WO2009153296A1 - Composition pharmaceutique comprenant un agoniste non stéréoïdien du récepteur des glucocorticoïdes combiné à un double antagoniste de l'histamine - Google Patents

Composition pharmaceutique comprenant un agoniste non stéréoïdien du récepteur des glucocorticoïdes combiné à un double antagoniste de l'histamine Download PDF

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Publication number
WO2009153296A1
WO2009153296A1 PCT/EP2009/057556 EP2009057556W WO2009153296A1 WO 2009153296 A1 WO2009153296 A1 WO 2009153296A1 EP 2009057556 W EP2009057556 W EP 2009057556W WO 2009153296 A1 WO2009153296 A1 WO 2009153296A1
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pharmaceutical composition
aqueous pharmaceutical
methyl
composition according
phenyl
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PCT/EP2009/057556
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English (en)
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Gavin Bone
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Glaxo Group Limited
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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
    • A61K31/13—Amines
    • 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 pharmaceutical compositions comprising a nonsteroidal glucocorticoid receptor agonist or a pharmaceutically acceptable salt thereof optionally in combination with a dual histamine antagonist or a pharmaceutically acceptable salt thereof, to processes for their preparation, and to their use in the treatment of various inflammatory and/or allergic conditions, such as allergic rhinitis.
  • Nuclear receptors are a class of structurally related proteins involved in the regulation of gene expression.
  • the steroid hormone receptors are a subset of this family whose natural ligands typically comprise endogenous steroids such as estradiol (estrogen receptor), progesterone (progesterone receptor) and Cortisol (glucocorticoid receptor).
  • estradiol estradiol
  • progesterone progesterone receptor
  • Cortisol glucocorticoid receptor
  • Glucocorticoids exert their actions at the glucocorticoid receptor (GR) through at least two intracellular mechanisms, transactivation and transrepression (see: Schacke, H., Docke, W-D. & Asadullah, K. (2002) Pharmacol and Therapeutics 96:23-43; Ray, A., Siegel, M. D., Prefontaine, K.E. & Ray, P. (1995) Chest 107:139S; and Konig, H., Ponta, H., Rahmsdorf, HJ. & Herrlich, P. (1992) EMBO J 11 :2241-2246).
  • GR glucocorticoid receptor
  • Transactivation involves direct binding of the glucocorticoid receptor to distinct deoxyribonucleic acid (DNA) response elements (GREs) within gene promoters, usually but not always increasing the transcription of the downstream gene product.
  • GREs deoxyribonucleic acid
  • the GR can also regulate gene expression through an additional pathway (transrepression) in which the GR does not bind directly to DNA.
  • This mechanism involves interaction of the GR with other transcription factors, in particular NFkB and AP1 , leading to inhibition of their pro-transcriptional activity (Schacke, H., Docke, W-D. & Asadullah, K. (2002) Pharmacol and Therapeutics 96:23-43; and Ray, A., Siegel, M. D., Prefontaine, K.E.
  • glucocorticoids have proved useful in the treatment of inflammation, tissue rejection, auto-immunity, various malignancies, such as leukemias and lymphomas, Cushing's syndrome, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation/apoptosis, HPA axis suppression and regulation, hypercortisolemia, modulation of the Th1/Th2 cytokine balance, chronic kidney disease, stroke and spinal cord injury, hypercalcemia, hypergylcemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia and Little's syndrome.
  • malignancies such as leukemias and lymphomas, Cushing's syndrome, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines
  • Glucocorticoids are especially useful in disease states involving systemic inflammation such as inflammatory bowel disease, systemic lupus erythematosus, polyarteritis nodosa, Wegener's granulomatosis, giant cell arteritis, rheumatoid arthritis, osteoarthritis, seasonal rhinitis, allergic rhinitis, vasomotor rhinitis, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, organ transplantation, hepatitis and cirrhosis.
  • Glucocorticoids have also been used as immunostimulants and repressors and as wound healing and tissue repair agents.
  • Glucocorticoids have also found use in the treatment of conditions such as inflammatory scalp alopecia, panniculitis, psoriasis, discoid lupus erythemnatosus, inflamed cysts, atopic dermatitis, pyoderma gangrenosum, pemphigus vulgaris, bullous pemphigoid, systemic lupus erythematosus, dermatomyositis, herpes gestationis, eosinophilic fasciitis, relapsing polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, type 1 reactive leprosy, capillary hemangiomas, contact dermatitis, atopic dermatitis, lichen planus, exfoliative dermatitis, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiform and cutaneous
  • Glucocorticoids with proven anti-inflammatory properties and which are marketed for the treatment of allergic rhinitis include but are not limited to, beclomethasone dipropionate which is marketed under the trademark BeconaseTM, fluticasone furoate which is marketed under the trademark VeramystTM and fluticasone propionate which is marketed under the trademark FlixonaseTM.
  • anti-histamines antagonists of the histamine H1 receptor
  • dual antagonists of the histamine H1 and H3 receptors such as those compounds disclosed in International Patent Application No. PCT/EP2007/053773, published 1 st November 2007 as WO2007/122156 (Glaxo Group Limited).
  • rhinitis is used herein to refer to all types of rhinitis including allergic rhinitis such as seasonal rhinitis (for example hayfever) or perennial rhinitis, and non- allergic rhinitis or vasomotor rhinitis.
  • Allergic rhinitis, pulmonary inflammation and congestion are medical conditions that are often associated with other conditions such as asthma and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • these conditions are mediated, at least in part, by inflammation associated with the release of histamine from various cells, in particular mast cells.
  • Allergic rhinitis affects a large proportion of the population worldwide.
  • Seasonal allergic rhinitis is commonly known as 'hay fever'. It is caused by allergens which are present in the air at specific times of the year, for example tree pollen during spring and summer.
  • Perennial allergic rhinitis is caused by allergens which are present in the environment during the entire year, for example dust mites, mould, mildew and pet dander.
  • the clinical symptoms of seasonal allergic rhinitis typically include nasal itching and irritation, sneezing and watery rhinorrhea, which is often accompanied by nasal congestion.
  • allergic rhinitis The clinical symptoms of perennial allergic rhinitis are similar, except that nasal blockage may be more pronounced. Either type of allergic rhinitis may also cause other symptoms, such as itching of the throat and/or eyes, epiphora and oedema around the eyes. The symptoms of allergic rhinitis may vary in intensity from the nuisance level to debilitating.
  • the medicament To formulate an effective pharmaceutical nasal composition, the medicament must be delivered readily to all portions of the nasal cavities (the target tissues) where it performs its pharmacological function. Additionally, the medicament should remain in contact with the target tissues for relatively long periods of time. The longer the medicament remains in contact with the target tissues, the greater the efficacy, and therefore the medicament must be capable of resisting those forces in the nasal passages that function to remove particles from the nose. Such forces, referred to as 'mucociliary clearance', are recognised as being extremely effective in removing particles from the nose in a rapid manner, for example, within 10 to 30 minutes from the time the particles enter the nose.
