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WO2010116127A1 - Combinaison de cétirizine et d'acide méfénamique pour le traitement d'exacerbations de l'asthme - Google Patents

Combinaison de cétirizine et d'acide méfénamique pour le traitement d'exacerbations de l'asthme Download PDF

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Publication number
WO2010116127A1
WO2010116127A1 PCT/GB2010/000676 GB2010000676W WO2010116127A1 WO 2010116127 A1 WO2010116127 A1 WO 2010116127A1 GB 2010000676 W GB2010000676 W GB 2010000676W WO 2010116127 A1 WO2010116127 A1 WO 2010116127A1
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Prior art keywords
pharmaceutically acceptable
acceptable derivative
cetirizine
mefenamic acid
respiratory disorder
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PCT/GB2010/000676
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English (en)
Inventor
Malcolm Philip Young
Philip Mckeown
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E Therapeutics PLC
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E Therapeutics PLC
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Publication of WO2010116127A1 publication Critical patent/WO2010116127A1/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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • 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

Definitions

  • the present invention provides medicaments and methods for the treatment of respiratory disorders.
  • the present invention provides a novel therapy that is administered twice daily or less for the treatment of respiratory disorders such as asthma, to methods of treatment related thereto and to novel pharmaceutical compositions.
  • Asthma is a chronic disease of the respiratory system or airways in which the muscles around the walls of the airways constrict and the lining of the airways becomes inflamed. Sometimes excessive mucus builds up which further narrows the airway.
  • the obstruction of the respiratory tract in asthma is variable and reversible. There are acute episodes or exacerbations in asthma when the intensity of this inflammation increases. Possible triggers include exposure to an environmental stimulant or allergen, cold air, exercise or exertion, or emotional stress.
  • the airway constriction causes symptoms such as wheezing, shortness of breath, chest tightness, and coughing.
  • the symptoms of asthma which can range from mild to life threatening, can usually be controlled with the administration of a medicament, or combination of medicaments, with the exception of some cases of severe asthma.
  • a medicament or combination of medicaments, with the exception of some cases of severe asthma.
  • people are currently receiving treatment for asthma, including 1.1m children.
  • Treatment of asthma usually comprises the administration of relief medication and/or preventative medication.
  • Relief medication is usually taken immediately to relieve asthma symptoms.
  • Such medications quickly relax the muscles surrounding the narrowed airways, allowing the airways to open wider, making it easier to breathe again.
  • Relief medication usually comprises a short-acting, selective beta 2 -adrenoceptor agonist, such as salbutamol, levosalbutamol or terbutaline.
  • Less selective relief medications include the use of adrenergic agonists, such as inhaled epinephrine and ephedrine tablets, or anticholinergic agents, such as ipratropium bromide.
  • Preventative medications include inhaled corticosteroids, which help to suppress inflammation and reduce the swelling of the lining of the airways as well as reducing the secretion of mucus.
  • Preventive corticosteroids include ciclesonide, beclomethasone dipropionate, budesonide, flunisolide, fluticasone and mometasone.
  • corticosteroids can be associated with side effects such as hoarseness, sore throat and thrush or other yeast infection in the mouth, and if used at high doses for prolonged periods in children, adrenal suppression and growth failure. Orally administered, e.g.
  • corticosteroids for the treatment of severe asthma include, for example, prednisone, prednisolone and dexamethasone.
  • prednisone prednisolone
  • dexamethasone dexamethasone
  • long-acting beta-2 agonist (LABA) is advocated for all persistent asthma patients who remain symptomatic on inhaled corticosteroid alone.
  • long-acting beta-2 agonists include salmeterol and formoterol.
  • Antihistamines are commonly used to treat disorders like allergic rhinitis (also known as hay fever). Histamine is a chemical released from allergic cells in the body (such as mast cells) usually in response to an allergen. When histamine is released by allergic cells in the nose and eyes, the result is sneezing, runny nose, itchy eye/nose/throat, nasal congestion and post nasal-drip. Antihistamines are medications that block a receptor for histamine, thereby stopping the symptoms that histamine causes. Antihistamines are the most commonly used medications to treat allergic rhinitis. Examples of antihistamines include diphenhydramine, chlorpheniramine, hydroxyzine, cetirizine, fexofenadine, desloratidine and loratidine.
  • Wilson Andrew M. "The Role of Antihistamines in Asthma Management”; Treatments in Respiratory Medicine, Volume 5, Number 3, 2006, pp. 149-158(10); described that antihistamines have been shown to have bronchodilatory effects, effects on allergen-, exercise-, and adenosine-monophosphate-challenge testing, and additionally prevent allergen-induced nonspecific airways hyperresponsiveness.
