WO2012107765A2 - Formulation de particules - Google Patents

Formulation de particules Download PDF

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Publication number
WO2012107765A2
WO2012107765A2 PCT/GB2012/050283 GB2012050283W WO2012107765A2 WO 2012107765 A2 WO2012107765 A2 WO 2012107765A2 GB 2012050283 W GB2012050283 W GB 2012050283W WO 2012107765 A2 WO2012107765 A2 WO 2012107765A2
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WO
WIPO (PCT)
Prior art keywords
pharmacologically active
particle formulation
formulation according
particle
formulation
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PCT/GB2012/050283
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English (en)
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WO2012107765A3 (fr
Inventor
Mark Henry SAUNDERS
Marcel De Matas
Jason Robert Jones
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Kuecept Ltd
Lena Nanoceutics Ltd
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Publication of WO2012107765A2 publication Critical patent/WO2012107765A2/fr
Publication of WO2012107765A3 publication Critical patent/WO2012107765A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • the present inventions relates to combination particle formulations comprising a plurality of pharmacologically active ingredients. Particularly particle formulations prepared from nanoparticles wherein the pharmaceutically active ingredients are crystalline.
  • the invention further comprises methods for making said particle formulations and method of using said particle formulations in therapeutic treatments, particularly when delivered as inhaled formulations to the human airways and lungs.
  • Nanoparticles are particles with a dimension in the nanometer range. In general, they are of interest because they bridge between bulk materials and atomic or molecular structures. A bulk material tends to have constant physical properties regardless of it's size but at the nanoscale size dependent properties are often observed As particles decrease in size the surface area to volume ratio increases and it is the large relative surface area which often leads to the interesting and sometimes unexpected properties of nanoparticles.
  • Nanoparticles have applications in a number of technologies, for example, semiconductors, textiles and drug delivery systems, such as inhaled
  • GlaxoSmithkline's (GSK's) Seretide fluticasone/ salmeterol
  • AstraZeneca's Symbicort budesonide/ formoterol
  • ICS/LABA combination inhaled corticosteroid/long-acting beta2-agonist
  • ICS/LABA combinations are usually prescribed to patients who are not benefiting from low doses of ICS alone and where combination therapy is regarded as more effective than prescribing the single drug treatment.
  • the combination therapy ensures that LABA is prescribed alongside ICS. Prescribing the combination drugs also ensures better patient compliance and simplification of the disease management process.
  • a downside of the two combination products currently on the market is that they require twice daily dosing, which re-creates issues with compliance.
  • Drug candidates currently in later stages of development GlaxoSmithKline's Beyond Advair (currently in Phase III for COPD) and Novartis's mometasone/indacaterol (in Phase II for asthma and COPD), will be once-daily products. These two candidates are expected to take a substantial portion of the market as a result of the differentiating feature of having a favorable dosing regimen in comparison to marketed and other pipeline products. This demonstrates the importance of developing combination products with greater efficacy, leading to better compliance and improved dosing regimen.
  • particles comprising a plurality of pharmacologically active ingredients, suitable for use for use as therapeutics, particularly useful in inhaled therapeutics.
  • a particle formulation suitable for use in an inhalation formulation comprising a plurality of pharmacologically active ingredients characterized in that the pharmacologically active ingredients are crystalline.
  • a particle formulation suitable for use in an inhalation formulation comprising a plurality of
  • pharmacologically active ingredients for example crystalline pharmacologically active ingredients
  • the ratio of the pharmacologically active substances has a distribution across the particles of less than ⁇ 5% of the target ratio as measured by Impactor testing (for example Twin Stage Impinger (TSI) or Next Generation Impactor (NGI)).
  • Impactor testing for example Twin Stage Impinger (TSI) or Next Generation Impactor (NGI)
  • a particle formulation suitable for use in an inhalation formulation comprising a plurality of
  • pharmacologically active ingredients for example crystalline pharmacologically active ingredients
  • the ratio of the pharmacologically active substances has a distribution across the particles of less than or equal to ⁇ 5% of the target ratio as measured by the NGI impactor.
  • the ratio in the impactor testing is less than or equal ⁇ 4%, less than or equal to ⁇ 3% or less than or equal to ⁇ 2%.
  • the ratios relate to the ratio averaged across all stages of the impactor instrument. In one embodiment the ratios are less than or equal ⁇ 5%, less than or equal ⁇ 4%, less than or equal to ⁇ 3% or less than or equal to ⁇ 2% at each stage of the impactor instrument.
  • the pharmacologically active ingredients are crystalline. In a further embodiment the pharmacologically active ingredients are amorphous. In a yet further embodiment the pharmacologically active ingredients are a mixture of amorphous and crystalline ingredients. Examples of amorphous ingredients include insulin.
  • a particle formulation suitable for use in an inhalation formulation comprising a plurality of crystalline pharmacologically active ingredients characterized in that it is formed by spray drying of a nanoparticle formulation, for example an aqueous
  • nanoparticle formulation Drug powders used in dry powder inhalers are normally prepared by crystallization followed by micronisation to the optimal particle size range for deep lung delivery. However, this often results in highly cohesive, highly charged and crystallographically defective materials which are difficult to process downstream and can potentially lead to highly variable dose accuracy and poor aerosol performance.
  • spray drying of crystalline nanoparticulate formulations offers the capability of generating ultrafine, free flowing, non cohesive dispersible particles which, unlike conventional spray drying that converts a liquid feed, gives a highly crystalline and stable product.
  • Particles of the invention have improved processing properties over prior art particle formulations, including improved bulk density, powder flow, cohesion / adhesion balance and lower surface energies.
  • Particles of the invention have improved stability over prior art particle formulations, particularly for formulation of compounds which adversely interact in a combination formulation.
  • Adverse interactions include aggregation, chemical decomposition and dimer formation.
  • a particle formulation comprising a porous aggregate, comprising a plurality of
  • pharmacologically active ingredients for example crystalline pharmacologically active ingredients.
  • formulations of the invention comprise both porous and non-porous formulations.
  • porous formulations of the invention would be expected to occur with an average particle sizes of greater than about 5 ⁇ .
  • Porous aggregates may be amorphous or crystalline, for example crystalline porous aggregates.
  • one or more active ingredients are crystalline and the other active ingredient or ingredients are amorphous.
  • a particle formulation comprising a crystalline porous aggregate, comprising a plurality of pharmacologically active ingredients, characterized in that it is formed by spray drying of a nanoparticle formulation, for example an aqueous nanoparticle formulation.
  • a particle formulation comprising a crystalline porous aggregate, comprising a plurality of pharmacologically active ingredients.
  • a particle formulation comprising an amorphous porous aggregate, comprising a plurality of pharmacologically active ingredients.
  • particles of the invention have a substantially uniform matrix which is not hollow and does not have significantly sized voids.