  • a nasal composition is effective in treating a broad spectrum of inflammatory and/or allergic symptoms, which offers the potential for a convenient dosing regimen and an improved side effect profile, it must not contain ingredients which cause the user discomfort, that it has satisfactory stability and shelf-life properties, and that it does not include constituents that are considered to be detrimental to the environment, for example ozone depletors.
  • the potential for any undesirable side effects should preferably be minimised.
  • an aqueous pharmaceutical composition which comprises a compound which is 1- ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2- (methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino ⁇ -6-methyl-1H- indazol-1-yl)phenyl]carbonyl ⁇ -D-prolinamide or a pharmaceutically acceptable salt thereof.
  • an aqueous pharmaceutical composition which comprises a compound which is 1- ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2- (methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H- indazol-1-yl)phenyl]carbonyl ⁇ -D-prolinamide
  • compositions of the invention may be used in the compositions of the invention in the form of its free base or as a pharmaceutically acceptable salt.
  • an aqueous pharmaceutical formulation comprising 1- ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2- (trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1-yl)phenyl]carbonyl ⁇ -D- prolinamide or a pharmaceutically acceptable salt thereof, which is an aqueous solution.
  • an aqueous pharmaceutical formulation comprising 1 - ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4- methyl-2-(trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1-yl)phenyl]carbonyl ⁇ -D- prolinamide as the free base, which is an aqueous solution.
  • compositions comprising 1- ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2- (methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino ⁇ -6-methyl-1H- indazol-1-yl)phenyl]carbonyl ⁇ -D-prolinamide may include that the compositions demonstrate good anti-inflammatory properties, good antiallergic properties, an attractive side-effect profile, rapid onset of action, long duration of action, and compatibility with a convenient regime of treatment in human patients, improved efficacy, and/or may be amenable to once per day dosing.
  • compositions that comprise a glucocorticoid receptor agonist and an anti-histamine may be particularly effective in the treatment of inflammatory and/or allergic conditions.
  • an aqueous pharmaceutical composition which comprises:
  • an aqueous pharmaceutical formulation wherein 1- ⁇ [3-(4- ⁇ [(2R)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2- (trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1-yl)phenyl]carbonyl ⁇ -D- prolinamide is in the form of the free base.
  • an aqueous pharmaceutical formulation wherein 4-[(4-chlorophenyl)methyl]-2-( ⁇ (2R)-1-[4-(4- ⁇ [3-(hexahydro-1 H-azepin-1- yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)-1 (2H)-phthalazinone is in the form of a pharmaceutically acceptable salt.
  • an aqueous pharmaceutical formulation wherein 4-[(4-chlorophenyl)methyl]-2-( ⁇ (2/?)-1- [4-(4- ⁇ [3-(hexahydro-1 H-azepin-1-yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)- 1 (2H)-phthalazinone is in the form of the dihydrochloride salt.
  • an aqueous pharmaceutical formulation wherein 4-[(4- chlorophenyl)methyl]-2-( ⁇ (2R)-1-[4-(4- ⁇ [3-(hexahydro-1 H-azepin-1- yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)-1 (2H)-phthalazinone is in the form of the 1 , 5-napthalene disulfonate monohydrate salt.
  • an aqueous pharmaceutical formulation wherein 1- ⁇ [3-(4- ⁇ [(2R)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2- (trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1-yl)phenyl]carbonyl ⁇ -D- prolinamide is in the form of the free base and 4-[(4-chlorophenyl)methyl]-2-( ⁇ (2/?)-1- [4-(4- ⁇ [3-(hexahydro-1 H-azepin-1-yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)- 1 (2H)-phthalazinone is in the form of a pharmaceutically acceptable salt.
  • an aqueous pharmaceutical formulation wherein 1- ⁇ [3-(4- ⁇ [(2R)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2- (trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1-yl)phenyl]carbonyl ⁇ -D- prolinamide is in the form of the free base and 4-[(4-chlorophenyl)methyl]-2-( ⁇ (2/?)-1- [4-(4- ⁇ [3-(hexahydro-1 H-azepin-1-yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)- 1 (2H)-phthalazinone is in the form of the 1 , 5-napthalene disulfonate monohydrate salt or dihydrochloride salt.
  • an aqueous pharmaceutical formulation wherein 1- ⁇ [3-(4- ⁇ [(2R)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2- (trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1-yl)phenyl]carbonyl ⁇ -D- prolinamide is in the form of the free base and 4-[(4-chlorophenyl)methyl]-2-( ⁇ (2/?)-1- [4-(4- ⁇ [3-(hexahydro-1 H-azepin-1-yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)- 1 (2H)-phthalazinone is in the form of the 1 , 5-napthalene disulfonate monohydrate salt.
  • Pharmaceutical compositions comprising one medicament in solution and one medicament in suspension are encompassed within the scope of the present invention.
  • a pharmaceutical composition wherein 1- ⁇ [3-(4- ⁇ [(2R)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2- (trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1-yl)phenyl]carbonyl ⁇ -D- prolinamide or a pharmaceutically acceptable thereof is completely dissolved in the composition and 4-[(4-chlorophenyl)methyl]-2-( ⁇ (2/?)-1-[4-(4- ⁇ [3-(hexahydro-1 H- azepin-1-yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)-1 (2H)-phthalazinone or a pharmaceutically acceptable salt thereof is in suspension.
  • the aqueous component of the compositions of the invention is typically a high grade quality of water such as purified water, for example USP purified water, PhEur purified water or water
  • the compound(s) for use in the compositions of the invention will typically have a mass mean diameter (MMD) of less than 20 ⁇ m, such as between 0.5 to 10 ⁇ m, for example between 1 to 10 ⁇ m as measured by laser diffraction, for example.
  • MMD mass mean diameter
  • Particle size reduction may be achieved by techniques well known in the art such as micronisation, milling and/or microfluidisation.
  • compositions of the invention may be suitable for topical administration, which includes intranasal, inhaled and ocular administration.
  • Compositions suitable for intranasal administration are of particular interest.
  • an aqueous pharmaceutical composition which is hypertonic with fluids of the nasal cavity. In another embodiment there is provided an aqueous pharmaceutical composition which is hypertonic with fluids of the eye.
  • an aqueous pharmaceutical composition which is isotonic with fluids of the nasal cavity. In another embodiment there is provided an aqueous pharmaceutical composition which is isotonic with fluids of the eye.
  • (w/w) is an abbreviation used to describe the amount in g of a material per 10Og of composition.
  • each metered dose or "spray" of aerosol contains from 0.25 to 200 ⁇ g, such as from 0.5 to 100 ⁇ g, for example from 0.5 to 25 ⁇ g.
  • Suitable unit doses may be administered once a day, or more than once a day, for example two or three times a day or as desired. Such therapy may extend for a number of weeks or months.
  • the proportion of 1- ⁇ [3-(4- ⁇ [(2R)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4- methyl-2-(trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1-yl)phenyl]carbonyl ⁇ -D- prolinamide or a pharmaceutically acceptable salt thereof, in the aqueous pharmaceutical compositions of the invention will depend on the composition to be prepared and the particular route of administration, but will generally be within the range of from 0.0005 to 0.1% (w/w), such as from 0.001 to 0.05% (w/w), based on the total weight of the composition.