  • Wilson reported that clinical studies have shown mixed results, with some studies reporting beneficial effects of azelastine, cetirizine, desloratadine, and fexofenadine on asthma symptoms or physiological measures in patients with asthma.
  • Wilson also described how the combination of an antihistamine and a leukotriene receptor antagonist (such as montelukast) has been shown to have additive effects in certain studies.
  • a specific antihistamine is cetirizine.
  • Cetirizine is 2-[2-[4-[(chlorphenyl)-phenyl- methyl]piperazin-l-yl]ethoxy]acetic acid and is described in European Patent Application No. 0 058 146.
  • Cetirizine has been shown to reduce the severity of a number of asthma symptoms (chest tightness, wheezing, shortness of breath and nocturnal asthma) in patients with allergic rhinitis and concomitant perennial asthma (Aaronson DW et at). While the acute bronchoconstriction associated with histamine release is well recognized, the ability of histamine to induce phosphorylation of an intercellular adhesion molecule, called (VE)-cadherin, found in vascular endothelial cells has received less attention (And ⁇ opoulou, et at). It has also been suggested that histamine triggers the release of cytokines and inflammatory mediators by leukocytes.
  • VE intercellular adhesion molecule
  • cetirizine may have beneficial effects on asthma symptoms in patients suffering from both asthma and rhinitis
  • certain combination therapies comprising cetirizine in combination with certain other medicaments, which are suitable for the treatment or alleviation of respiratory disorders, in particular asthma.
  • the anti-inflammatory agent mefenamic acid has been studied in bronchial asthmatics whilst maintaining their existing treatment regimen. Encouraging results were obtained with improved pulmonary function tests and decreased corticosteroid requirements observed in 40% of patients (Jackson HR et a ⁇ ). No exacerbations in asthma were observed during the study period of 12 weeks and 70% of patients requested to continue on mefenamic acid upon completion of the study.
  • a therapy comprising a combination of cetirizine and mefenamic acid is described in our co-pending International Patent application No. PCT/GB2008/003338.
  • the compositions described therein may be administered in a daily dose regime with, for example, mefenamic acid, being taken four times daily.
  • an objective of the present invention is to provide a novel and effective once or twice daily therapy for the treatment or alleviation of respiratory disorders in particular asthma, and more particularly on administration at the time of onset of symptom worsening.
  • a respiratory disorder therapy for administration twice daily or less comprising a therapeutically effective amount of cetirizine, or a pharmaceutically acceptable derivative thereof, and a therapeutically effective amount of mefenamic acid, or a pharmaceutically acceptable derivative thereof.
  • the therapy according to the invention may comprise a daily dosage of cetirizine, or a pharmaceutically acceptable derivative thereof, of from 5mg to 20mg and a daily dosage of mefenamic acid, or a pharmaceutically acceptable derivative thereof, of from 500mg to 1500mg.
  • the therapy as hereinbefore described may comprise the administration of a therapeutically effective amount of cetirizine, or a pharmaceutically acceptable derivative thereof, and a therapeutically effective amount of mefenamic acid, or a pharmaceutically acceptable derivative thereof, simultaneously, sequentially or separately.
  • the therapy according to the invention may comprise administration of cetirizine, or a pharmaceutically acceptable derivative thereof, and a therapeutically effective amount of mefenamic acid, or a pharmaceutically acceptable derivative thereof, twice daily (bis in die), once daily, every other day (diebus alternis) or three times a week.
  • the therapy comprises a once a day therapy.
  • the therapy may comprise a course of therapeutic dosages as hereinbefore described, thus for example for the treatment or alleviation of a respiratory disorder, such as asthma, the therapy may comprise a multi day course, for example over 3 to 14 days.
  • the therapy may comprise a course of therapeutic dosages as hereinbefore described, thus for example for the treatment or alleviation of an acute respiratory disorder, the therapy may comprise a multi day course, for example over 3 to 7 days, e.g. five days.
  • the therapy may comprise the treatment or alleviation of a chronic respiratory disorder, as a multi day course, for example over 3 to 14 days, e.g. seven days.
  • cetirizine, or a pharmaceutically acceptable derivative thereof, and a therapeutically effective amount of mefenamic acid, or a pharmaceutically acceptable derivative thereof may be the same or different.
  • the cetirizine, or a pharmaceutically acceptable derivative thereof may be administered twice daily (bis in die), once daily, every other day (diebus alternis) or three times a week.
  • the mefenamic acid or a pharmaceutically acceptable derivative thereof may be administered in a different dosage regime to the cetirizine, for example, twice daily (bis in die), once daily, every other day (diebus alternis) or three times a week.