  • the particles of the formulations of the invention have a diameter between 1 ⁇ to 40 ⁇ , 1 ⁇ to 35 ⁇ , 1 ⁇ to 20 ⁇ , for example between 2 ⁇ to 16 ⁇ , such as between 2 ⁇ and 8 ⁇ or between 2 ⁇ and 5 ⁇ .
  • particles of the formulation comprise particles with a diameter of between 25 ⁇ and 40 ⁇ , for example between 30 ⁇ and 35 ⁇ .
  • the particles of the formulations of the invention have a diameter between 100nm to 40 ⁇ , 100nm to 35 ⁇ , 100nm to 20 ⁇ , for example between 100nm to 16 ⁇ , such as between 200nm and 8 ⁇ , between 100nm and 8 ⁇ , between 200nm and 8 ⁇ , between 200nm and 5 ⁇ , between 100nm and 5 ⁇ , between 200nm and 2 ⁇ or 100nM to 2 ⁇ .
  • a range is expressed as for example between 1 ⁇ and 40 ⁇ , this includes 1 ⁇ and 40 ⁇ ,
  • the top and bottom values includes a tolerance of +/- 10%, for example +/- 5%, for examples +/- 2% and for example +/- 1 %.
  • Porous formulations of the invention are particularly advantageous due to their porous nature which provides favorable aerodynamic characteristics.
  • Porous formulations of the invention have a small pore size. Small pores sizes are particularly advantageous since there is less potential for moisture ingress and therefore a markedly diminished propensity for moisture-related instability. Particles have different aerodynamic properties due their shape and density, therefore it is necessary to use a particle size definition that directly relates to how the particle behaves in a fluid such as air.
  • aerodynamic diameter has been developed by aerosol physicists in order to provide a simple means of categorizing the sizes of particles having different shapes and densities with a single dimension.
  • the aerodynamic diameter is the diameter of a spherical particle having a density of 1 gm/cm 3 that has the same inertial properties [i.e.
  • the particles of formulations of the invention have a particularly advantageous aerodynamic diameter, for example between about 1 ⁇ and about 10 ⁇ or about 1 ⁇ and about 8 ⁇ . For example between about 1 ⁇ and about 7 ⁇ , between about 2 ⁇ and about 7 ⁇ , between about 2 ⁇ and about 3.5 ⁇ or about 5 ⁇ and about 7 ⁇ . For example comprising particles with an aerodynamic diameter of about 6 ⁇ or about 3 ⁇ .
  • Formulations of the invention are particularly suitable for combination formulations where one active ingredient is in excess over one or more of the other active ingredients. For example, where one component is less than 10%, less than 5%, less than 2%, less than 1 % or less than 0.5% of the active ingredients in the formulation. In two component formulations, for example the components are in the ratio, 1 :5, 1 :10, 1 :20, 1 :30, 1 :40, 1 :50, 1 :75, 1 :100 or 1 :200.
  • Particle formulations of the invention optionally further comprise an additive, for example a surface stabiliser.
  • an additive for example a surface stabiliser.
  • the surface stabiliser is at a low level in the formulation for example less than 16%, such as less than 10%, less than 8%, less than 7%, less than 6%, less than 5% or less than 4% w/w
  • Suitable surface stabilizers include, but are not limited to, known organic and inorganic pharmaceutical excipients.
  • excipients include various polymers, low molecular weight oligomers, natural products, and surfactants.
  • Surface stabilizers include nonionic, ionic, anionic, cationic, and zwitterionic surfactants.
  • the surface stabilizer is selected from one or more of the group consisting of a non-ionic surface stabilizer, an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, and an ionic surface stabilizer.
  • surface stabilizers include but are not limited to hydroxypropyl methylcellulose (now known as hypromellose), hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinate, gelatin, casein, lecithin (phosphatides), dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., the commercially available Tweens (Registered trademark) such as e.g., Tween 20 (Registered trademark) and Tween 80 (
  • polyoxyethylene stearates colloidal silicon dioxide, phosphates, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), 4-(1 ,1 ,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol, superione, and triton), poloxamers (e.g., Pluronics F68 (Registered trademark) and F108 (Registered trademark) , which are block copolymers of ethylene oxide and propylene oxide); poloxamines (e.g., Tetronic 908 (Registered trademark) , also known as Poloxamine 908 (Registered trademark) , which is a
  • tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, N.J.)); Tetronic 1508 (Registered trademark) (T-1508) (BASF
  • Tritons X-200 which is an alkyl aryl polyether sulfonate (Rohm and Haas); Crodestas F-1 10 (Registered trademark) , which is a mixture of sucrose stearate and sucrose distearate (Croda Inc.); p-isononylphenoxypoly-(glycidol), also known as Olin-IOG
  • nonanoyl-N-methylglucamide n-noyl(-D-glucopyranoside; octanoyl-N- methylglucamide; n-octyl-(-D-glucopyranoside; octyl(-D-thioglucopyranoside; PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, lysozyme, random copolymers of vinyl pyrrolidone and vinyl acetate, and the like.
  • cationic surface stabilizers include, but are not limited to, polymers, biopolymers, polysaccharides, cellulosics, alginates, phospholipids, and nonpolymeric compounds, such as zwitterionic stabilizers, poly-n- methylpyridinium, anthryul pyridinium chloride, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylate
  • HDMAB hexyldesyltrimethylammonium bromide
  • polyvinylpyrrolidone-2- dimethylaminoethyl methacrylate dimethyl sulfate polyvinylpyrrolidone-2- dimethylaminoethyl methacrylate dimethyl sulfate.
  • cationic stabilizers include, but are not limited to, cationic lipids, sulfonium, phosphonium, and quaternary ammonium compounds, such as stearyltrimethylammonium chloride, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride or bromide, coconut methyl dihydroxyethyl ammonium chloride or bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride or bromide, C12-15dimethyl hydroxyethyl ammonium chloride or bromide, coconut dimethyl hydroxyethyl ammonium chloride or bromide, myristyl trimethyl ammonium methyl sulfate, lauryl dimethyl benzyl ammonium chloride or bromide, lauryl dimethyl
  • N-alkyl (C12-18)dimethylbenzyl ammonium chloride N-alkyl (C14-18)dimethyl-benzyl ammonium chloride, N- tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C12-14) dimethyl 1 -napthylmethyl ammonium chloride, trimethylammonium halide, alkyl-trimethylammonium salts and dialkyl- dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkyamidoalkyldialkylammonium salt and/or an ethoxylated trialkyl ammonium salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium
  • choline esters such as choline esters of fatty acids
  • benzalkonium chloride such as choline esters of fatty acids
  • stearalkonium chloride compounds such as stearyltrimonium chloride and distearyldimonium chloride
  • cetyl pyridinium bromide or chloride halide salts of quaternized polyoxyethylalkylamines, MIRAPOL and ALKAQUAT (Alkaril Chemical Company), alkyl pyridinium salts
  • amines such as alkylamines, dialkylamines, alkanolamines,
  • polyethylenepolyamines ⁇ , ⁇ -dialkylaminoalkyl acrylates, and vinyl pyridine
  • amine salts such as lauryl amine acetate, stearyl amine acetate, alkylpyridinium salt, and alkylimidazolium salt, and amine oxides; imide azolinium salts;
  • quaternary acrylamides protonated quaternary acrylamides
  • methylated quaternary polymers such as poly[diallyl dimethylammonium chloride] and poly-[N-methyl vinyl pyridinium chloride]
  • cationic guar a poly[diallyl dimethylammonium chloride] and poly-[N-methyl vinyl pyridinium chloride]
  • cationic guar a poly[diallyl dimethylammonium chloride] and poly-[N-methyl vinyl pyridinium chloride]
  • Such exemplary cationic surface stabilizers and other useful cationic surface stabilizers are described in J. Cross and E. Singer, Cationic Surfactants: Analytical and Biological Evaluation (Marcel Dekker, 1994); P. and D. Rubingh (Editor), Cationic Surfactants: Physical Chemistry (Marcel Dekker, 1991 ); and J. Richmond, Cationic Surfactants: Organic Chemistry, (Marcel Dekker, 1990).