  • Particular concentrations of 1- ⁇ [3-(4- ⁇ [(2/?)-4-[5- fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino ⁇ -6- methyl-1 H-indazol-1-yl)phenyl]carbonyl ⁇ -D-prolinamide as the free base include about 0.001% (w/w), about 0.008% (w/w), about 0.0175% (w/w), about 0.025% (w/w) and about 0.05% (w/w), based on the total weight of the composition.
  • the dose of 4-[(4-chlorophenyl)methyl]-2-( ⁇ (2R)-1-[4-(4- ⁇ [3-(hexahydro-1H-azepin-1- yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)-1 (2H)-phthalazinone or a pharmaceutically acceptable salt thereof used will vary in the usual way with the seriousness of the conditions to be treated and other factors, for example the weight of the sufferer.
  • aerosol compositions are preferably arranged so that each metered dose or "spray" of aerosol contains from 0.05 to 1000mg, such as from 0.05 to 200mg, for example from 0.05 to 2mg and in a further embodiment from 0.05 to 1 mg.
  • 0.05 to 1000mg such as from 0.05 to 200mg, for example from 0.05 to 2mg and in a further embodiment from 0.05 to 1 mg.
  • two metered doses are sprayed up each nostril (one unit dose)
  • one metered dose is sprayed up each nostril (one unit dose).
  • Suitable unit doses may be administered once a day, or more than once a day, for example two or three times a day or as desired. Such therapy may extend for a number of weeks or months.
  • the proportion of 4-[(4-chlorophenyl)methyl]-2-( ⁇ (2R)-1-[4-(4- ⁇ [3-(hexahydro-1 H- azepin-1-yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)-1 (2H)-phthalazinone or a pharmaceutically acceptable salt thereof, in the aqueous pharmaceutical compositions of the invention will depend on the composition to be prepared and the particular route of administration, but will generally be within the range of from 0.005 to 2% (w/w), such as from 0.01 to 1 % (w/w), based on the total weight of the composition.
  • Particular concentrations of 4-[(4-chlorophenyl)methyl]-2-( ⁇ (2/?)-1-[4-(4- ⁇ [3-(hexahydro-1 H-azepin-1-yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)-1 (2H)- phthalazinone as the free base are about 0.01% (w/w), about 0.025% (w/w), about 0.05% (w/w), about 0.1% (w/w), about 0.25% (w/w) and about 0.5 % (w/w), based on the total weight of the composition.
  • the concentration will depend on the salt chosen but will be such as to provide the desired concentration of compound as the free base.
  • the pharmaceutically acceptable salt is the dihydrochloride salt.
  • the pharmaceutically acceptable salt is the 1 ,5-naphthalene sulfonate monohydrate salt.
  • concentrations of 4-[(4-chlorophenyl)methyl]-2-( ⁇ (2/?)-1-[4-(4- ⁇ [3- (hexahydro-1 H-azepin-1 -yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)-1 (2H)- phthalazinone 1 ,5-naphthalene sulfonate monohydrate salt are in the range of from 0.01 to 0.75% (w/w), for example from 0.01478 to 0.739% (w/w), based on the total weight of the composition, to provide 0.01 to 0.5% (w/w) of the free base.
  • Intranasal compositions may permit the compound(s) to be delivered to all areas of the nasal cavities (the target tissue) and further, may permit the compound(s) to remain in contact with the target tissue for longer periods of time.
  • a suitable dosing regime for intranasal compositions would be for the patient to inhale slowly through the nose subsequent to the nasal cavity being cleared. During inhalation the composition would be administered to one nostril while the other is manually compressed. This procedure would then be repeated for the other nostril. Typically, one or two sprays per nostril would be administered by the above procedure up to two or three times each day, ideally once daily. Of particular interest are intranasal compositions suitable for once daily administration.
  • Aqueous pharmaceutical compositions of the invention may optionally contain one or more excipients, for example, one or more suspending agents/thickening agents, one or more preservatives, one or more surfactants, one or more tonicity adjusting agents, one or more co-solvents and/or a buffer as desired.
  • excipients for example, one or more suspending agents/thickening agents, one or more preservatives, one or more surfactants, one or more tonicity adjusting agents, one or more co-solvents and/or a buffer as desired.
  • the compositions of the invention for example suitable for intranasal administration, may optionally further contain other excipients, such as antioxidants (for example sodium metabisulphite) and taste-masking agents.
  • excipients may perform more than one function, depending on the excipients used in that composition and the properties of the medicament compound(s) contained therein.
  • an aqueous pharmaceutical composition of the invention comprising a suspending agent/thickening agent.
  • the suspending agent(s)/thickening agent(s), if included, will typically be present in an amount of from 0.1 to 5% (w/w), such as from 1.5% to 2.4% (w/w), based on the total weight of the composition.
  • pharmaceutically acceptable suspending agents/thickening agents include, but are not limited to, Avicel® (which is microcrystalline cellulose and carboxymethylcellulose sodium), carboxymethylcellulose sodium, veegum, tragacanth, bentonite, methylcellulose, xanthan gum, carbopol and polyethylene glycols.
  • the suspending agents/thickening agents are microcrystalline cellulose and carboxymethylcellulose sodium.
  • an aqueous pharmaceutical composition of the invention comprising a preservative.
  • compositions of the invention may be protected from microbial or fungal contamination and growth by inclusion of one or more preservatives.
  • pharmaceutically acceptable anti-microbial agents or preservatives may include, but are not limited to, quaternary ammonium compounds (e.g. benzalkonium chloride, benzethonium chloride, cetrimide, cetylpyridinium chloride, lauralkonium chloride and myristyl picolinium chloride), mercurial agents (e.g. phenylmercuric nitrate, phenylmercuric acetate and thimerosal), alcoholic agents (e.g.
  • antibacterial esters e.g. esters of para-hydroxybenzoic acid
  • chelating agents such as disodium edetate (EDTA) and other anti-microbial agents such as chlorhexidine, chlorocresol, sorbic acid and its salts (such as potassium sorbate) and polymyxin.
  • pharmaceutically acceptable anti-fungal agents or preservatives may include, but are not limited to, sodium benzoate, sorbic acid, sodium propionate, methylparaben, ethylparaben, propylparaben and butylparaben.
  • the preservative(s), if included, may be present in an amount of from 0.001 to 1% (w/w), such as from 0.015% to 0.5% (w/w), based on the total weight of the composition.
  • the preservative is selected from benzalkonium chloride, EDTA and/or potassium sorbate. In a further embodiment, the preservative is EDTA and/or potassium sorbate.
  • an aqueous pharmaceutical composition of the invention which is preservative free.
  • an aqueous pharmaceutical composition of the invention comprising a surfactant.
  • Compositions may include one or more surfactants which functions to facilitate dissolution of the medicament particles in the aqueous phase of the composition.