  • both the cetirizine, or a pharmaceutically acceptable derivative thereof, and mefenamic acid or a pharmaceutically acceptable derivative thereof are administered on a once daily basis.
  • the daily dosage of cetirizine, or a pharmaceutically acceptable derivative thereof may be from 6mg to 18mg, preferably from 7 to 16mg, more preferably from 8 to 14mg or 9 to 12 mg.
  • An especially preferred daily dosage of cetirizine is 10mg.
  • a pharmaceutically acceptable derivative of cetirizine may be a salt, such as the hydrochloride salt.
  • the daily dosage of mefenamic acid, or a pharmaceutically acceptable derivative thereof may be from 600mg to 1400mg, preferably from 700 to 1300mg, more preferably from 800 to 1200mg or 900 to 1100 mg.
  • An especially preferred daily dosage of cetirizine is lOOOmg.
  • a pharmaceutical composition comprising a therapeutically effective amount of cetirizine, or a pharmaceutically acceptable derivative thereof, and a therapeutically effective amount of mefenamic acid, or a pharmaceutically acceptable derivative thereof, optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for administration to a patient twice daily or less.
  • the composition may comprise from 5mg to 20mg of cetirizine, or a pharmaceutically acceptable derivative thereof, and from 500mg to 1500mg of mefenamic acid, or a pharmaceutically acceptable derivative thereof.
  • a controlled release pharmaceutical composition comprising a therapeutically effective amount of cetirizine, or a pharmaceutically acceptable derivative thereof, and a therapeutically effective amount of mefenamic acid, or a pharmaceutically acceptable derivative thereof, optionally in admixture with a suitable adjuvant, diluent or carrier.
  • the controlled release composition as hereinbefore described may vary and may, for example, comprise both active ingredients in controlled release form.
  • the controlled release composition may comprise one active ingredient in controlled release form and the other in fast or normal release form.
  • the composition may comprise a therapeutically effective amount of cetirizine, or a pharmaceutically acceptable derivative thereof, in controlled release form and a therapeutically effective amount of mefenamic acid, or a pharmaceutically acceptable derivative thereof, in fast or normal release form.
  • the composition may comprise a therapeutically effective amount of mefenamic acid, or a pharmaceutically acceptable derivative thereof, in controlled release form and a therapeutically effective amount of cetirizine, or a pharmaceutically acceptable derivative thereof, in fast or normal release form.
  • composition of the invention provides a therapeutically effective amount of cetirizine, or a pharmaceutically acceptable derivative thereof, in controlled release form and a therapeutically effective amount of mefenamic acid, or a pharmaceutically acceptable derivative thereof, in controlled release form, optionally in admixture with a suitable adjuvant, diluent or carrier.
  • Such a preferred composition is advantageous in that, inter alia, a controlled release anti-inflammatory action is desirable for continually lowering and/or maintaining a low level of inflammation in a patient suffering from a respiratory disorder. Furthermore, such a controlled release composition provides improved convenience for the patient and consequently provides improved patient compliance.
  • controlled release is defined for purposes of the present invention as a method of oral drug delivery where the rate of release of the active pharmaceutical ingredient from the formulation is not solely dependent on the concentration of active pharmaceutical ingredient remaining in the formulation and/or the solubility of the active pharmaceutical ingredient in the medium surrounding the formulation, and where the time course and/or location of release of an active ingredient from a pharmaceutical formulation are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms.
  • the therapy or composition of the invention may desirably be administered orally.
  • the orally administered pharmaceutical composition may be in a form which is generally known per se.
  • the form may generally be a tablet form.
  • the dosage form may be, for example, a capsule in which the active ingredient may be present in the form of controlled release granule or the like. Therefore, in the following description reference to the structure of a controlled release tablet will be understood by the person skilled in the art to be applicable to, for example, granules, etc. which may be made up in capsule form.
  • the controlled release composition of the invention may comprise a tablet, pellet, bead or granule comprising a core e.g. a controlled release core and a coating, optionally a controlled release coating.
  • the core of a tablet, pellet, bead or granule of the invention may include at least one active ingredient and a matrix, these components associated in such a way that release of the active ingredient from the matrix is controlled.
  • Particular embodiments include a core containing one or more active ingredients as hereinbefore described in which the core contains between about 10% and 90% of the total active ingredients present in the tablet, pellet, bead or granule, e.g. about 45 to 50% of the total.
  • a matrix of the core may be a cross-linked high amylose starch, for example, as described in U.S. Patent No. 6,607,748.