  • Nonpolymeric surface stabilizers are any nonpolymeric compound, such benzalkonium chloride, a carbonium compound, a phosphonium compound, an oxonium compound, a halonium compound, a cationic organometallic compound, a quarternary phosphorous compound, a pyridinium compound, an anilinium compound, an ammonium compound, a hydroxylammonium compound, a primary ammonium compound, a secondary ammonium compound, a tertiary ammonium compound, and quarternary ammonium compounds of the formula NR1 R2R3R4(+).
  • R1 -R4 two of R1 -R4 are CH3, one of R1 -R4 is C6H5CH2, and one of R1 -R4 is an alkyl chain of seven carbon atoms or less;
  • R1 -R4 two of R1 -R4 are CH3, one of R1 -R4 is C6H5CH2, and one of R1 -R4 is an alkyl chain of nineteen carbon atoms or more;
  • R1 -R4 two of R1 -R4 are CH3, one of R1 -R4 is C6H5CH2, and one of R1 -R4
  • R1 -R4 two of R1 -R4 are CH3, one of R1 -R4 is C6H5CH2, and one of R1 -R4
  • Such compounds include, but are not limited to, behenalkonium chloride, benzethonium chloride, cetyl pyridinium chloride, behentrimonium chloride, lauralkonium chloride, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cethylamine hydrofluoride, chlorallylmethenamine chloride (Quaternium- 15), distearyldimonium chloride (Quaternium-5), dodecyl dimethyl ethylbenzyl ammonium chloride (Quaternium-14), Quaternium-22, Quaternium-26,
  • Quaternium-18 hectorite dimethylaminoethylchloride hydrochloride, cysteine hydrochloride, diethanolammonium POE (10) oletyl ether phosphate,
  • diethanolammonium POE (3)oleyl ether phosphate, tallow alkonium chloride, dimethyl dioctadecylammoniumbentonite, stearalkonium chloride, domiphen bromide, denatonium benzoate, myristalkonium chloride, laurtrimonium chloride, ethylenediamine dihydrochloride, guanidine hydrochloride, pyridoxine HCI, iofetamine hydrochloride, meglumine hydrochloride, methylbenzethonium chloride, myrtrimonium bromide, oleyltrimonium chloride, polyquaternium-1 , procainehydrochloride, cocobetaine, stearalkonium bentonite,
  • stearalkoniumhectonite stearyl trihydroxyethyl propylenediamine dihydrofluoride, tallowtrimonium chloride, and hexadecyltrimethyl ammonium bromide.
  • Povidone polymers are exemplary surface stabilizers for use in formulating an injectable nanoparticulate leukotriene receptor antagonist/corticosteroid formulation.
  • Povidone polymers also known as polyvidon(e), povidonum, PVP, and polyvinylpyrrolidone, are sold under the trade names Kollidon (Registered trademark) (BASF Corp.) and Plasdone (Registered trademark) (ISP).
  • They are polydisperse macromolecular molecules, with a chemical name of 1 -ethenyl-2-pyrrolidinone polymers and 1 -vinyl-2-pyrrolidinone polymers.
  • Povidone polymers are produced commercially as a series of products having mean molecular weights ranging from about 10,000 to about 700,000 daltons. To be useful as a surface modifier for a drug compound to be administered to a mammal, the povidone polymer must have a molecular weight of less than about 40,000 daltons, as a molecular weight of greater than 40,000 daltons would have difficulty clearing the body.
  • Povidone polymers are prepared by, for example, Reppe's process, comprising: (1 ) obtaining 1 ,4-butanediol from acetylene and formaldehyde by the Reppe butadiene synthesis; (2) dehydrogenating the 1 ,4-butanediol over copper at 2000 to form gamma -butyrolactone; and (3) reacting gamma -butyrolactone with ammonia to yield pyrrolidone.
  • Polymerization is carried out by heating in the presence of H20 and NH3.
  • the manufacturing process for povidone polymers produces polymers containing molecules of unequal chain length, and thus different molecular weights.
  • the molecular weights of the molecules vary about a mean or average for each particular commercially available grade.
  • the K-values of various grades of povidone polymers represent a function of the average molecular weight, and are derived from viscosity measurements and calculated according to Fikentscher's formula.
  • the weight-average of the molecular weight, Mw is determined by methods that measure the weights of the individual molecules, such as by light scattering.
  • Exemplary useful commercially available povidone polymers for injectable formulations include, but are not limited to, Plasdone C-15TM, Kollidon 12 PFTM, Kollidon 17 PFTM, Kollidon 25TM. and Kollidon 30TM.
  • Suitable surface stabilizer compounds include: hydroxyl propyl methyl cellulose (HPMC), carboxymethylcellulose sodium, sodium lauryl sulphate (SLS) and poly vinyl pyrollidone (PVP), soy lecithin, polysorbate (20, to 80), Span (20 or 80), dipalmitoylphosphotidylcholine, poloxomers, sodium deoxycholate, sodium docusate, PLA-PEG, Cremophors and Solutol.
  • HPMC hydroxyl propyl methyl cellulose
  • SLS sodium lauryl sulphate
  • PVP poly vinyl pyrollidone
  • soy lecithin soy lecithin
  • Span (20 or 80) dipalmitoylphosphotidylcholine
  • poloxomers sodium deoxycholate
  • PLA-PEG Cremophors and Solutol.
  • Combination formulations of the invention suitable for delivery as inhalation formulations may also be delivered by other routes of administration, for example orally.
  • compositions of the invention may also comprise one or more binding agents, filling agents, lubricating agents, suspending agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents,
  • disintegrants effervescent agents, and other excipients depending upon the route of administration and the dosage form desired.
