-called cysteinyl-leukotrienes, to which LTC 4 , LTD and
  • LTE leukotrienes
  • the leukotrienes are very potent substances, producing a variety of biological effects when present in the nanomolar or picomolar concentration range. They have been implicated in a variety of disease states, including allergic rhinitis and adult respiratory distress syndrome.
  • Leukotriene receptor (LT) antagonists such as montelukast, have been shown to antagonize the effects of cysteinyl- leukotrienes, particularly LTD 4 .
  • the histamine H 4 receptors has recently been identified. It is a 390 amino- acid, seven-transmembrane G protein coupled receptor with approximately 40 % homology to the histamine H 3 receptor. In contrast to the H 3 receptor which is primarily located in the brain, the H 4 receptor is expressed at greater levels in neutrophils and mast cells, among other inflammatory cells.
  • the present invention provides a pharmaceutical composition containing a combination of a leukotriene antagonist and a histamine H 4 receptor antagonist.
  • histamine H4 receptor antagonists and leukotriene receptor antagonists produce synergistic relief of the signs and symptoms of allergic rhinitis, as assessed by methods such as nasal congestion, nasal and ocular itching and lachrymation, and also in other measures of airway inflammation such as allergic lung inflammation.
  • Suitable compounds are those that are potent and selective, have no significant toxic effect at the therapeutic dose, and preferably are bioavailable following administration.
  • Potency of the histamine H 4 receptor antagonist can be determined according to the assays known to the skilled person, Preferred histamine H 4 receptor ligands have a potency, expressed as one or other well-accepted measure of affinity for the human H receptor e.g. K ⁇ of 15 ⁇ M or less. Suitable assays and references are described in the experimental section hereafter.
  • histamine H 4 receptor antagonists A background on histamine H 4 receptor antagonists can be found in Expert Opin. Ther. Patents (2003) 13(6):851-865. Examples of histamine H 4 receptor antagonists for use in the present invention are described in WO02/072548 (Ortho Mc Neil) and J. Med. Chem., 2003; 46(19), pp/ 3957-3960.
  • suitable H 4 antagonists for use in the present invention are compounds having formula (I):
  • Ri is R a , R a Rb-, Ra-O-Rb-, or (R c )(Rd)N-Rb-, where R a is H, C1-C10 alkyl, C 3 -C8 alkenyl, C 3 -C 8 cycloalkyl, C 2 -C 5 heterocyclic radical, or phenyl; where R is C ⁇ -C 8 alkylene, C3-C8 alkenylene, C 3 -Cs cycloalkylene, bivalent
  • R c and R are each independently H, C-i-Cs alkyl, C 2 -Cs alkenyl, C3-C8 cycloalkyl, or phenyl;
  • R 2 is ortho or meta, and is methyl or H
  • X1 is CR 3 ;
  • R 3 is F, Cl, Br, R f> R f R g -, R f -O-R g -, or (R h )(Rj)N-R g -, where R f is H, d-C 6 alkyl,
  • R g is Ci-C ⁇ alkylene, C2-C6 alkenylene, C 3 -C 6 cycloalkylene, bivalent C 3 -C 6 heterocyclic radical, or phenylene; and R h and Rj are each independently H,
  • X 2 is NR e or O, provided that X 2 is NR e where X 1 is N; R e is H or C C 6 alkyl;
  • X 3 is N
  • WO02/072548 is referred to.
  • R 1 is H, methyl or ethyl; where R 1 is H, R 2 is methyl or H, otherwise R 2 is H;
  • Xi is CR 3 , where R 3 is H, F, Cl or Br;
  • X 2 is NH or N(C C 3 alkyl);
  • R 5 is H, F, Cl, Br, COOH, OH, amino, cyano, C-i-C 4 alkoxy or C ⁇ -C 4 alkyl;
  • R 7 is H, F, Cl, Br, C C alkyl, C ⁇ -C 4 alkoxy, cyano or amino; provided that at least one of R 5 and R 7 is not H.
  • Alkyl includes straight chain and branched hydrocarbons. Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, 1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, octyl, and so on.
  • Alkenyl includes straight chain and branched hydrocarbon radicals as above with at least one carbon-carbon double bond (sp2). Alkenyls include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), isopropenyl (or Imethylvinyl), but- 1-enyl, but-2-enyl, butadienyls, pentenyl, hexa-2,4-dienyl, and so on.
  • AlkynyTin include straight chain and branched hydrocarbon radicals as above with at least one carbon-carbon triple bond (sp).
  • Alkynyls include ethynyl, propynyls, butynyls, and pentynyls.
  • Hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-4-ynyl, are grouped as alkynyls herein.
  • Alkoxy includes a straight chain or branched alkyl group with a terminal oxygen linking the alkyl group to the rest of the molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and so on.
  • Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and so on.
  • Heterocyclic radicals include aromatic and nonaromatic rings having carbon atoms and at least one heteroatom (O, S, N) or heteroatom moiety (SO 2 , CO, CONH, COO) in the ring. Unless otherwise indicated, a heterocyclic radical may have a valence connecting it to the rest of the molecule through a carbon atom, such as 3-furyl or 2-imidazolyl, or through a heteroatom, such as N-piperidyl or 1-pyrazolyl.
  • heterocyclic radicals include thiazoylyl, furyl, pyranyl, isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolyl, furazanyl, pyrrolidinyl, pyrrolinyl, imdazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, and morpholinyl.
  • preferred heterocyclic radicals for Ra include morpholinyl, piperazinyl, pyrrolidinyl, pyridyl, cyclohexylimino, cycloheptylimino, and more preferably, piperidyl.
  • Halo includes fluoro, chloro, bromo, and iodo, and preferably fluoro or chloro.
  • a particular suitable compound to be used in the present invention is;
  • Preferred leukotriene receptor antagonists are: montelukast (Singulair®, CAS 151767-02-1 ):
  • histamine H 4 receptor antagonist is combined with montelukast, in particular montelukast sodium.
  • the ideal ratio of these therapeutic principles is that which delivers free concentrations of each compound which are active at their respective receptors i.e. typically in the range of 1-5 x their respective pA2 values (Smith D, Jones B and Walker D (1996) "Design of drugs involving the concepts and theories of drug metabolism and pharmacokinetics", Medicinal Research Reviews, 16(3), 243-266) or other functionally equivalent measures of potency (such as pK b or Ki).
  • the combination according to the invention can be used for the treatment of a patient (a mammal, in particular a human being) suffering from a H 4 mediated disease and/or leukotriene mediated disease.
  • the combination is used for treating a patient suffering from an allergic and/or inflammatory condition. Examples of such allergic and/or inflammatory conditions are seasonal and perennial allergic rhinits, non-allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), sinusitis, colds, dermatitis and uriticaria.
  • the histamine H 4 receptor antagonist and the leukotriene receptor antagonist according to the invention can be administered sequentially, separately or simultaneously.