  • the matrix makes up between about 10% and about 90% by weight of the core i.e., the ratio of the matrix of the core to the active ingredient(s) of the core (w/w) is between about 0.1 and about 10, or between about 0.2 and about 9, or between about 0.2 and about 8, or between about 0.3 and about 7, or between about 0.4 and about 6, or between about 0.5 and about 5, or between about 0.6 and about 4, or between about 0.7 and about 4 or between about 1 and about 4, or between about 1 and about 3 and about 1.5 and about 2.5.
  • the core composition of the present invention may optionally include a pharmaceutically acceptable carrier or vehicle. Such carriers or vehicles are known to those skilled in the art and are found, for example, in Remington's Pharmaceutical Sciences, 14th Ed. (1970).
  • Such carriers or vehicles include lactose, starch, dicalcium phosphate, calcium sulphate, kaolin, mannitol and powdered sugar. Additionally, when required, suitable binders, lubricants, and disintegrating agents can be included. If desired, dyes, as well as sweetening or flavouring agents can be included.
  • the core composition of the present invention may optionally include accessory ingredients including, but not limited to dispersing agents such as microcrystalline cellulose, starch, cross-linked starch, cross-linked poly(vinyl pyrrolidone), and sodium carboxymethyl cellulose; flavouring agents; colouring agents; binders; preservatives; surfactants and the like.
  • dispersing agents such as microcrystalline cellulose, starch, cross-linked starch, cross-linked poly(vinyl pyrrolidone), and sodium carboxymethyl cellulose
  • flavouring agents such as microcrystalline cellulose, starch, cross-linked starch, cross-linked poly(vinyl pyrrolidone), and sodium carboxymethyl cellulose
  • flavouring agents such as microcrystalline cellulose, starch, cross-linked starch, cross-linked poly(vinyl pyrrolidone), and sodium carboxymethyl cellulose
  • flavouring agents such as microcrystalline cellulose, starch, cross-linked starch, cross-linked poly(vinyl pyrrolidone), and sodium
  • the core can, optionally, also include one or more suitable binders known to one of ordinary skilled in the art.
  • Suitable forms of microcrystalline cellulose may be included, for example; MCC- PHlOl, MCC-102, MCC-105, etc.
  • Suitable lubricants such as those known to the skilled person, may also be included for example, magnesium stearate, vegetable oil, talc, sodium-stearyl fumarate, calcium stearate, static acid, etc.
  • Suitable glidants or flow aids known in the art, may also be included. Examples of such glidants include, but are not limited to talc, colloidal silicon dioxide, etc.
  • the active ingredients) as hereinbefore described may be present at levels ranging from about 1 to about 90% w/w of the total weight of the core, preferably from about 10 to about 70% w/w of the total composition of the core, more preferably from about 20 to about 60% w/w of the total composition of the core, and probably most often between about 30 to about 50% w/w of the total composition of the core.
  • the coating may include one or more binding agents.
  • Suitable binding agents for the present invention include, but are not limited to, plant extracts, gums, synthetic or natural polysaccharides, polypeptides, alginates, synthetic polymers, or a mixture thereof.
  • the controlled release composition of the invention may comprise a tablet, such as a matrix tablet.
  • a matrix tablet may be based on a swellable gel e.g. a hydrogel, wherein the gel is adapted to swells when it comes into contact with a fluid, such as water, gastric juices, etc, to form a hydrogel.
  • a fluid such as water, gastric juices, etc.
  • the release of one or more of the active ingredients is governed by, for example, hydration and/or diffusion through the hydrogel as well as the erosion of the hydrogel as it passes through the gastro intestinal tract of the patient.
  • Suitable plant extracts to be used as gelling agents include, but are not limited to, agar, ispaghula, psyllium, cydonia, ceratonia or a mixture thereof.
  • Suitable gums to be used as gelling agents include, but are not limited to, xanthan gum, guar gum, acacia gum, ghatti gum, karaya gum, tragacanth gum or a mixture thereof.
  • Suitable synthetics or natural hydrophilic polysaccharides to be used as gelling agents include, but are not limited to, hydroxyalkylcelluloses, such as hydroxypropylmethylcellulose (HPMC), e.g. Methocel KlOO LV, cellulose ethers, cellulose esters, nitrocelluloses, dextrin, agar, carrageenan, pectin, furcellaran, starch or starch derivatives, cross-linked high amylose starch, or a mixture thereof.
  • HPMC hydroxypropylmethylcellulose
  • Suitable polypeptides to be used as gelling agents include, but are not limited to, gelatin, collagen, polygeline or a mixture thereof.
  • Suitable alginates to be used as gelling agents include, but are not limited to, alginic acid, propylene glycol alginate, sodium alginate or a mixture thereof.