  • filling agents are lactose monohydrate, lactose anhydrous, and various starches
  • binding agents are various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose, such as Avicel (Registered trademark) PH101 and Avicel (Registered trademark) PH102, microcrystalline cellulose, and silicified microcrystalline cellulose (ProSolv SMCC (Registered Trademark) ).
  • Suitable lubricants including agents that act on the flowability of the powder to be compressed, are colloidal silicon dioxide, such as Aerosil (Registered trademark) 200, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel.
  • colloidal silicon dioxide such as Aerosil (Registered trademark) 200, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel.
  • sweeteners are any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acsulfame.
  • flavoring agents are Magnasweet (Registered trademark) (trademark of MAFCO), bubble gum flavor, and fruit flavors, and the like.
  • preservatives examples include potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, and quarternary compounds such as benzalkonium chloride.
  • Suitable diluents include pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of the foregoing.
  • diluents include microcrystalline cellulose, such as Avicel (Registered trademark) PH101 and Avicel (Registered trademark) PH102;
  • lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose (Registered trademark) DCL21 ; dibasic calcium phosphate such as Emcompress (Registered trademark) ; mannitol; starch; sorbitol; sucrose; and glucose.
  • Suitable disintegrants include lightly crosslinked polyvinyl pyrrolidone, corn starch, potato starch, maize starch, and modified starches, croscarmellose sodium, cross-povidone, sodium starch glycolate, and mixtures thereof.
  • effervescent agents examples include effervescent couples, such as an organic acid and a carbonate or bicarbonate.
  • Suitable organic acids include, for example, citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides and acid salts.
  • Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate.
  • the sodium bicarbonate component of the effervescent couple may be present.
  • the invention encompasses dry powder aerosols of the formulations of the invention and liquid dispersion aerosols of the formulations of the invention.
  • the aerosol droplets comprising the particulate formulations of the invention for aqueous dispersion aerosols, or the dry powder aggregates comprising the particulate formulations of the invention for dry powder aerosols have a mass media aerodynamic diameter of less than or equal to about 100 microns.
  • the aerosol droplets comprising the particulate formulations of the invention for aqueous dispersion aerosols, or the dry powder aggregates comprising the particulate formulations of the invention for dry powder aerosols have a mass media aerodynamic diameter (MMAD) of (1 ) about 30 to about 60 microns; (2) about 0.1 to about 10 microns; (3) about 2 to about 6 microns; or (4) less than about 2 microns.
  • MMAD mass media aerodynamic diameter
  • Particles of the invention are particularly advantageous since they have very low levels of components other than the pharmacologically active ingredients.
  • no other components except for low levels of stabilisers are used in the nanoparticle suspension used to make the particles of the invention.
  • a pharmacologically active ingredient is any compound which when dosed to an animal or human produces a therapeutically beneficial effect.
  • Pharmaceutically active ingredients may have side effects in addition to the therapeutic benefit.
  • the pharmacologically active ingredient is one or more of the following classes :corticosteroids such as Inhaled Corticosteroid (ICS) and Long Acting Beta Agonists (LABA), Short Acting Beta Agonists (SABA),
  • ICS Inhaled Corticosteroid
  • LAA Long Acting Beta Agonists
  • SABA Short Acting Beta Agonists
  • LM Leukotriene Modifiers
  • Immunomodulators are Leukotriene Modifiers (LM) and Immunomodulators.
  • Corticosteroid drugs include betamethasone (CelestoneTM), budesonide (EntocortTM), cortisone (CortoneTM), dexamethasone (DecadronTM),
  • hydrocortisone (CortefTM), methylprednisolone (MedrolTM), prednisolone
  • prednisone prednisone
  • CortanTM DeltasoneTM
  • Liquid PredTM MeticortenTM
  • OrasoneTM Panasol-STM
  • Prednicen-MTM Prednicen-MTM and SterapredTM
  • triamcinolone KenacortTM, KenalogTM
  • inhalation corticosteroids examples include beclomethasone (aerosol, capsules for inhalation, and powder for inhalation); beclomethasone dipropionate HFA (aerosol); budesonide (powder for inhalation and suspension for inhalation); flunisolide (aerosol); and triamcinolone (aerosol).
  • Example of a leukotriene Modifier include a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist, such as zileuton; ABT-761 ; fenleuton; tepoxalin; Abbott- 79175; Abbott-85761 ; N-(5-substituted)-thiophene-2-alkylsulfonamides; 2,6-di- tert-butylphenolhydrazones; methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661 ; a pyridinyl-substituted 2-cyanonaphthalene
  • 5-LO 5-lipoxygenase
  • FLAP 5-lipoxygenase activating protein
  • a 2-cyanoquinoline compound such as L- 746,530
  • indole and/or a quinoline compound such as MK-591 , MK-886 and/or BAY 1005;
  • Example of leukotriene modifiers also include a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4, selected from the group consisting of the phenothiazin-3-1s, such as L-651 ,392; amidino compounds, such as CGS- 25019c; benzoxalamines, such as ontazolast; benzenecarboximidamides, such as BIIL 284/260; and compounds, such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A) and BAY * 7195;
  • LT leukotrienes
  • LTC4, LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-1s, such as L-651 ,392; amidino compounds, such as CGS- 250
  • a leukotriene modifiers is selected from zafirlukast, montelukast, and zileuton.
  • beta agonists examples include: salbutamol (albuterol (US name), VentolinTM), bitolterol mesylate, fenoterol, hexoprenal in, levosalbutamol (levalbuterol (US name), Xopenex), metaproterenol (AlupentTM), orciprenalin, pirbuterol (MaxairTM), procaterol, reproterol, ritodrine and/or terbutalin
  • beta agonists examples include: salmeterol (Serevent Diskus) formoterol (ForadilTM, SymbicortTM), bambuterol, clenbuterol and indacaterol.
  • immunomodulators examples include thiopurines such as 6- mercaptopurine.
  • Examples of pharmacologically active ingredients sutiable for use in formulation of the invention also include:
  • non-steroidal anti-inflammatory drugs such as Aspirin (acetylsalicylic acid), Diflunisal, Salsalate, ibuprofen, Naproxen, Fenoprofen, Ketoprofen,
  • anti-inflammatory agents for example adrenocorticoids, corticosteroids, (e.g., beclomethasone, budesonide, flunisolide, fluticasone, triamcinolone, methylprednisolone, prednisolone, prednisone, hydrocortisone), glucocorticoids, steroids
  • Sulphonyl ureas such as Carbutamide, Acetohexamide, Chlorpropamide, Tolbutamide, Tolazamide, Glipizide, Gliclazide, Glibenclamide (glyburide), Glibornuride, Gliquidone, Glisoxepide, Glyclopyramide, and Glimepiride;
  • xanthine derivatives such as caffeine, aminophylline, IBMX (3-isobutyl-1 - methylxanthine), paraxanthine, pentoxifylline, theobromine, and
  • Suitable pharmacologically active ingredients for formulations of the inventions include any pharmaceutical agent which exists in a crystalline form.
