WO2003088945A1 - Aerosol containing a particulate active substance - Google Patents
Aerosol containing a particulate active substance Download PDFInfo
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- WO2003088945A1 WO2003088945A1 PCT/GB2003/001665 GB0301665W WO03088945A1 WO 2003088945 A1 WO2003088945 A1 WO 2003088945A1 GB 0301665 W GB0301665 W GB 0301665W WO 03088945 A1 WO03088945 A1 WO 03088945A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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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
- A61K9/0012—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]
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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
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
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- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
- B01J2/02—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by dividing the liquid material into drops, e.g. by spraying, and solidifying the drops
- B01J2/04—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by dividing the liquid material into drops, e.g. by spraying, and solidifying the drops in a gaseous medium
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
Definitions
- the present invention relates to active substances in particulate form, to methods for preparing them, to formulations containing them and to uses of such substances and formulations.
- Certain pharmaceuticals may be delivered to the nose and/or lungs of a patient by inhalation, using an inhaler device of which there are several known types.
- the drug or a formulation containing the drug, for instance together with a pharmaceutically acceptable excipient such as lactose
- a fluid vehicle which acts to transport the drug in a suitably disperse state towards the intended site of administration.
- the vehicle may be a pressurised propellant fluid if the drug is to be delivered in aerosolised form.
- MDIs Metal dose inhalers
- budesonide PulmicortTM, AstraZeneca
- salbutamol VentolinTM, Glaxo SmithKline and ProventilTM HFA, Schering Plough
- salmeterol xinafoate SereventTM, Glaxo SmithKline
- fluticasone FloventTM, Glaxo SmithKline
- Typical propellant fluids include hydrofluoroalkanes such as 1,1,1,2-tetrafluoroethane (available as HFA 134a), 1,1,1,2,3,3,3-heptafluoropropane (available as HFA 227ea) and 1,1,2,2,3- pentafluoropropane.
- hydrofluoroalkanes such as 1,1,1,2-tetrafluoroethane (available as HFA 134a), 1,1,1,2,3,3,3-heptafluoropropane (available as HFA 227ea) and 1,1,2,2,3- pentafluoropropane.
- the particulate drug must be suspended as uniformly as possible in the fluid vehicle. This is usually achieved by shaking the inhalation device prior to dispensing a dose of the drug. It is clearly desirable that the drug remains suspended in the vehicle for a sufficient length of time after shaking to allow it to reach the intended site of administration.
- particulate drag/propellant suspensions tend only to be stable for limited periods of time. Where the drug is more dense than the propellant, the tendency is for it to "settle” or "flocculate", ie, to fall out of suspension. Where it is less dense than the propellant, the drug tends to "cream” or float towards the top of the propellant volume. This can reduce the efficiency and therefore also accuracy of drug dosage delivery.
- dispersion enhancing agents such as surfactants need to be added to the drug/propellant mixture to achieve and sustain a suitably uniform suspension. Even using such techniques, it has typically proved difficult to prepare inhalable suspensions which are stable during normal storage periods and conditions and which give uniform dosing throughout the useful life of the average inhaler.
- Particulate active substances such as drugs
- Particulate active substances may be produced by a variety of known methods, including for example crystallisation from solution, anti-solvent precipitation from solution, milling, micronisation, spray drying, freeze drying or combinations of such processes.
- particle formation processes which make use of supercritical or near-critical fluids, either as solvents for the substance of interest - as in the process known as RESS (Rapid Expansion of Supercritical Solution- see Tom & Debenedetti, J Aerosol. Sci., 22 (5), 555-584 (1991)) - or as anti-solvents to cause the substance to precipitate from another solution - as in the process known as GAS (Gas Anti-Solvent) precipitation (see Gallagher et al, ACSSymp. Ser., 406, p334 (1989)).
- RESS Rapid Expansion of Supercritical Solution- see Tom & Debenedetti, J Aerosol. Sci., 22 (5), 555-584 (1991)
- GAS Gas Anti-
- an active substance in particulate form which is insoluble in the fluid vehicle 1,1,1,2-tetrafluoroethane (HFA 134a) and which when suspended in that vehicle, at a concentration of from 0.2 to 5 % w/v, exhibits a flocculation volume of 35 % or greater after 5 minutes.
- the invention provides an active substance in particulate form, which is insoluble in the fluid vehicle 1,1,1,2,3,3,3-heptafluoropropane (HFA 227 ea) and which when suspended in that vehicle, at a concentration of from 0.2 to 5 % w/v, exhibits a flocculation volume of 35 % or greater after 5 minutes.
- Flocculation volume is a measure of the amount of the vehicle which is occupied by the particulate suspension; a higher value therefore indicates less flocculation (in the case where the active substance is more dense than the vehicle) or less creaming (in the case where the active substance is less dense than the vehicle), and accordingly improved performance due to the more uniform dispersion of the solid in the vehicle.