  • Suitable synthetic polymers to be used as gelling agents include, but are not limited to, carboxyvinyl polymer, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycols, copolymers of ethylene oxide and propylene oxide and their copolymers or a mixture thereof.
  • the gelling agent is a gum such as xanthan gum, guar gum, acacia gum, ghatti gum, karaya gum, tragacanth gum or a mixture thereof, PEO 7,000,000 and HPMC KlOO M.
  • the gelling agent is xanthan gum.
  • the coating may also include one or more colouring agents which are known to the person skilled in the art. Such colourants may be included in a film coat or any sub- coat (if desired, e.g. to separate the tablet from an enteric film coat)
  • the tablet or capsule composition of this aspect of the invention can be administered through, but not limited to, a number of routes such as oral, sublingual, and rectal.
  • routes such as oral, sublingual, and rectal.
  • the preferred route of administration of the compositions of the present invention is oral.
  • compositions of the present invention that are suitable for oral administration may be presented as discrete units such as tablets or granules.
  • the compositions of the present invention are presented in a tablet form.
  • Such tablets may be conventionally formed by compression or moulding.
  • Compressed tablets may be prepared by compressing in a suitable machine the mixture of one or more components described above.
  • Moulded tablets may be made by moulding in a suitable machine the above components, which can be optionally moistened with an inert liquid diluent.
  • the tablets may optionally be coated and/or have other identifying indicia visible to the consumer.
  • a tablet can also be in a variety of forms, e.g., uncoated, dry coated, or film coated, etc.
  • a tablet can also be in a variety of shapes (e.g. oval, sphere, etc.) and sizes.
  • shapes e.g. oval, sphere, etc.
  • sizes e.g. oval, sphere, etc.
  • a comprehensive discussion of tablets can be found in references such as The Theory and Practice of Industrial Pharmacy by Lachman et al., 3rd Ed. (Lea & Febiger, 1986).
  • enteric coating we mean a coating which is resistant to the acidic environment of the stomach but dissolves, disintegrates or becomes bioavailable when it reaches the intestines of a patient. Since mefenamic acid is known to exhibit certain side effects, for example, nausea, stomach pain, heartburn, dyspepsia, diarrhoea, etc. it is therefore desirable that at least the mefenamic acid portion of the therapy is provided with an enteric coating.
  • the therapy or composition of the invention may comprise, for example, a tablet, pellets, beads or granules with an enteric coating as an outer layer.
  • the coating may be a pH- sensitive enteric coating, that is, a coating that is stable at acidic pH, but breaks down rapidly at neutral or basic pH.
  • Such a coating material may, for example, comprise at least one material selected from the group consisting of an acid-resistant acrylic polymer, acid-resistant methacrylic or a methacrylate polymer, modified cellulose, hydroxypropylmethylcellulose (HPMC), methacrylic acid copolymers, cellulose acetate (and its succinate and phthalate version), styrol maleic acid co-polymers, polymethacrylic acid/acrylic acid copolymer, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, hydroxyethylethylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate tetrahydrophthalate, acrylic resin, timellitate, shellac, and combinations thereof.
  • an acid-resistant acrylic polymer acid-resistant methacrylic or a methacrylate polymer
  • modified cellulose hydroxypropylmethylcellulose (HPMC)
  • HPMC hydroxypropylmethylcellulose
  • the coating may be designed to prevent the release in the stomach of the patient, of the cetirizine, or a salt thereof, or the mefenamic acid or both.
  • an enteric coating shall be designed to prevent the release of some or all of the mefenamic acid in the stomach of the patient.
  • the active ingredients e.g. the mefenamic acid and the cetirizine, or a salt thereof
  • the mefenamic acid and the cetirizine, or a salt thereof may be formulated into the same region of the tablet.
  • a bi-layer of active ingredients may be desirable, so that the rate of release of, for example, the mefenamic acid, may be varied compared to the rate of release of the cetirizine, or a salt thereof.
  • Mefenamic acid and cetirizine, or a salt thereof are particularly desirable and compatible as a combination therapy since, inter alia, generally, mefenamic acid is less soluble than cetirizine, or a salt thereof, whereas cetirizine, or a salt thereof, has a longer plasma half life compared to mefenamic acid. Therefore, in a preferred aspect of the present invention, the mefenamic acid is provided in a more prolonged or sustained release form, for example, up to 10 hours, e.g. for a twice a day administration, or up to 18 hours, e.g. for once a day administration, compared to the cetirizine, or a salt thereof.
  • the cetirizine, or a salt thereof may be provided in a more rapid release form, for example, up to 2 or 3 hours, e.g. for a once or a twice a day administration.
  • compositions of the invention may be administered in a daily dose regime.