  • examples include: ibuprofen [(RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid], glibenclamide, theophylline, salmeterol, fluticasone, formoterol, budesonide, beclometasone and carmoterol.
  • ibuprofen and glibenclamide or fluticasone and salmeterol or budesonide and codisterol or budesonide and formoterol are examples of ibuprofen and glibenclamide or fluticasone and salmeterol or budesonide and codisterol or budesonide and formoterol.
  • the term 'plurality' refers to one or more. In one embodiment the term 'plurality' refers to two or more, for example two or three.
  • the liquid for example water comprises further components, for example stabilisers.
  • a stabiliser is any compound which prevents aggregation of the nanoparticles in liquid form.
  • Example of suitable stabilizer compounds include: hydroxyl propyl methyl cellulose (HPMC), sodium lauryl sulphate (SLS) and poly vinyl pyridone (PVP).
  • Example of suitable stabilizer compounds include: hydroxyl propyl methyl cellulose (HPMC), carboxymethylcellulose sodium lauryl sulphate (SLS) and poly vinyl pyrollidone (PVP), soy lecithin, polysorbate (20, to 80), Span (20 or 80), dipalmitoylphosphotidylcholine, poloxomers, sodium deoxycholate, sodium docusate, PLA-PEG, Cremophors and Solutol.
  • the stabalisers comprise a povidone polymer and a lecithin.
  • the stabaliser are selected from a povidone polymer and soy lecithin, for example PVP and soy lecithin.
  • the povidone polymer and lecithin are in the ratio:
  • the povidone and lecithin further comprise carboxymethylcellulose (CMC), such as the sodium salt of CMC.
  • CMC carboxymethylcellulose
  • the CMC is present at a ratio compared to the PVP in the range about 10 :1 to about 2 : 1 , for example about 5 to about 1 or about 4 to about 1 or about 3 to about 1 and/or at a ratio compared to the lecithin about 3 :1 to about 1 : 3,
  • 'lecithin' refers to a yellow-brownish fatty substances occurring in animal and plant tissues, and in egg yolk, comprising phosphoric acid, choline, fatty acids, glycerol, glycolipids, triglycerides, and phospholipids (e.g.,
  • phosphatidylcholine phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol
  • Stabilizers are added to the suspension at a concentration sufficient to prevent aggregation of the nanoparticles. In general in the range 0.1 -1 %. In one embodiment one or more of the following stabilizers are added: about 0.5%PVP, about 0.5% HPMC and about 0.1 % SLS.
  • the aqueous suspension contains no other solvents. This has the advantage that there are no residual solvents in the particle formulation of the invention.
  • particles of the formulations of the invention have a diameter between 1 ⁇ to 10 ⁇ .
  • modification of the spray drying conditions will modify the size of particles formed. For example particles as small as 0.2 ⁇ and as large as 20 ⁇ can be formed depending of the requirements of the pharmaceutical formulation for which the particles are intended.
  • the nanoparticles used in the practice of the present invention are particles with one dimension in the nanometer (nm) size range, that is, from about 1 to 1 ,000 nm.
  • the nanoparticles are in the size range of about about 100 to about 1000 nm, for example in the range about 200 to about 1000 nm, such as particles with an average particle size of about 200 to about 600nm, for example about 200 to about 400, about 200 to about 300 or about 200 to about 250nm.
  • the nanoparticles may have any shape.
  • nanoparticles examples include:
  • nanoparticles are made using the Dena particle reduction machine, using the following condition:
  • the impellor of the rig rotates at about 1400 rotations per minute in the clockwise direction.
  • the grinding media used are Yttrium stabilized zirconium beads of size 0.2mm at a volume of 150 ml_ which enable the production of an average particle size of approximately 250-300nm.
  • the particle diameter can be manipulated by changing the dimensions of the grinding media with larger media (0.4 mm) giving coarser particles and smaller media (0.1 mm or 0.15 mm) giving rise to finer particulates.
  • the volume of grinding media can also be adjusted to modify the efficiency of size reduction, with larger media volumes typically giving rise to smaller particulates. With increased media volumes, the batch size of suspension that can be processed must however be reduced accordingly with some reduction in the solids content of the suspension also necessary to enable free flow of the formulation. (iii) Batch volumes
  • the heat exchanger attached to the size reduction system enables the temperature of the sample suspensions to be controlled during processing.
  • the water inlet tube is connected into the heat exchanger from a cold water source which allows for efficient heat transfer and cooling of the formulation during processing.
  • the temperature of the sample suspensions are maintained between 15-30°C (Coolant systems can also be used to maintain temperatures at cool levels ( ⁇ 10°C).
  • a range of solids contents 2%w/v to 40%w/v can be processed using the Dena size reduction systems, which can be maximized through use of a reduced volume of grinding media.
  • Formulations of the invention are, in general, prepared by spray drying.
  • the skilled man would be familiar with a number of apparatuses and conditions for spray drying suspensions of particles. Conditions used in spray drying
  • methodologies, used to prepare particles of the invention include:
  • a pharmaceutical composition comprising a particle formulation of the invention in association with one or more pharmaceutical carriers, excipients or diluents.
  • Suitable carriers, excipients or diluents may be selected having regard to the intended mode of administration and standard practice.
  • the pharmaceutical compositions may be for human or animal usage in human and veterinary medicine, preferably for treatment of a condition, disease or disorder as herein defined.
  • Pharmaceutical compositions may be in the form of a dry powder, an aerosol, a spray, a capsule or a tablet.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, dispersible powders or granules), for topical use for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder).
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as crospovidone, croscarmellose sodium, sodium starch glycollate, corn starch or algenic acid; binding agents such as starch, polyvinylpyrollidone, or hydroxypropylmethylcellulose; lubricating agents such as magnesium stearate, stearic acid, sodium stearyl fumarate or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • inert diluents such as lactos
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, mannitol, lactose or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate, mannitol, lactose or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
  • compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid.
  • Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
  • the unit dose of the active ingredient may generally be in the range of from 0.1 ⁇ g to 10000 ⁇ g, 0.1 to 5000 ⁇ g, 0.1 to 1000 ⁇ g, 0.1 to 500 ⁇ g, 0.1 to 200 ⁇ g, 0.1 to 200 ⁇ g, 0.1 to 100 ⁇ g, 0.1 to 50 ⁇ g, 5 ⁇ g to 5000 ⁇ g, 5 to 1000 ⁇ g, 5 to 500 ⁇ g, 5 to 200 ⁇ g, 5 to 100 ⁇ g, 5 to 50 ⁇ g, 10 to 5000 ⁇ g, 10 to 1000 ⁇ g, 10 to 500 ⁇ g, 10 to 200 ⁇ g, 10 to 100 ⁇ g, 10 to 50 ⁇ g, 20 to 5000 ⁇ g, 20 to 1000 ⁇ g, 20 to 500 ⁇ g, 20 to 200 ⁇ g, 20 to 100 ⁇ g, 20 to 50 ⁇ g, 50 to 5000 ⁇ g, 50 to 1000 ⁇ g, 50 to 500 ⁇ g, 50 to 200 ⁇ g, 50 to 100 ⁇ g, 20 to
  • the active ingredient is desirably finely divided, i.e. the particles of active ingredient have a mass median diameter of less 10 ⁇ .