  • surfactants include fatty alcohols, esters and ethers, such as polyoxyethylene (20) sorbitan monooleate (Polysorbate 80), macrogol ethers and poloxamers.
  • the surfactant may be present in an amount of between about 0.01 to 10% (w/w), such as from 0.01 to 0.75% (w/w), for example about 0.5% (w/w), based on the total weight of the composition.
  • the surfactant is polyoxyethylene (20) sorbitan monooleate (Polysorbate 80).
  • an aqueous pharmaceutical composition of the invention comprising a tonicity adjusting agent.
  • One or more tonicity adjusting agent(s) may be included to achieve tonicity with body fluids e.g. fluids of the nasal cavity or fluids of the eye, resulting in reduced levels of irritancy.
  • pharmaceutically acceptable tonicity adjusting agents include, but are not limited to, sodium chloride, dextrose, xylitol, calcium chloride, glucose, glycerine and sorbitol.
  • a tonicity adjusting agent, if present, may be included in an amount of from 0.1 to 10% (w/w), such as from 4.5 to 5.5% (w/w), for example about 5.0% (w/w), based on the total weight of the composition.
  • the tonicity adjusting agents are dextrose (e.g. anhydrous dextrose) and/or xylitol.
  • the tonicity adjusting agent is xylitol.
  • an aqueous pharmaceutical composition of the invention comprising no additional tonicity adjusting agent.
  • an aqueous pharmaceutical composition of the invention comprising a buffering agent.
  • compositions of the invention may be buffered by the addition of suitable buffering agents such as sodium citrate, citric acid, trometamol, phosphates such as disodium phosphate (for example the dodecahydrate, heptahydrate, dihydrate and anhydrous forms) or sodium phosphate and mixtures thereof.
  • suitable buffering agents such as sodium citrate, citric acid, trometamol, phosphates such as disodium phosphate (for example the dodecahydrate, heptahydrate, dihydrate and anhydrous forms) or sodium phosphate and mixtures thereof.
  • the buffering agents are sodium citrate and/or citric acid.
  • a buffering agent if present, may be included in an amount of from 0.1 to 5% (w/w), for example 1 to 3% (w/w) based on the total weight of the composition.
  • the amount of citric acid is from 0.1 to 1.5g, for example from 0.5 to 1.Og, and the amount of sodium citrate is from 0.5 to 2.Og, for example from 1.0 to 2.Og, per 100ml of solution.
  • the weights given relate in each case to the anhydrous substances.
  • taste-masking agents include sucralose, sucrose, saccharin or a salt thereof, fructose, dextrose, glycerol, corn syrup, aspartame, acesulfame-K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, thaumatin, neotame, mannitol, menthol, eucalyptus oil, camphor, a natural flavouring agent, an artificial flavouring agent, and combinations thereof.
  • the taste-masking agent is sucralose and/or menthol.
  • an aqueous pharmaceutical composition of the invention comprising a co-solvent.
  • co-solvent(s) may be included to aid solubility of the medicament compound(s) and/or other excipients.
  • pharmaceutically acceptable co- solvents include, but are not limited to, propylene glycol, dipropylene glycol, ethylene glycol, glycerol, ethanol, polyethylene glycols (for example PEG300 or PEG400) and methanol.
  • the co-solvent is propylene glycol.
  • the co-solvent(s), if present, may be included in an amount of from 0.05 to 30% (w/w), such as from 1 to 25% (w/w), for example from 1 to 10% (w/w) based on the total weight of the composition.
  • an aqueous pharmaceutical composition of the invention comprising a) 1- ⁇ [3-(4- ⁇ [(2R)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2- (trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1-yl)phenyl]carbonyl ⁇ -D- prolinamide; b) a preservative; c) a surfactant; d) a co-solvent; and e) a buffer.
  • an aqueous pharmaceutical composition of the invention further comprising 4-[(4-chlorophenyl)methyl]-2-( ⁇ (2/?)-1-[4-(4- ⁇ [3- (hexahydro-1 H-azepin-1 -yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)-1 (2H)- phthalazinone.
  • an aqueous pharmaceutical composition further comprising a tonicity adjusting agent.
  • an aqueous pharmaceutical composition further comprising a suspending agent/thickening agent.
  • an aqueous pharmaceutical composition further comprising a suspending agent/thickening agent and a tonicity adjusting agent.
  • an aqueous pharmaceutical composition which comprises 0.001 to 1 % (w/w) based on the total weight of the composition of a preservative. In a further embodiment there is provided an aqueous pharmaceutical composition, which comprises 0.015% to 0.5% (w/w) based on the total weight of the composition of a preservative.
  • an aqueous pharmaceutical composition wherein the preservative is disodium edetate (EDTA) and/or potassium sorbate.
  • EDTA disodium edetate
  • an aqueous pharmaceutical composition which comprises 0.01 to 10% (w/w) based on the total weight of the composition of a surfactant. In a further embodiment there is provided an aqueous pharmaceutical composition which comprises about 0.5% (w/w) based on the total weight of the composition of a surfactant.
  • an aqueous pharmaceutical composition wherein the surfactant is polyoxyethylene (20) sorbitan monooleate (Polysorbate 80).
  • an aqueous pharmaceutical composition which comprises 0.05 to 30% (w/w) based on the total weight of the composition of a co- solvent. In a further embodiment there is provided an aqueous pharmaceutical composition which comprises 1 to 10% (w/w) based on the total weight of the composition of a co-solvent.
  • an aqueous pharmaceutical composition wherein the co-solvent is propylene glycol. In one embodiment there is provided an aqueous pharmaceutical composition which comprises from 1 to 3% (w/w) based on the total weight of the composition of a buffering agent.
  • an aqueous pharmaceutical composition wherein the buffering agent comprises sodium citrate and citric acid.
  • an aqueous pharmaceutical composition which comprises from 0.1 to 10% (w/w) based on the total weight of the composition of a tonicity adjusting agent. In a further embodiment there is provided an aqueous pharmaceutical composition which comprises from 4.5 to 5.5% (w/w) based on the total weight of the composition of a tonicity adjusting agent.
  • an aqueous pharmaceutical composition which comprises no additional tonicity adjusting agent.
  • an aqueous pharmaceutical composition wherein the tonicity adjusting agent is xylitol.
  • an aqueous pharmaceutical composition which comprises 1.5% to 2.4% (w/w) based on the total weight of the composition of a suspending agent/thickening agent.
  • an aqueous pharmaceutical composition wherein the suspending agent/thickening agent comprises microcrystalline cellulose and/or carboxy methylcellulose sodium.
  • an aqueous pharmaceutical composition of the invention further comprising a) 0.001 - 1% (w/w) preservative; b) 0.01 - 10% (w/w) surfactant; c) 0.05 - 30% (w/w) co-solvent; and d) 0.1 - 5% (w/w) buffer.
  • an aqueous pharmaceutical composition of the invention further comprising a) 0.015 - 0.5% (w/w) preservative; b) 0.01 - 0.75% (w/w) surfactant; c) 1 - 10% (w/w) co-solvent; and d) 1 - 3% (w/w) buffer.