  • a suitable daily dosage of cetirizine hydrochloride may be lOmg for up to seven days, e.g. five days, whilst a suitable daily dosage for mefenamic acid may be lOOOmg for up to seven days, e.g. five days.
  • the present invention provides the use of cetirizine, or a pharmaceutically acceptable derivative thereof, and/or mefenamic acid, or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for administration twice daily or less for the treatment or alleviation of a respiratory disorder.
  • the present invention provides cetirizine, or a pharmaceutically acceptable derivative thereof, and/or mefenamic acid, or a pharmaceutically acceptable derivative thereof, as a combination therapy for administration twice daily or less, simultaneously, sequentially or separately, for the treatment or alleviation of a respiratory disorder.
  • the present invention further provides mefenamic acid as a combination therapy for administration simultaneously, sequentially or separately, with cetirizine, or a pharmaceutically acceptable derivative thereof, twice daily or less for the treatment or alleviation of a respiratory disorder.
  • the invention also provides the use of mefenamic acid in the manufacture of a medicament for the treatment or alleviation of a respiratory disorder and particularly in the manufacture of a combination therapy that is twice daily or less with cetirizine, or a pharmaceutically acceptable derivative thereof, for administration simultaneously, sequentially or separately.
  • the use according to the invention may comprise the manufacture of a medicament as hereinbefore described for administration simultaneously, sequentially or separately.
  • the use comprises the manufacture of a medicament for simultaneous administration and therefore, the use comprises the manufacture of a composition as hereinbefore described.
  • the present invention provides a method of treatment or alleviation of symptoms of a patient suffering from a respiratory disorder, said method comprising the administration twice daily or less of a therapeutically effective amount of a combination therapy comprising cetirizine, or a pharmaceutically acceptable derivative thereof, and mefenamic acid, or a pharmaceutically acceptable derivative thereof.
  • the method of the invention may comprise the administration of a combination therapy comprising cetirizine, or a pharmaceutically acceptable derivative thereof, and mefenamic acid, or a pharmaceutically acceptable derivative thereof, simultaneously, sequentially or separately.
  • the method of the invention comprises the simultaneous administration of cetirizine or a pharmaceutically acceptable derivative thereof, and mefenamic acid, or a pharmaceutically acceptable derivative thereof.
  • the cetirizine, or a pharmaceutically acceptable derivative thereof, and mefenamic acid, or a pharmaceutically acceptable derivative thereof may be formulated as a composition according to the invention as hereinbefore described.
  • the method of the invention may comprise the separate or sequential administration of cetirizine or a pharmaceutically acceptable derivative thereof, and mefenamic acid, or a pharmaceutically acceptable derivative thereof.
  • composition of the invention may be administered orally.
  • compositions of the invention may be administered in combination with one or more other treatments known per se for the treatment or alleviation of a respiratory disorder.
  • a therapy or a composition as hereinbefore described which includes another therapeutically active ingredient useful in the treatment or alleviation of respiratory disorders simultaneously, sequentially or separately.
  • Examples of other medicaments known to be efficacious in the treatment or alleviation of a respiratory disorder include, but shall not be limited to, ⁇ 2-agonists, e.g. fenoterol, formoterol, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol and terbutaline; non-selective beta-stimulants such as isoprenaline; xanthine bronchodilators, e.g. theophylline, aminophylline and choline theophyllinate; anticholinergics, e.g. ipratropium bromide; mast cell stabilisers, e.g.
  • bronchial anti-inflammatory agents e.g. nedocromil sodium
  • steroids e.g. beclomethasone dipropionate, fluticasone, budesonide, flunisolide and ciclesonide, and isomers and/or salts or derivatives thereof.
  • combination therapies which may be co-administered with the composition of the present invention include, but shall not be limited to, combinations of steroids, such as, beclomethasone dipropionate and formoterol; beclomethasone dipropionate and salmeterol; fluticasone and formoterol; fluticasone and salmeterol; budesonide and formoterol; budesonide and salmeterol; flunisolide and formoterol; and flunisolide and salmeterol.
  • steroids such as, beclomethasone dipropionate and formoterol; beclomethasone dipropionate and salmeterol; fluticasone and formoterol; fluticasone and salmeterol; budesonide and formoterol; budesonide and salmeterol; flunisolide and formoterol; and flunisolide and salmeterol.
  • each component of the invention may be put up as a tablet, capsule, dragee, suppository, suspension, solution, injection, e.g. intravenously, intramuscularly or intraperitoneally, implant, a topical, e.g. transdermal, preparation such as a gel, cream, ointment, aerosol or a polymer system, or an inhalation form, e.g. an aerosol or a powder formulation.
  • the composition of the invention may be administered orally.