  • the finely divided active ingredient may be suspended in a propellant (e.g. a HFA) with the assistance of a dispersant, such as a C-8-C20 fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
  • a propellant e.g. a HFA
  • a dispersant such as a C-8-C20 fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
  • the finely divided compound may be coated by another substance.
  • Dry powder formulations are used in a dry powder inhaler.
  • the inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
  • the active ingredient is generally formulated in association with carriers/diluents to facilitate accurate dosing from an inhaler.
  • carriers/diluents include for example, a mono-, di- or polysaccharide, and sugars for example, lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol and starch.
  • dry powdered formulation comprises fine particles of the active ingredient, coarse particles of carrier/diluent, and optionally small and/or fine particles of carrier/diluent.
  • This form of dry powder formulation is known in the art as an Ordered mixture'.
  • coarse carrier /diluent refers to carrier/diluent having a mass median diameter of greater than 25 ⁇ ; small carrier /diluent refers to
  • mass median diameter is measured by a laser diffraction instrument (e.g. a Malvern
  • dry powder formulation is where the fine particles of the drug are mixed with fine and/or small particles of carrier/diluent, and the mixture of particles agglomerated into spheres, which break up during the inhalation procedure e.g. see US 5,551 ,489.
  • the spheres may be filled into the drug reservoir of a multidose inhaler, for example, that known as TurbuhalerTM in which a dosing unit meters the desired dose which is then inhaled by the patient.
  • TurbuhalerTM a multidose inhaler
  • the active ingredient with or without a carrier substance, is delivered to the patient.
  • the amount of active ingredient (typically less than 10 mg for inhalation, but probably less than 600 mg for oral) that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
  • a particle formulation of the invention for use as a medicament.
  • a formulation of the invention in the prevention or treatment of a respiratory disease, for example asthma or COPD.
  • a formulation of the invention in the manufacture of a medicament for prevention or treatment of a respiratory disease, for example asthma or COPD.
  • a formulation of the invention for the prevention or treatment of a respiratory disease for example asthma or COPD.
  • a respiratory disease for example asthma or COPD
  • a formulation of the invention in an amount sufficient to treat the condition.
  • a respiratory disease for example asthma or COPD
  • said method comprising administering to a subject in need thereof, a formulation of the invention in an amount sufficient to treat the condition.
  • Respiratory diseases include: obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug- induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper- responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung va
  • Figure 1 - shows a twin stage Impinger wherein the following parts are marked:
  • Figure 2.- shows the average particle size distribution for 15% ibuprofen and : 3% Glibenclamide nano suspension at 5, 20, 30, 45 and 60 minutes after processing using the D100 size reduction system.
  • Figure 3 - shows a scanning electron micrograph of a spray dried
  • Ibuprofen/Glibenclamide particle formulation of the invention Ibuprofen/Glibenclamide particle formulation of the invention.
  • Figure 4.- shows a differential scanning calorimetry plots for:
  • Figure 5 - shows the X-ray powder diffraction patterns for:
  • Figure 6- shows a DSC plot for
  • Figure 7- shows an X-ray diffraction pattern for:
  • Figure 8 - shows the stage by stage deposition of the Flu:Sal formulation using the NGI test (see Example 3).
  • the x -axis shows the data for the different stages of the NGI instrument and the Y axis shows percentage normalized mass deposited as a function of recovered dose.
  • the left bar is Flu and the right bar is Sal.
  • Ibuprofen USP was purchased from Albermarle Europe sprl, (Belgium).
  • Glibenclamide BP/EP was purchased from Anzen Exports, Na, India.
  • HPMC Hydroxy propyl methyl cellulose
  • SLS Sodium lauryl sulfate
  • PVP K-30 was purchased from BASF (Aktiengesellschaft Ludwigshafen, Germany). Soya lecithin was purchased from Rectapur, BDH, UK. All other materials used were of analytical grade and purchased from established suppliers.
  • the particle size for sample suspensions collected at time intervals was analysed by Dynamic Light Scattering (DLS) using the nano Zetasizer (Malvern Instruments Ltd, Malvern, UK).
  • Figure 2 demonstrates the overlayed average particle size distribution profiles for Ibu : Gli nano suspension generated at 5, 20, 30, 45 and 60 minutes using the DM100 size reduction system.
  • the average particle size determined by nano zetasizer for the lbu:gli nano- suspension at 5mins was 581 nm (represented by the red coloured profile (a) in figure 2) and was further reduced to 224nm at 60mins (represented by pink coloured profile (b) in figure 2).
  • the processed suspension was analysed for active content by a
  • the ratio of Ibu : Gli in the nano suspension when determined by a validated HPLC method was found to be 4.96 : 1. This indicates that the 5:1 ibu : gli ratio was maintained in the nano suspension even after processing using the DM100 size reduction system.
  • a comparative DSC plot for nano suspension, glibenclamide (gli) raw powder and ibuprofen (Ibu) raw powder is given in Figure 4.
  • Spray-drying was carried out using a Buchi 190 Mini Spray Dryer fitted with a two-fluid nozzle and peristaltic pump.
  • the processing parameters comprised an inlet temperature of 120°C, an atomizing air flow rate of 600 l/h and a liquid feed rate of 5%. A resulting outlet temperature of 72°C was observed.
  • the lbu:Gli suspension was diluted to 1.5% in distilled water and spray dried using the above conditions.
  • the resultant powder produced by spray-drying was then analysed for active agent content using the same HPLC method described above with associated evaluation by scanning electron microscopy (SEM), X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC).
  • SEM scanning electron microscopy
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • DSC Differential scanning calorimetry
  • a comparative DSC plot for lbu:gli spray dried powder, nano suspension, glibenclamide (gli) raw powder and ibuprofen (Ibu) raw powder is given in Figure 4.
  • the DSC plot given in Figure 4 shows the melting transitions of ibuprofen and glibenclamide in the ibu:gli spray dried powder and when isolated from suspension. While the melting endotherm for Ibuprofen is sharp, the melting endotherm for glibenclamide in the spray dried powder is visible as a broad peak which is possibly related to changes in the particle size or through its interaction with ibuprofen which is present in the molten state at
  • the active agent content data shows the ratio of ibuprofen : glibenclamide in the spray dried powder for six replicates.
  • the average ratio is 4.56:1 , which indicates that even after spray drying the ratio of ibuprofen : glibenclamide is maintained in the spray dried powder, although some losses of ibuprofen have been incurred.