  • an aqueous pharmaceutical composition of the invention further comprising a) 0.001 - 1% (w/w) preservative; b) 0.01 - 10% (w/w) surfactant; c) 0.05 - 30% (w/w) co-solvent; d) 0.1 - 5% (w/w) buffer; and e) 0.1 - 10% (w/w) tonicity agent.
  • an aqueous pharmaceutical composition of the invention further comprising a) 0.015 - 0.5% (w/w) preservative; b) 0.01 - 0.75% (w/w) surfactant; c) 1 - 10% (w/w) co-solvent; d) 1 - 3% (w/w) buffer; and e) 4.5 - 5.5% (w/w) tonicity agent.
  • an aqueous pharmaceutical composition of the invention further comprising a) 0.015 - 0.5% (w/w) preservative; b) 0.01 - 1.0% (w/w) surfactant; c) 1 - 2.5% (w/w) co-solvent; d) 1 - 3% (w/w) buffer; and e) 0.0 - 0.75% (w/w) tonicity agent.
  • an aqueous pharmaceutical composition of the invention further comprising a) 0.001 - 1% (w/w) preservative; b) 0.01 - 10% (w/w) surfactant; c) 0.05 - 30% (w/w) co-solvent; d) 0.1 - 5% (w/w) buffer; e) 0.1 -10% (w/w) tonicity agent; and f) 0.1 - 5% (w/w) suspending agent/thickening agent.
  • an aqueous pharmaceutical composition of the invention further comprising a) 0.015 - 0.5% (w/w) preservative; b) 0.01 - 0.75% (w/w) surfactant; c) 1 - 10% (w/w) co-solvent; d) 1 - 3% (w/w) buffer; e) 4.5 - 5.5% (w/w) tonicity agent; and f) 1.5 - 2.4% (w/w) suspending agent/thickening agent.
  • an aqueous pharmaceutical composition which comprises benzalkonium chloride, EDTA and/or potassium sorbate (as preservative(s)); polyoxyethylene (20) sorbitan monooleate (supplied as polysorbate 80) (as surfactant); and citrate/citric acid (as a buffer).
  • the preservative is selected from EDTA and/or potassium sorbate.
  • an aqueous pharmaceutical composition which comprises benzalkonium chloride, EDTA and/or potassium sorbate (as preservative(s)); polyoxyethylene (20) sorbitan monooleate (supplied as polysorbate 80) (as surfactant); citrate/citric acid (as a buffer); and propylene glycol (as co- solvent).
  • the preservative is selected from EDTA and/or potassium sorbate.
  • an aqueous pharmaceutical composition which comprises benzalkonium chloride, EDTA and/or potassium sorbate (as preservative(s)); polyoxyethylene (20) sorbitan monooleate (supplied as polysorbate 80) (as surfactant); dextrose and/or xylitol (as tonicity adjusting agents) and citrate/citric acid (as a buffer).
  • the preservative is selected from EDTA and/or potassium sorbate.
  • an aqueous pharmaceutical composition which comprises benzalkonium chloride, EDTA and/or potassium sorbate (as preservative(s)); polyoxyethylene (20) sorbitan monooleate (supplied as polysorbate 80) (as surfactant); dextrose and/or xylitol (as tonicity adjusting agents); citrate/citric acid (as a buffer) and propylene glycol (as co-solvent).
  • the preservative is selected from EDTA and/or potassium sorbate.
  • an aqueous pharmaceutical composition which comprises benzalkonium chloride, EDTA and/or potassium sorbate (as preservative(s)); polyoxyethylene (20) sorbitan monooleate (supplied as polysorbate 80) (as surfactant); dextrose and/or xylitol (as tonicity adjusting agents); citrate/citric acid (as a buffer) and microcrystalline cellulose and carboxymethyl cellulose sodium (as suspending agents/thickening agents).
  • the preservative is selected from EDTA and/or potassium sorbate.
  • an aqueous pharmaceutical composition which comprises benzalkonium chloride, EDTA and/or potassium sorbate (as preservative(s)); polyoxyethylene (20) sorbitan monooleate (supplied as polysorbate 80) (as surfactant); dextrose and/or xylitol (as tonicity adjusting agents); citrate/citric acid (as a buffer); propylene glycol (as co-solvent); and microcrystalline cellulose and carboxymethyl cellulose sodium (as suspending agents/thickening agents).
  • the preservative is selected from EDTA and/or potassium sorbate.
  • compositions for administration topically, to the nose for example, for the treatment of rhinitis, for example allergic rhinitis include pressurised aqueous aerosol compositions and aqueous compositions delivered to the nasal cavities by pressurised pump.
  • Aqueous compositions which are non-pressurised and adapted to be administered topically to the nasal cavity are of particular interest.
  • Aqueous compositions may also be administered to the nose by nebulisation.
  • aqueous pharmaceutical compositions of the invention are provided in a suitable container depending on the choice of route of administration. Further, for compositions comprising both compounds it will be appreciated that said container may be capable of delivering each compound sequentially in a separate pharmaceutical composition as well as simultaneously in a combined pharmaceutical composition.
  • a fluid dispenser typically used to deliver the aqueous pharmaceutical compositions of the invention to the nasal cavities may have a dispensing nozzle or dispensing orifice through which a metered dose of the fluid composition is dispensed upon the application of a user-applied force to a pump mechanism of the fluid dispenser.
  • Such fluid dispensers are generally provided with a reservoir of multiple metered doses of the fluid composition, the doses being dispensable upon sequential pump actuations.
  • the dispensing nozzle or orifice may be configured for insertion into the nostrils of the user for spray dispensing of the fluid composition into the nasal cavity.
  • a fluid dispenser of the aforementioned type is described and illustrated in WO2005/044354 the entire content of which is hereby incorporated herein by reference.
  • the dispenser has a housing which houses a fluid discharge device having a compression pump mounted on a container for containing a fluid composition.
  • the housing has at least one finger-operable side lever which is movable inwardly with respect to the housing to cam the container upwardly in the housing to cause the pump to compress and pump a metered dose of the composition out of a pump stem through a nasal nozzle of the housing.
  • the fluid dispenser is of the general type illustrated in Figures 30-40 of 2005/044354.
  • aqueous pharmaceutical compositions of the invention may be delivered by a pump as disclosed in WO2007/138084, for example as disclosed with reference to Figures 22-46 thereof, or as disclosed in GB0723418.0, for example as disclosed with reference to Figures 7-32 thereof, both of which prior patent applications are incorporated herein by reference in their entirety.
  • the pump may be actuated by an actuator as disclosed in Figures 1-6 of said GB0723418.0.
  • fluid dispensers for use with the aqueous pharmaceutical compositions of the invention may be capable of holding 8 to 5OmL (or less) of composition and each spray will typically deliver 50 to 100 ⁇ l_ (or less, for example 25 ⁇ l_) of composition. Typically therefore the fluid dispenser will be capable of providing at least 100 metered doses.
  • a container comprising an aqueous pharmaceutical composition of the invention.
  • the container is suitable for delivering an aqueous pharmaceutical composition of the invention to the nasal cavities.