  • compositions suitable for enteral/oral administration include tablets, capsules, dragees, liquid suspensions, solutions and syrups; compositions suitable for topical administration to the skin include creams, e.g. oil-in- water emulsions, water-in-oil emulsions, ointments or gels; examples of such adjuvants, diluents or carriers are: for tablets and dragees - fillers, e.g. lactose, such as anhydrous lactose, starch, microcrystalline cellulose, talc and stearic acid; lubricants/glidants, e.g.
  • magnesium stearate (as a lubricant) and colloidal silicon dioxide (as a flow aid); disintegrants, e.g. sodium starch glycolate and sodium carboxymethylcellulose; for capsules - pregelatinised starch or lactose; for oral or injectable solutions or enemas - water, glycols, alcohols, glycerine, vegetable oils; for suppositories - natural or hardened oils or waxes.
  • compositions and methods described herein may be used prophylactically as a means to prevent the development, exacerbation and/or onset of a respiratory disorder.
  • respiratory disorder will be understood by the person skilled in the art to include, inter alia, asthma, allergic asthma, so-called intrinsic' asthma (in which no sensitivity to extrinsic antigen can be demonstrated), reversible obstructive airways disease (ROAD), chronic obstructive pulmonary disorder (COPD), bronchitis, paediatric bronchitis, respiratory infections, coughs and the bronchial obstruction associated with the common cold, inflammatory or obstructive airways diseases.
  • ROAD reversible obstructive airways disease
  • COPD chronic obstructive pulmonary disorder
  • bronchitis paediatric bronchitis
  • respiratory infections coughs
  • coughs and the bronchial obstruction associated with the common cold, inflammatory or obstructive airways diseases.
  • Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic (non- allergic) asthma and extrinsic (allergic) asthma.
  • Treatment of asthma is also to be understood as embracing treatment of subjects, e.g. of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "whez infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics. (For convenience this particular asthmatic condition is referred to as "whez-infant syndrome”.)
  • the therapy or composition of the invention may also be used prophylactically.
  • Prophylactic efficacy in the treatment of asthma may be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e. therapy for or intended to restrict or abort symptomatic attack when it occurs, for example anti-inflammatory (e.g. corticosteroid) or bronchodilatory.
  • Prophylactic benefit in asthma may in particular be apparent in subjects prone to "morning dipping".
  • “Morning dipping” is a recognised asthmatic syndrome, common to a substantial percentage of asthmatics and characterised by asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant from any previously administered symptomatic asthma therapy.
  • inflammatory or obstructive airways diseases and conditions to which the present invention is applicable include adult/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary or airways disease (COPD or COAD), including chronic bronchitis, or dyspnoea associated therewith, emphysema, as well as exacerbation of airways hyperactivity consequent to other drug therapy, in particular other inhaled drug therapy.
  • ARDS adult/acute respiratory distress syndrome
  • COAD or COAD chronic obstructive pulmonary or airways disease
  • the invention is also applicable to the treatment of bronchitis of whatever type or genesis including, e.g., acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis.
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • aluminosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • aluminosis anthracosis
  • asbestosis chalicosis
  • cystic fibrosis ptilosis
  • siderosis silicosis
  • tabacosis tabacosis and byssinosis.
  • a therapeutically effective amount of cetirizine, or a pharmaceutically acceptable derivative thereof, and a therapeutically effective amount of mefenamic acid, or a pharmaceutically acceptable derivative thereof, may be provided in kit form.
  • the present invention provides for a kit comprising, in a first part, cetirizine, or a pharmaceutically acceptable derivative thereof, as hereinbefore described, and, in a second part, cetirizine, or a pharmaceutically acceptable derivative thereof.
  • the first and second parts may be supplied in separate containers or in a single container with the two parts separated by a barrier which is removed or broken prior to use.
  • kits according to this aspect of the invention is desirably suitable for the treatment or alleviation of a respiratory disorder.
  • the kit may comprise a daily dosage of cetirizine, or a pharmaceutically acceptable derivative thereof, of from 5mg to 20mg and a daily dosage of mefenamic acid, or a pharmaceutically acceptable derivative thereof, of from 500mg to 1500mg.
  • the kit may comprise a course of therapeutic dosages, for example, a multi day course of treatment, for example over 3 to 7 days, e.g. five days, for treatment or alleviation of a chronic or acute respiratory disorder.
  • composition or therapy comprises the following illustrative ingredients:
  • Hydroxypropylmethyl cellulose e.g. Methocel KlOO LV
  • controlled release agent e.g. Methocel KlOO LV
  • the trial was designed to evaluate the anti-asthmatic activity of the combination of cetirizine and mefenamic acid in a population of asthmatic patients, administered at the onset of symptom worsening, by comparing the incidence of asthma exacerbations, changes in consumption of beta-2 agonists and corticosteroids, or unscheduled healthcare visits for asthma.