  • Table 3 gives the ratio of Ibuprofen and glibenclamide deposited on the various stages of the twin-stage impinger. Table 3 Ratio of lbu:gli deposited in Twin Stage Impinger
  • the data demonstrates the ratios of the two drugs has typically been maintained following aerosolisation, although the finer material ⁇ 5.2 microns is slightly richer in glibenclamide that it's coarser counterpart. This indicates a potential for substantial co-deposition in respiratory tract.
  • a 6.0%: 0.6% fluticasone:salmeterol formulation (i.e. 10:1 ) with an average particle size of about 300nm was prepared as follows. (i) Processing of 6%w/v fluticasone : 0.6%w/v salmeterol nano-suspension Fluticasone and salmeterol in 10:1 ratio (6%w/w: 0.6%w/w) were dispersed in an aqueous stabilizer solution containing 0.5%PVP and 0.1 %soya lecithin. The resultant suspension was processed using the Dena particle size reduction machine (DM100, Dena Technologies Ltd, Mapplewell, Barnsley, UK) as described above. Samples were collected at 5 minutes, 35, 50 and 75 minutes.
  • DM100 Dena particle size reduction machine
  • Table-1 gives average particle size for flu : sal nano suspension generated at 5, 35, 50 and 75 minutes using the DM100 size reduction system.
  • the average particle size determined by nano zetasizer for the flu:sal nano- suspension at 5mins was 350nm and was further reduced to 250nm at 75mins.
  • the poly dispersity index was 0.31 and 0.24 respectively.
  • the processed suspension was analysed for active content by HPLC method.
  • a Waters Alliance (Water systems, UK) 2695 separations module with 2487 dual wavelength absorbance detector at 228nm was used with (Vydac Technology Ltd., UK) C-18 silica based 25 ⁇ 4.6 ⁇ 5 ⁇ column.
  • the mobile phase was methanol:0.6% aqs ammonium acetate (75:25).
  • the flow rate was set to
  • Table-2 demonstrates the concentration of fluticasone and salmeterol in the processed nano suspension determined by the HPLC and the ratio of flu : sal in the nano suspension before spray drying.
  • the ratio of flu:sal in the nano suspension when determined by a validated HPLC method was found to be 9.63 : 1. This indicates that the 10:1 flu:sal ratio is maintained in the nano suspension even after processing using the DM100 size reduction system.
  • the suspension was then spray-dried at described above.
  • Table-3 demonstrates the concentration of fluticasone and salmeterol in the spray dried powder determined by the HPLC and the ratio of flu : sal in the spray dried powder.
  • Samples were collected from the throat, neck tube, upper stage base, lower stage base, capsule + aerolizer. These samples were then injected in the HPLC for determining the ratio using a standard HPLC method.
  • Table-1 gives the %deposition (%D) of fluticasone and Table-2 gives the %deposition of Salmeterol on the twin stage impinger.
  • Figure -1 gives the differential thermal analysis (DSC) plot for the Salmeterol raw powder, Fluticasone raw powder and flu_sal spray dried powder.
  • Figure-2 gives the X-ray diffraction comparison plot for salmeterol raw powder, fluticasone raw powder, fluticasone : salmeterol (10: 1 ) mixture (two compounds mixed physically) and fluticasone: salmeterol spray dried powder.
  • Combination particles of FP/SX were formulated into a drug-only pMDI (pressurized metered dose inhaler) with HFA 134a (1 , 1 , 1 ,2-tetrafluoroethane) such that the nominal dose of FP was 250 meg and SX was 25 meg.
  • a 50 ⁇ valve was employed to dispense the formulation.
  • NGI Next Generation Impactor
  • GE Motors vacuum pump
  • the NGI apparatus was dismantled and the actuator and each part of the NGI was washed down into known volumes of HPLC mobile phase.
  • the mass of drug deposited on each part of the NGI was determined by HPLC as described above. This protocol was repeated three times for the can, following which, the fine particle dose (FPD) and fine particle fraction of the targeted delivered amount (FPFTDA) were determined.
  • FPD fine particle dose
  • FPFTDA fine particle fraction of the targeted delivered amount
  • stage by stage deposition shows evidence of co-delivery of both actives on all stages including the actuator, mouthpiece and throat.
  • the MMAD is small and more importantly the same for both drugs. Therefore, these data conclude that crystalline combination particles are aerosolized efficiently from a metered dose inhaler.

Abstract

La présente invention porte sur des formulations de particules combinées, appropriées pour être utilisées dans une formulation d'inhalateur comprenant plusieurs ingrédients pharmacologiquement actifs caractérisés en ce que les ingrédients pharmacologiquement actifs sont cristallins. La présente invention comprend en outre une formulation de particules appropriée pour être utilisée dans une formulation d'inhalation comprenant plusieurs ingrédients pharmacologiquement actifs, par exemple des ingrédients pharmacologiquement actifs cristallins caractérisés en ce que le rapport des substances pharmacologiquement actives présente une distribution de moins de ±5 % du rapport cible tel que mesuré par un test d'impacteur. En particulier, la présente invention porte sur des formulations de particules préparées à partir de nanoparticules, par exemple par séchage par pulvérisation d'une suspension aqueuse de nanoparticules. L'invention comprend en outre des procédés de fabrication desdites formulations de particules et un procédé d'utilisation desdites formulations de particules dans des traitements thérapeutiques pour parvenir à une co-localisation d'agents dans le corps, en particulier lorsqu'elles sont administrées sous la forme de formulations inhalées aux voies aériennes et aux poumons d'êtres humains.