- the vehicles HFA 134a and HFA 227ea are referred to as suitable reference standards in which to measure flocculation volume.
- An active substance according to the invention may, however, be used in suspension in any suitable nonsolvent vehicle to give improved flocculation performance.
- the flocculation volume after 5 minutes is preferably 40 % or greater, more preferably 50 % or greater, still more preferably at least 60 % or 70 % or 75 % or 80 % or 85 % or 90 % or 95 % or 98 %.
- the figure achieved may depend on the nature of the active substance, and factors such as its particle size and morphology, as described below.
- This flocculation volume is preferably exhibited after 6 minutes, more preferably after 8 minutes, still more preferably after 10 minutes, most preferably after 15, 30 or 60 minutes or in some cases after 2, 6, 12 or even 24 hours. It is certainly exhibited after only 0.5 or 1 or 2 minutes.
- the flocculation volume is preferably measured at a concentration of above 0.5 % w/v, more preferably from 0.5 to 3 or 4 % w/v, most preferably from 0.5 to 1.5 or 2 % w/v or from 0.8 to 1.3 or 1.5 % w/v, such as 1 % w/v.
- the above described flocculation performance may also be exhibited at lower active substance concentrations, for instance down to 0.15 or even 0.1 % w/v.
- the flocculation volume is preferably greater than 50 % after 20 seconds, more preferably after 30 or 40 or 60 or 90 seconds, most preferably after 2 or 3 or even 5 minutes.
- the active substances of the invention preferably exhibit the above described flocculation performance in other nonsolvent fluid vehicles, in particular hydrofluorocarbon propellants or mixtures thereof (for example, in a mixture of HFA 134a and HFA 227ea).
- the active substances of the invention exhibit the above described flocculation behaviour in the absence of dispersion enhancing or stabilising additives (eg, surfactants) in the active substance/vehicle mixture, or at least at lower levels of such additives than have previously been necessary for the same active substance/vehicle pair, for instance at additive (in particular surfactant) levels of less than 0.1 % w/w based on the weight of the active substance, preferably less than 0.01 % w/w or less than 0.001 or 0.0001 % w/w.
- additives eg, surfactants
- flocculation volumes are preferably measured in suspensions containing only, or consisting essentially of, the active substance and the relevant vehicle.
- the active substances of the invention preferably exhibit the above described behaviour in the absence of (or at low levels of, such as less than 0.1 or 0,01 or 0.001 % w/v based on the total suspension volume) lubricity enhancing additives, either in the active substance/vehicle mixture or on the internal surfaces of the container in which the flocculation performance of the mixture is tested.
- lubricity enhancing additives which are currently used in aerosol formulations include polyvinyl pyrrolidones and polyethylene glycols; coatings which are often used on the surfaces of for example aerosol canisters include epoxy resins or phenolic vinyl type coatings.
- the flocculation volume of the active substance in the vehicle may be measured in a container made of for example glass or aluminium, the internal surfaces of which need not carry or incorporate any lubricity enhancing materials.
- the mass median diameter (MMD) of the active substance particles is preferably less than 15 or in particular less than 10 ⁇ m, more preferably less than 5 or 4 ⁇ m, most preferably less than 3.5 or 3.3 or 3 or 2 or even 1 ⁇ m. It may be greater than 1 or 2 or even 2.5 ⁇ m.
- the mass median aerodynamic diameter (MMAD) of the active substance particles is preferably less than 10 ⁇ m, more preferably less than 5 ⁇ m, most preferably less than 3.5 ⁇ m.
- active substances according to the invention can demonstrate significantly better flocculation performance than the corresponding chemical entities made by conventional techniques such as spray drying, freeze drying and in particular micronisation.
- Particle sizes may be measured for instance using (a) an AerosizerTM time-of-flight instrument (which gives an aerodynamic equivalent particle diameter, MMAD) or (b) a laser diffraction sensor such as the HelosTM system available from Sympatec GmbH, Germany (which provides a geometric projection equivalent MMD). MMADs may also be assessed using a cascade impactor. Volume mean diameters may be obtained in both cases using commercially available software packages. Active substances according to the present invention preferably have a volume- weighted median aerodynamic diameter (VMAD, measured for instance by laser diffraction analysis) of 5 ⁇ m or less, more preferably of 4 ⁇ m or 3.5 ⁇ m or less.
- VAD volume- weighted median aerodynamic diameter
- the active substances of the invention are preferably in the form of solid (eg, as opposed to hollow, porous (which includes perforated) or at least partially fluid-containing) particles. They are preferably, although not necessarily, in a crystalline or semi-crystalline (as opposed to amorphous) foi . More preferably they are crystalline, ideally highly crystalline, since the crystalline form of a material is often more stable in suspension than its amo ⁇ hous or partially crystalline forms which may more readily dissolve in the fluid vehicle, with a risk of re- crystallisation and/or particle growth.