  • Non-smoking adults (aged 18-65) were included in the study if they had moderate to severe persistent asthma, classed as having a history of bronchial asthma for more than one year with FEV (Forced Expiratory Volume) of ⁇ 80% of predicted value. All patients recruited to the study had no serious medical illness apart from asthma, did not regularly use medications (except beta-2 agonists and inhaled corticosteroids), and had not had respiratory tract infections or asthma exacerbations within 2 weeks of enrolment. Treatments:
  • the investigational drugs were administered in tablet form orally. Supplies of both mefenamic acid and cetirizine were from commercially available sources. Mefenamic acid was taken in a dose of 250mg QBD for a duration of 5 days at a time. Cetirizine was taken in a dose of lOmg once daily, at bedtime, for a duration of 5 days (the same
  • the remaining three mefenamic acid doses were taken with breakfast, lunch and evening meal.
  • Peak Expiratory Flow values were obtained six times daily from all patients. There was no significant difference in the number of days that the PEF value was below 80% of the predicted value in the two groups.
  • Peak Expiratory Flow variability was not significantly different between the two groups when the average variability over visits 1 and 4 were examined.
  • the variability in the experimental group was greater than the control groups.
  • cet ⁇ rizine and mefenamic acid were well tolerated. In particular, no sensitivity to the NSAID component was detected.
  • the investigational drugs will be administered in tablet form orally. Patients will receive a placebo or matching tablet containing cetirizine only or matching tablet containing mefenamic acid only or tablet containing cetirizine and mefenamic acid.
  • mefenamic acid When administered, mefenamic acid will be taken in a dose of 750 mg once, at bedtime, daily for a duration of 5 days at a time.
  • cetirizine When administered, cetirizine will be taken in a dose of 10 mg once daily, at bedtime, for a duration of 5 days (the same 5 days as mefenamic acid) at a time.
  • OBJECTIVE To evaluate the anti-asthmatic activity of a combination of cetirizine and mefenamic acid, administered at the time of onset of symptom worsening, by comparing the effects on incidence of asthma exacerbations, changes in the consumptions of beta-2 agonists and corticosteroids or unscheduled healthcare visits for asthma with placebo and each drug administered alone but in addition to their established asthma medication regimen.
  • the main study analysis will be performed after data lock when all subjects have completed their participation in the trial and data collection is complete.

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Abstract

L'invention porte sur une thérapie des troubles respiratoires avec administration deux fois par jour ou moins d'une quantité thérapeutiquement efficace de cétirizine, ou d'un dérivé pharmaceutiquement acceptable de celle-ci, et d'une quantité thérapeutiquement efficace d'acide méfénamique ou d'un dérivé pharmaceutiquement acceptable de celui-ci.
PCT/GB2010/000676 2009-04-06 2010-04-01 Combinaison de cétirizine et d'acide méfénamique pour le traitement d'exacerbations de l'asthme Ceased WO2010116127A1 (fr)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
WO1999015173A1 (fr) * 1997-09-19 1999-04-01 The Procter & Gamble Company Compositions et procedes de traitement de troubles respiratoires
WO1999052553A1 (fr) * 1998-04-14 1999-10-21 Sepracor Inc. Methodes, et compositions afferentes, d'utilisation de cetirizine en combinaison avec des inhibiteurs de leucotriene pour traiter des troubles consecutifs a l'inhibition de leucotriene
WO2001054685A1 (fr) * 2000-01-31 2001-08-02 Genaera Corporation Inhibiteurs de synthese de la mucine
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Publication number Priority date Publication date Assignee Title
WO1999015173A1 (fr) * 1997-09-19 1999-04-01 The Procter & Gamble Company Compositions et procedes de traitement de troubles respiratoires
WO1999052553A1 (fr) * 1998-04-14 1999-10-21 Sepracor Inc. Methodes, et compositions afferentes, d'utilisation de cetirizine en combinaison avec des inhibiteurs de leucotriene pour traiter des troubles consecutifs a l'inhibition de leucotriene
WO2001054685A1 (fr) * 2000-01-31 2001-08-02 Genaera Corporation Inhibiteurs de synthese de la mucine
WO2009044141A1 (fr) * 2007-10-05 2009-04-09 E-Therapeutics Plc Compositions comprenant de la cétirizine et un non-agoniste du bêta-2-adrénorécepteur, un agoniste du bêta-2-adrénorécepteur ou un anti-inflammatoire et leur utilisation pour le traitement de troubles respiratoires

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