PCT/GB2012/050283 2011-02-09 2012-02-09 Formulation de particules WO2012107765A2 (fr)

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8765725B2 (en) 2012-05-08 2014-07-01 Aciex Therapeutics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
WO2016019253A1 (fr) * 2014-07-31 2016-02-04 Otitopic Inc. Formulations de poudre sèche à inhaler
US9757529B2 (en) 2012-12-20 2017-09-12 Otitopic Inc. Dry powder inhaler and methods of use
US9757395B2 (en) 2012-12-20 2017-09-12 Otitopic Inc. Dry powder inhaler and methods of use
CN107205936A (zh) * 2014-10-08 2017-09-26 纪元技术有限责任公司 包含至少一种通过喷雾干燥得到的增加制剂稳定性的干粉的组合物
US9815865B2 (en) 2013-01-07 2017-11-14 Nicox Ophthalmics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
DE102016218604A1 (de) 2016-09-27 2018-03-29 Constantin Adams Partikuläres Stoffgemisch, vorzugsweise zur Verwendung bei der Prophylaxe und/oder Behandlung einer Atemwegsstörung
US9993488B2 (en) 2014-02-20 2018-06-12 Otitopic Inc. Dry powder formulations for inhalation
US10149823B2 (en) 2013-04-30 2018-12-11 Otitopic Inc. Dry powder formulations and methods of use
US10174071B2 (en) 2012-05-08 2019-01-08 Nicox Ophthalmics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
US10195147B1 (en) 2017-09-22 2019-02-05 Otitopic Inc. Dry powder compositions with magnesium stearate
US10786456B2 (en) 2017-09-22 2020-09-29 Otitopic Inc. Inhaled aspirin and magnesium to treat inflammation
WO2021216710A1 (fr) * 2020-04-24 2021-10-28 The Medical College Of Wisconsin, Inc. Utilisation du salmétérol en tant qu'agent antiviral

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5551489A (en) 1993-10-01 1996-09-03 Astra Aktiebolag Agglomeration of finely divided powders
WO2007020407A2 (fr) 2005-08-12 2007-02-22 Brian Sulaiman Systeme de broyage fin
US7572430B2 (en) 2000-11-09 2009-08-11 Cyprus Amax Minerals Company Method for producing nano-particles
US20090317504A1 (en) 2006-10-24 2009-12-24 Beneq Oy Device and method for producing nanoparticles

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7521068B2 (en) * 1998-11-12 2009-04-21 Elan Pharma International Ltd. Dry powder aerosols of nanoparticulate drugs
FI20002215A0 (fi) * 2000-10-06 2000-10-06 Orion Yhtymae Oyj Yhdistelmäpartikkelit
EP2050437A1 (fr) * 2007-10-15 2009-04-22 Laboratoires SMB Compositions de poudre sèche pharmaceutiquement améliorées pour l'inhalation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5551489A (en) 1993-10-01 1996-09-03 Astra Aktiebolag Agglomeration of finely divided powders
US7572430B2 (en) 2000-11-09 2009-08-11 Cyprus Amax Minerals Company Method for producing nano-particles
WO2007020407A2 (fr) 2005-08-12 2007-02-22 Brian Sulaiman Systeme de broyage fin
US20090317504A1 (en) 2006-10-24 2009-12-24 Beneq Oy Device and method for producing nanoparticles

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
"Cationic Surfactants: Physical Chemistry", 1991, MARCEL DEKKER
"Comprehensive Medicinal Chemistry", vol. 5, 1990, PERGAMON PRESS
"European Pharmacopoeia (Ph.Eur.", 16 September 2004
"Handbook of Pharmaceutical Excipients", 2000, AMERICAN PHARMACEUTICAL ASSOCIATION AND THE PHARMACEUTICAL SOCIETY OF GREAT BRITAIN
"The Merck Index", 1983, MERCK & CO., pages: 7581
BINGBING JIANG; LING HU; CHANGYOU GAO; JIACONG SHEN, INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 304, 2005, pages 220 - 230
CRISTINI, F.; DELALONDE, M.; JOUSSOT-DUBIEN, C.; BATAILLE, B.: "Proceedings of the 6th International Symposium on Supercritical Fluids", 2003, article "Elaboration of ibuprofen microcomposites in supercritical C02", pages: 1917 - 1922
J. CROSS; E. SINGER: "Cationic Surfactants: Analytical and Biological Evaluation", 1994, MARCEL DEKKER
J. RICHMOND: "Cationic Surfactants: Organic Chemistry", 1990, MARCEL DEKKER
MARPLE ET AL., JOURNAL OF AEROSOL MEDICINE, vol. 16, 2003, pages 283 - 99
MARPLE ET AL., JOURNAL OF AEROSOL MEDICINE, vol. 16, 2003, pages 301 - 24
MARPLE ET AL., JOURNAL OF AEROSOL MEDICINE, vol. 17, 2004, pages 335 - 43
PATEL ET AL.: "An Overview: Nanoparticles.", INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES AND NANOTECHNOLOGY, vol. 1, no. 3, pages 215 - 220
SUBRATA MALLICKA; SATYANARAYAN PATTNAIKA; KALPANA SWAINA; PINTU K. DEB; ARINDAM SAHAB; GAURISANKAR GHOSHALB; ARIJIT MONDALB: "Formation of physically stable amorphous phase of ibuprofen by solid state milling with kaolin.", EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, vol. 68, no. 2, 2008, pages 346 - 351, XP022415428, DOI: doi:10.1016/j.ejpb.2007.06.003
VIJAYKUMAR, N.; VENKATESWARLU, V.; RAVIRAJ, P.: "Development of oral tablet dosage form incorporating drug nanoparticles", RJPBCS, vol. 1, no. 4, 2010, pages 952

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US8765725B2 (en) 2012-05-08 2014-07-01 Aciex Therapeutics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
US10174071B2 (en) 2012-05-08 2019-01-08 Nicox Ophthalmics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
US9822142B2 (en) 2012-05-08 2017-11-21 Nicox Ophthalmics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
US10954263B2 (en) 2012-05-08 2021-03-23 Nicox Ophthalmics, Inc Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
US9757395B2 (en) 2012-12-20 2017-09-12 Otitopic Inc. Dry powder inhaler and methods of use
US9757529B2 (en) 2012-12-20 2017-09-12 Otitopic Inc. Dry powder inhaler and methods of use
US9815865B2 (en) 2013-01-07 2017-11-14 Nicox Ophthalmics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
US11865210B2 (en) 2013-04-30 2024-01-09 Vectura Inc. Dry powder formulations and methods of use
US10149823B2 (en) 2013-04-30 2018-12-11 Otitopic Inc. Dry powder formulations and methods of use
US11819569B2 (en) 2013-04-30 2023-11-21 Vectura Inc. Treating inflammation with inhaled aspirin
US9993488B2 (en) 2014-02-20 2018-06-12 Otitopic Inc. Dry powder formulations for inhalation
WO2016019253A1 (fr) * 2014-07-31 2016-02-04 Otitopic Inc. Formulations de poudre sèche à inhaler
EP3179986B1 (fr) 2014-07-31 2023-03-15 Vectura Inc. Formulations de poudre sèche à inhaler
CN107205936A (zh) * 2014-10-08 2017-09-26 纪元技术有限责任公司 包含至少一种通过喷雾干燥得到的增加制剂稳定性的干粉的组合物
DE102016218604A1 (de) 2016-09-27 2018-03-29 Constantin Adams Partikuläres Stoffgemisch, vorzugsweise zur Verwendung bei der Prophylaxe und/oder Behandlung einer Atemwegsstörung
US11077058B2 (en) 2017-09-22 2021-08-03 Otitopic Inc. Dry powder compositions with magnesium stearate
US10786456B2 (en) 2017-09-22 2020-09-29 Otitopic Inc. Inhaled aspirin and magnesium to treat inflammation
US10195147B1 (en) 2017-09-22 2019-02-05 Otitopic Inc. Dry powder compositions with magnesium stearate
WO2021216710A1 (fr) * 2020-04-24 2021-10-28 The Medical College Of Wisconsin, Inc. Utilisation du salmétérol en tant qu'agent antiviral

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