  • the container is suitable for delivering the delivering an aqueous pharmaceutical composition of the invention to the eye.
  • compositions of the invention have potentially beneficial anti-inflammatory and/or anti-allergic effects, particularly upon topical administration to the nose, demonstrated by, for example the activity of 1- ⁇ [3-(4- ⁇ [(2R)-4-[5-fluoro-2- (methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino ⁇ -6-methyl-1/-/- indazol-1-yl)phenyl]carbonyl ⁇ -D-prolinamide or a pharmaceutically acceptable salt thereof at the glucocorticoid receptor, and (if present) the ability of 4-[(4- chlorophenyl)methyl]-2-( ⁇ (2R)-1-[4-(4- ⁇ [3-(hexahydro-1 H-azepin-1- yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)-1 (2H)-phthalazinone, or a pharmaceutically acceptable salt thereof, to antagonise
  • compositions of the invention may be useful in the treatment of inflammatory and/or allergic conditions, for example inflammatory and/or allergic conditions of the respiratory tract, particularly upon topical administration to the nose.
  • compositions according to the invention may be useful in the treatment of inflammatory and/or allergic disorders of the nose, especially in once per day therapy.
  • aqueous pharmaceutical compositions of the invention may have potentially beneficial anti-inflammatory and/or anti-allergic effects
  • inflammatory and/or allergic conditions of the respiratory tract such as allergic rhinitis (seasonal and perennial) or other conditions such as vasomotor rhinitis, bronchitis (including chronic bronchitis), asthma (including allergen-induced asthmatic reactions), chronic obstructive pulmonary disease (COPD) and sinusitis.
  • allergic rhinitis seasonal and perennial
  • vasomotor rhinitis bronchitis (including chronic bronchitis)
  • asthma including allergen-induced asthmatic reactions
  • COPD chronic obstructive pulmonary disease
  • aqueous pharmaceutical compositions of the invention may be of use in the treatment of skin conditions such as psoriasis, eczema, allergic dermatitis, neurodermatitis and hypersensitivity reactions. Also, the aqueous pharmaceutical compositions of the invention may be useful in the treatment of insect bites and stings.
  • aqueous pharmaceutical compositions of the invention may also be of use in the treatment of nasal polyposis, conjunctivitis (e.g. allergic conjunctivitis) or pruritis.
  • a disease of particular interest is allergic rhinitis.
  • references herein to treatment or therapy may extend to prophylaxis as well as the treatment of established conditions.
  • an aqueous pharmaceutical composition which comprises 1- ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2- (trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1-yl)phenyl]carbonyl ⁇ -D- prolinamide or a pharmaceutically acceptable salt thereof, for use in medical therapy.
  • an aqueous pharmaceutical composition which comprises 1 - ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl- 2-(trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1-yl)phenyl]carbonyl ⁇ -D- prolinamide or a pharmaceutically acceptable salt thereof and 4-[(4- chlorophenyl)methyl]-2-( ⁇ (2R)-1-[4-(4- ⁇ [3-(hexahydro-1H-azepin-1- yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)-1 (2H)-phthalazinone or a pharmaceutically acceptable salt thereof, for use in medical therapy.
  • an aqueous pharmaceutical composition which comprises 1 - ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl- 2-(trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1-yl)phenyl]carbonyl ⁇ -D- prolinamide or a pharmaceutically acceptable salt thereof, for use in the treatment (and/or prophylaxis) of inflammatory and/or allergic conditions.
  • an aqueous pharmaceutical composition which comprises 1 - ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl- 2-(trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1-yl)phenyl]carbonyl ⁇ -D- prolinamide or a pharmaceutically acceptable salt thereof and 4-[(4- chlorophenyl)methyl]-2-( ⁇ (2R)-1-[4-(4- ⁇ [3-(hexahydro-1H-azepin-1- yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)-1 (2H)-phthalazinone or a pharmaceutically acceptable salt thereof, for use in the treatment (and/or prophylaxis) of inflammatory and/or allergic conditions.
  • an aqueous pharmaceutical composition which comprises 1 - ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl- 2-(trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1-yl)phenyl]carbonyl ⁇ -D- prolinamide or a pharmaceutically acceptable salt thereof, for use in the treatment (and/or prophylaxis) of allergic rhinitis.
  • an aqueous pharmaceutical composition which comprises 1 - ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl- 2-(trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1-yl)phenyl]carbonyl ⁇ -D- prolinamide or a pharmaceutically acceptable salt thereof and 4-[(4- chlorophenyl)methyl]-2-( ⁇ (2R)-1-[4-(4- ⁇ [3-(hexahydro-1H-azepin-1- yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)-1 (2H)-phthalazinone or a pharmaceutically acceptable salt thereof, for use in the treatment (and/or prophylaxis) of allergic rhinitis.
  • an aqueous pharmaceutical composition which comprises 1 - ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl- 2-(trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1-yl)phenyl]carbonyl ⁇ -D- prolinamide or a pharmaceutically acceptable salt thereof, for use in treatment (and/or prophylaxis) once per day.
  • an aqueous pharmaceutical composition which comprises 1 - ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl- 2-(trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1-yl)phenyl]carbonyl ⁇ -D- prolinamide or a pharmaceutically acceptable salt thereof and 4-[(4- chlorophenyl)methyl]-2-( ⁇ (2R)-1-[4-(4- ⁇ [3-(hexahydro-1H-azepin-1- yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)-1 (2H)-phthalazinone or a pharmaceutically acceptable salt thereof, for use in treatment (and/or prophylaxis) once per day.
  • an aqueous pharmaceutical composition which comprises 1- ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2-(methyloxy)phenyl]-2- hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1- yl)phenyl]carbonyl ⁇ -D-prolinamide or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment (and/or prophylaxis) of inflammatory and/or allergic conditions.
  • an aqueous pharmaceutical composition which comprises 1- ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2-(methyloxy)phenyl]-2- hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1- yl)phenyl]carbonyl ⁇ -D-prolinamide or a pharmaceutically acceptable salt thereof and 4-[(4-chlorophenyl)methyl]-2-( ⁇ (2R)-1-[4-(4- ⁇ [3-(hexahydro-1H-azepin-1- yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)-1 (2H)-phthalazinone or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment (and/or prophylaxis) of inflammatory and/or allergic conditions.
  • an aqueous pharmaceutical composition which comprises 1- ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2-(methyloxy)phenyl]-2- hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 /-/-indazol-1- yl)phenyl]carbonyl ⁇ -D-prolinamide or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment (and/or prophylaxis) of allergic rhinitis.
  • an aqueous pharmaceutical composition which comprises 1- ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2-(methyloxy)phenyl]-2- hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1- yl)phenyl]carbonyl ⁇ -D-prolinamide or a pharmaceutically acceptable salt thereof and 4-[(4-chlorophenyl)methyl]-2-( ⁇ (2R)-1-[4-(4- ⁇ [3-(hexahydro-1 H-azepin-1- yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)-1 (2H)-phthalazinone or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment (and/or prophylaxis) of allergic rhinitis.