  • the compounds can be formulated as a single dose, as separate doses or as a kit.
  • kits containing a leukotriene antagonist and a histamine H 4 receptor antagonist for sequential, separate or simultaneous use in the treatment of inflammatory diseases.
  • the kit of the invention comprises two or more separate pharmaceutical compositions, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • a container, divided bottle, or divided foil packet An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically comprises directions for administration and may be provided with a so-called memory aid.
  • compositions of the leukotriene antagonists and the H antagonists to be used in the combination of the invention include the acid addition and base salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydro- bromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and triflu
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • Compounds used in the combination of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. They may be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • excipient is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995).
  • the compounds in the combination of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. The compounds in the combination of the invention may also be used in fast- dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, H (6), 981-986 by Liang and Chen (2001).
  • the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate.
  • the disintegrant will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • lactose monohydrate, spray-dried monohydrate, anhydrous and the like
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch dibasic calcium phosphate dihydrate
  • Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • surface active agents may comprise from 0.2 wt% to 5 wt% of the tablet, and glidants may comprise from 0.2 wt% to 1 wt% of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally comprise from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.
  • ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.
  • Exemplary tablets contain up to about 80% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt- granulated, melt congealed, or extruded before tabletting.
  • the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1-14 (2001 ). The use of chewing gum to achieve controlled release is described in WO 00/35298.
  • the compounds in the combination of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of compounds used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug- coated stents and PGLA microspheres.
  • the compounds in the combination of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).
  • topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTM, BiojectTM, etc.) injection.
  • Formulations for topical administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds in the combination of the invention can also be administered intranasally or by inhalation.
  • the combinations of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema.
  • Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds in the combination of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non- biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • Formulations for ocular/aural administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.
  • the compounds in the combination of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers
  • Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non- inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.
  • the total daily dose of the histamine H 4 receptor antagonist is typically in the range 0.1 mg to 100mg and the total daily dose of the leukotriene receptor antagonist is typically in the range of 1 mg to 10mg, depending, of course, on the mode of administration.
  • the total daily dose may be administered in single or divided doses. These dosages are based on an average human subject having a weight of about 65kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • the membrane pellet was resuspended in fresh buffer and the centrifugation step was repeated as described above.
  • the membrane pellet was resuspended in 50mM Tris-HCI in the same volume as the original cell pellet.
  • the efficacy of the combinations of the invention can be demonstrated in an animal model of airway inflammation or nasal congestion.
  • bronchoalveolar lavage Twenty-four hours later the rats were overdosed with sodium pentobarbitone and bronchoalveolar lavage (BAL) was performed. The trachea was exposed by a mid-ventral incision caudal to the larynx followed by blunt dissection. A cut- down Portex leur-fitting cannula (2.0 mm outside diameter) was inserted into the trachea and tied-in securely. Using a 2.5 ml syringe, 2.5 ml of room temperature PBS (pH 7.4) containing 2.6 mM EDTA was slowly instilled into the lungs via the cannula and the BAL fluid (BALf) was immediately aspirated and stored on ice.
  • BALf BAL fluid
  • Lung inflammation can be induced and modified according to the method of Yeadon et al (1993, Agents Actions, 38, 8-18). Briefly, male Dunkin-Hartely guinea-pigs were actively sensitized to ovalbumin by a single 50mg i.p. and s.c dose and 14 days later exposed to an aerosol of ovalbumin in a cloud chamber. At various times afterwards, animals were euthanised with sagatal overdose, the lungs lavaged and total and differential cell counts made by microscopy. Compounds were given orally or s.c, alone or in combination, as pretreatments.
  • Nasal congestion was determined in anesthetized cats according to the method of McLeod et al 1999 (Am J Rhonil, 13, 391-99). Briefly, pentobarbitone anesthetized cats were mechanically ventilated with ambient air. One nostril was sealed externally and a cuffed endotracheal tube inserted in a retrograde manner via the oesophagus into the nasopharynx. Using a constant air flow through the tube, the pressure (and thus resistance) was determined and modulated by nasal exposure to the mast cell degranulating agent 48/80, and pre or post treatment with H 4 receptor antagonists or leukotriene receptor antagonists, or a combination of these agents.
  • Nasal congestion as measured by acoustic rhinomanonmetry, was determined in anesthetized guinea-pigs, according to the method of Joynson et al 2003 (proceedings of the World Inflammation Congress, Vancouver). Briefly, male Dunkin-Hartley guinea-pigs were anaesthetized with urethane (50mg/kg i.p.) and placed in a supine position. The trachea was cannulated through which the animals breathed spontaneously.
  • An acoustic rhinomter (GJ Electronik, Denmark) was used to measure cross-sectional area of the nasal cavity as a function of distance, and was modulated by various stimuli including nasal allergen (ovalbumin) in previously actively sensitized animals. Test compounds were administered alone or in combination as pre- or post- treatments.