  • an aqueous pharmaceutical composition which comprises 1- ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2-(methyloxy)phenyl]-2- hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1- yl)phenyl]carbonyl ⁇ -D-prolinamide or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment (and/or prophylaxis) once per day.
  • an aqueous pharmaceutical composition which comprises 1- ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2-(methyloxy)phenyl]-2- hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1- yl)phenyl]carbonyl ⁇ -D-prolinamide or a pharmaceutically acceptable salt thereof and 4-[(4-chlorophenyl)methyl]-2-( ⁇ (2R)-1-[4-(4- ⁇ [3-(hexahydro-1 H-azepin-1- yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)-1 (2H)-phthalazinone or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment (and/or prophylaxis) once per day.
  • a method for the treatment of inflammatory and/or allergic conditions comprises administering to a patient in need thereof a pharmaceutically effective amount of an aqueous pharmaceutical composition which comprises 1- ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2-(methyloxy)phenyl]-2- hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1- yl)phenyl]carbonyl ⁇ -D-prolinamide or a pharmaceutically acceptable salt thereof.
  • a method for the treatment of inflammatory and/or allergic conditions comprises administering to a patient in need thereof a pharmaceutically effective amount of an aqueous pharmaceutical composition which comprises 1- ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2-(methyloxy)phenyl]-2- hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1- yl)phenyl]carbonyl ⁇ -D-prolinamide or a pharmaceutically acceptable salt thereof and 4-[(4-chlorophenyl)methyl]-2-( ⁇ (2R)-1-[4-(4- ⁇ [3-(hexahydro-1 H-azepin-1- yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)-1 (2H)-phthalazinone or a pharmaceutically acceptable salt thereof.
  • a method for the treatment of allergic rhinitis comprises administering to a patient in need thereof a pharmaceutically effective amount of an aqueous pharmaceutical composition which comprises 1- ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2- (trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1-yl)phenyl]carbonyl ⁇ -D- prolinamide or a pharmaceutically acceptable salt thereof.
  • a method for the treatment of allergic rhinitis comprises administering to a patient in need thereof a pharmaceutically effective amount of an aqueous pharmaceutical composition which comprises 1- ⁇ [3-(4- ⁇ [(2R)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2- (trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1-yl)phenyl]carbonyl ⁇ -D- prolinamide or a pharmaceutically acceptable salt thereof and 4-[(4- chlorophenyl)methyl]-2-( ⁇ (2R)-1-[4-(4- ⁇ [3-(hexahydro-1 H-azepin-1- yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)-1 (2H)-phthalazinone or a pharmaceutically acceptable salt thereof.
  • a method for treatment once per day comprises administering to a patient in need thereof a pharmaceutically effective amount of an aqueous pharmaceutical composition which comprises 1- ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2- (trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1-yl)phenyl]carbonyl ⁇ -D- prolinamide or a pharmaceutically acceptable salt thereof.
  • a method for treatment once per day comprises administering to a patient in need thereof a pharmaceutically effective amount of an aqueous pharmaceutical composition which comprises 1- ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2- (trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 /-/-indazol-1-yl)phenyl]carbonyl ⁇ -D- prolinamide or a pharmaceutically acceptable salt thereof and 4-[(4- chlorophenyl)methyl]-2-( ⁇ (2R)-1-[4-(4- ⁇ [3-(hexahydro-1 H-azepin-1- yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)-1 (2H)-phthalazinone or a pharmaceutically acceptable salt thereof.
  • aqueous pharmaceutical compositions of the invention may be prepared by a process comprising mixing the medicament ingredient(s) with water.
  • aqueous pharmaceutical compositions of the invention may be prepared according to the following general method:
  • the tonicity adjusting agent(s) is charged into a suitable mixing vessel containing purified water and dissolved with stirring.
  • the suspending agent(s)/thickening agent(s), if appropriate, is then charged into the mixing vessel and dispersed throughout the solution.
  • the resulting suspending vehicle is allowed to hydrate for an appropriate period of time to ensure cross-linkage and gelation, which may take 60 minutes or longer.
  • the preservative(s), if included, is pre-dissolved in purified water in a separate vessel, optionally with heating, for example to 50-60 0 C depending on the preservative chosen, to aid dissolution, and then added to the tonicity adjusting agent(s) and suspending agent(s)/thickening agent(s) with continuous stirring.
  • the buffering agents are dissolved in a minimum amount of purified water, optionally heated, for example to about 50-60 0 C as appropriate depending on the buffering agents chosen, and stirred to dissolve in separate containers.
  • the separate solutions are combined, mixed well and then added to the bulk solution with continuous stirring.
  • the surfactant(s) is mixed with purified water which optionally may be heated, for example to about 50-60 0 C as appropriate depending on the surfactant(s) chosen, and stirred to dissolve.
  • a slurry or solution of medicament compound(s) is then prepared by adding some of the resultant surfactant(s) solution and some co-solvent to the medicament compound(s), which may be particle size reduced for example micronised, and mixed prior to homogenising/refining.
  • the slurry or solution is then added to the bulk solution with continuous stirring.
  • the remaining surfactant(s) solution is then added to the bulk solution with mixing.
  • additional preservative(s), if needed, may be mixed with purified water and stirred to dissolve.
  • any additional preservative may be added to the bulk suspension and dispersed with continuous stirring.
  • Co-solvent(s), if included, may be added before or after the addition of the buffering agents. Alternatively, the co-solvent(s) may be added during the formation of the drug slurry or solution. Preservative(s), if included, may be added before or after the addition of the suspending agent(s)/thickening agent(s).
  • 1- ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4- methyl-2-(trifluoromethyl)pentyl]amino ⁇ -6-methyl-1H-indazol-1-yl)phenyl]carbonyl ⁇ -D- prolinamide is used in the form of its free base.
  • 4-[(4-chlorophenyl)methyl]-2-( ⁇ (2R)-1-[4-(4- ⁇ [3-(hexahydro-1H- azepin-1-yl) propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)-1 (2H)-phthalazinone is used in the form of its free base, as the 1 ,5-naphthalene disulfonate monohydrate salt, or as the dihydorchloride salt.
  • the term "pharmaceutically acceptable salt” means any pharmaceutically acceptable salt or solvate, which upon administration to the recipient is capable of providing (directly or indirectly) 1- ⁇ [3-(4- ⁇ [(2/?)-4-[5-fluoro-2- (methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H- indazol-1 -yl)phenyl]carbonyl ⁇ -D-prolinamide or 4-[(4-chlorophenyl)methyl]-2-( ⁇ (2/?)-1 - [4-(4- ⁇ [3-(hexahydro-1 H-azepin-1-yl)propyl]oxy ⁇ phenyl)butyl]-2-pyrrolidinyl ⁇ methyl)- 1 (2H)-phthalazinone, or an medicament metabolite or residue thereof.
  • a pharmaceutically acceptable salt may be readily prepared by using a desired acid as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • a pharmaceutically acceptable acid addition salt can be formed by reaction of 1- ⁇ [3- (4- ⁇ [(2R)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2- (trifluoromethyl)pentyl]amino ⁇ -6-methyl-1 H-indazol-1-yl)phenyl]carbonyl ⁇ -D- prolinamide with a suitable inorganic or organic acid or base.
  • Pharmaceutically acceptable acid addition salts may include those formed from strong acids, for example hydrochloric, hydrobromic and sulphuric acids, and strong sulphonic acids such as tosic, camphorsulphonic and methanesulphonic acids.
  • Pharmaceutically acceptable base salts include alkali metal salts such as those of sodium and potassium.
  • a pharmaceutically acceptable acid addition salt can be formed by reaction of 4-[(4- chlorophenyl)methyl]-2-( ⁇ (2R)-1-[4-(4- ⁇ [3-(hexahydro-1 H-azepin-1- yl)propyl]oxy ⁇ phenyl) butyl]-2-pyrrolidinyl ⁇ methyl)-1 (2H)-phthalazinone with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulphuric, nitric, phosphoric, succinc, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic (e.g.
  • a pharmaceutically acceptable acid addition salt of 4-[(4- chlorophenyl)methyl]-2-( ⁇ (2R)-1-[4-(4- ⁇ [3-(hexahydro-1 H-azepin-1- yl)propyl]oxy ⁇ phenyl) butyl]-2-pyrrolidinyl ⁇ methyl)-1 (2H)-phthalazinone can comprise or be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfon
  • aqueous pharmaceutical compositions of the invention may be prepared by the methods described above or by similar methods.
  • the following Examples illustrate the preparation of the aqueous pharmaceutical compositions but are not to be considered in limiting the scope of the disclosure in any way.
  • citric acid 48g was dissolved in approximately 25OmL of water and sodium citrate (74g) in approximately 25OmL of water.
  • the solutions were heated to 50-60 0 C to facilitate complete dissolution. Once each had dissolved, they were combined and mixed well.
  • the buffer solution was then added to the bulk solution with continuous stirring.
  • polysorbate 80 25Og was added to approximately 50OmL of hot water, the mixture was heated without boiling and mixed until the polysorbate 80 was dispersed in the water.
  • the remaining polysorbate 80 solution and propylene glycol were added to the bulk solution whilst mixing for 10 minutes.
  • Potassium sorbate (15g) was added to approximately 2OmL of water and heated without boiling to dissolve. When dissolved this was added to the bulk container and mixing of the bulk solution continued. The mixer was stopped and removed from the bulk solution while the solution was made to its final weight (5kg) with water.
  • the mixer was then replaced into the bulk solution and the mixing speed set so that it was sufficient to form a vortex and mix the solution for approximately 3 minutes.
  • Examples 2 to 5 were prepared by a similar general method to the method described above for Example 1.
  • Examples 6 to 10 may be prepared by a similar general method as described above for Example 1.
  • Examples 11 to 15 may be prepared by a similar general method as described above for Example 1.
  • Examples 16 to 20 may be prepared by a similar general method as described above for Example 1.
  • Examples 21 to 25 may be prepared by a similar general method to the method described above for Example 1.
  • Examples 26 to 30 may be prepared by a similar general method to the method described above for Example 1.
  • Examples 31 to 35 may be prepared by a similar general method as described above for Example 1.
  • Examples 36 to 40 may be prepared by a similar general method as described above for Example 1.
  • Examples 41 to 45 may be prepared by a similar general method as described above for Example 1.
  • Examples 46 to 50 may be prepared by a similar general method as described above for Example 1.
  • Example compositions may be filled into suitable containers depending on the chosen route of administration.
  • suitable containers are described hereinabove and typically are made of plastics and dispense 25 to 100 ⁇ l_ of composition per actuation.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L’invention concerne une composition pharmaceutique aqueuse comprenant un composé {[3-(4-{[(2R)-4-[5-fluoro-2-(méthyloxy)phényl]-2-hydroxy-4-méthyl-2- (trifluorométhyl)pentyl]amino}-6-méthyl-1H-indazol-1-yl)phényl]carbonyl}-D- prolinamide de formule (I) ou son sel pharmaceutiquement acceptable, facultativement combinée à un double antagoniste de l'histamine ou son sel pharmaceutiquement acceptable. Elle concerne leurs méthodes de préparation et leur utilisation dans le traitement de diverses pathologies inflammatoires et/ou allergiques, telles que la rhinite allergique.
PCT/EP2009/057556 2008-06-20 2009-06-18 Composition pharmaceutique comprenant un agoniste non stéréoïdien du récepteur des glucocorticoïdes combiné à un double antagoniste de l'histamine WO2009153296A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0811447.2 2008-06-20
GBGB0811447.2A GB0811447D0 (en) 2008-06-20 2008-06-20 Formulations

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WO2009153296A1 true WO2009153296A1 (fr) 2009-12-23

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PCT/EP2009/057556 WO2009153296A1 (fr) 2008-06-20 2009-06-18 Composition pharmaceutique comprenant un agoniste non stéréoïdien du récepteur des glucocorticoïdes combiné à un double antagoniste de l'histamine

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GB (1) GB0811447D0 (fr)
WO (1) WO2009153296A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007122165A1 (fr) * 2006-04-20 2007-11-01 Glaxo Group Limited Nouveaux composés
WO2007122156A1 (fr) * 2006-04-20 2007-11-01 Glaxo Group Limited Derives de 4-benzylphtalazinone substitues en 2 en tant qu'antagonistes des histamines hl et h3
WO2009050159A1 (fr) * 2007-10-16 2009-04-23 Glaxo Group Limited Combinaison de furoate de fluticasone avec de la 4-[(4-chlorophényl)méthyl]-2-({(2r)-1-[4-(4-{[3-(hexahydro-1h-azépin-1-yl)propyl]oxy}phényl)butyl]-2-pyrrolidinyl}méthyl)-1(2h)-phtalazinone

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007122165A1 (fr) * 2006-04-20 2007-11-01 Glaxo Group Limited Nouveaux composés
WO2007122156A1 (fr) * 2006-04-20 2007-11-01 Glaxo Group Limited Derives de 4-benzylphtalazinone substitues en 2 en tant qu'antagonistes des histamines hl et h3
WO2009050159A1 (fr) * 2007-10-16 2009-04-23 Glaxo Group Limited Combinaison de furoate de fluticasone avec de la 4-[(4-chlorophényl)méthyl]-2-({(2r)-1-[4-(4-{[3-(hexahydro-1h-azépin-1-yl)propyl]oxy}phényl)butyl]-2-pyrrolidinyl}méthyl)-1(2h)-phtalazinone

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CAUWENBERGE VAN P ET AL: "GLUCOCORTICOSTEROIDS IN ALLERGIC INFLAMMATION: CLINICAL BENEFITS IN ALLERGIC RHINITIS, RHINOSINUSITIS, AND OTITIS MEDIA", IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA, SAUNDERS, PHILADELPHIA, US, vol. 25, no. 3, 1 January 2005 (2005-01-01), pages 489 - 509, XP008058383, ISSN: 0889-8561 *

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