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Abstract

La présente invention concerne une composition pharmaceutique contenant une combinaison d'un antagoniste du récepteur leukotriène et d'un antagoniste du récepteur H4 de l'histamine, l'antagoniste du récepteur leukotriène étant pris particulièrement parmi le montelukast, le pranlukast et le zafirlukast. Cette composition peut s'utiliser pour le traitement d'états allergiques et/ou inflammatoires tels que la rhinite allergique saisonnière et apériodique, la rhinite non allergique, l'asthme, la broncho-pneumopathie chronique obstructive, la sinusite, les rhumes, la dermatite et l'urticaire.
PCT/IB2005/000594 2004-03-17 2005-03-07 Combinaison pour traitement de maladies inflammatoires WO2005089748A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0405995.2 2004-03-17
GB0405995A GB0405995D0 (en) 2004-03-17 2004-03-17 Combination for treating inflammatory diseases
US57678504P 2004-06-03 2004-06-03
US60/576,785 2004-06-03

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WO2005089748A1 true WO2005089748A1 (fr) 2005-09-29

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2201982A1 (fr) 2008-12-24 2010-06-30 INSERM (Institut National de la Santé et de la Recherche Médicale) Antagonistes du récepteur H4 de l'histamine pour le traitement de troubles vestibulaires
JP2015509509A (ja) * 2012-03-06 2015-03-30 ベイジン ウェイフオン イーミーン バイオ−テクノロジー リミティドカンパニー 慢性閉塞性疾患を治療するための医薬品組成物の製造のための、ルパタジンの使用
US9981039B2 (en) 2015-05-29 2018-05-29 Accolade Pharma Llc Composition, its preparation and method of use in treating skin disorders

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2201982A1 (fr) 2008-12-24 2010-06-30 INSERM (Institut National de la Santé et de la Recherche Médicale) Antagonistes du récepteur H4 de l'histamine pour le traitement de troubles vestibulaires
JP2015509509A (ja) * 2012-03-06 2015-03-30 ベイジン ウェイフオン イーミーン バイオ−テクノロジー リミティドカンパニー 慢性閉塞性疾患を治療するための医薬品組成物の製造のための、ルパタジンの使用
US9981039B2 (en) 2015-05-29 2018-05-29 Accolade Pharma Llc Composition, its preparation and method of use in treating skin disorders

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