- An active substance according to the invention is thus preferably from 80 % to 100 % or from 90 to 100 %, ideally 100 % crystalline. It may therefore contain less than 20 % w/w, prefer-ably less than 10 % w/w, more preferably less than 5 or 2 or 1 or even 0.5 % w/w, most preferably no, - detectable amo ⁇ hous phase regions.
- Crystallinity may be assessed in known ways for instance using X-ray diffraction (XRD) techniques, preferably high resolution X-ray powder diffraction such as using a synchrotron radiation source. Degree of crystallinity may be assessed for instance with respect to crystals of the same chemical entity produced by slow evaporative crystallisation from solution.
- X-ray diffraction line broadening can provide an indication of reduced crystallinity, for example of crystal lattice imperfections. Line broadening may be manifested for instance by an increased peak width (eg, full width at half maximum height, FWHM) for one or more of the diffraction peaks.
- a reduced level of crystal lattice imperfections, in a particulate product according to the invention may also be manifested by a shift in position, towards higher 2 ⁇ values (typically a shift of 0.0005 " or more, such as of from 0.0005 to 0.005 or from 0.001 to 0.003°), of one or more of the X-ray diffraction peaks, for instance compared to particles of the same chemical entity produced by micronisation.
- An active substance according to the invention preferably has an acicular crystalline form, ie, a crystalline form which is significantly longer in one dimension than in at least one other dimension; this embraces for example needle-like crystals and also, potentially, wafer-, blade- or plate-like crystals (which are significantly longer in two dimensions than in the third) and elongate prism-shaped crystals.
- an acicular crystalline form ie, a crystalline form which is significantly longer in one dimension than in at least one other dimension; this embraces for example needle-like crystals and also, potentially, wafer-, blade- or plate-like crystals (which are significantly longer in two dimensions than in the third) and elongate prism-shaped crystals.
- Needle-like crystals may be preferred for their flocculation performance, and in this case the mass median particle diameter may be greater than 3 or 4 or 5 ⁇ m, perhaps greater than 6 or 7 or 8 or even 10 ⁇ m, although preferably (especially for delivery by inhalation) it will be 6 ⁇ m or less, more preferably 5 ⁇ m or less.
- Plate- or blade-like particles may be preferred for use in inhalers, and may have a mass median particle diameter of greater than 3 or 4 or 5 or 6 ⁇ m, although again for inhalation a preferred diameter may be 6 ⁇ m or less, more preferably 5 ⁇ m or less.
- Particles of an active substance according to the present invention preferably have an aspect ratio (the ratio of the longest to the shortest particle dimension) of 2: 1 or greater, more preferably 3 : 1 or 4: 1 or greater, most preferably from 1.5:1 to 5:1 or from 2:1 to 4.5:1.
- the active substance is preferably in a substantially (eg, 95 % w/w or greater, preferably 98 % or 99 % w/w or 99.5 % w/w or greater) pure form. It preferably contains low levels of residual solvent, for example less than 500 ppm, more preferably less than 200 ppm, most preferably less than 150 or 100 ppm residual solvent, by which is meant solvent(s) which were present at the point of particle formation. Still more preferably the substance contains no detectable residual solvent, or at least only levels below the relevant quantification limit(s).
- the active substance is a substance capable of existing in two or more different polymo ⁇ hic forms, it preferably consists of only one such form, with a purity of 99.5 % w/w or greater, preferably of 99.8 % w/w or greater, with respect to the other polymo ⁇ hic form(s).
- Polymo ⁇ hic purity may be assessed for instance using melting point data (eg, differential scanning calorimetry) or more preferably using X-ray powder diffraction (for instance the small-angle X-ray scattering (SAXS) technique) to detect polymo ⁇ hic transitions during heating, based on the diffraction peaks characteristic of the polymo ⁇ hs.
- melting point data eg, differential scanning calorimetry
- X-ray powder diffraction for instance the small-angle X-ray scattering (SAXS) technique
- active substance in the present context is meant a substance capable of performing some useful function in an end product, whether pharmaceutical, pesticidal or whatever.
- the active substance may be a single active substance or a mixture of two or more. It may be monomeric, oligomeric or polymeric, organic (including organometallic) or inorganic, hydrophilic or hydrophobic, polar or non-polar. It may be a small molecule, for instance a synthetic drug like paracetamol, or a macromolecule such as a protein or peptide (including enzymes, hormones, antibodies and antigens), nucleotide, nucleoside or nucleic acid. Other potential active substances include vitamins, amino acids, lipids including phosphohpids and aminolipids, carbohydrates such as mono-, di-, oligp- or polysaccharides, cells and viruses.
- the active substance preferably comprises (more preferably is) a pharmaceutically or nutraceutically active substance, or a pharmaceutically or nutraceutically acceptable excipient, or a mixture of two or more thereof. More preferably the active substance is a pharmaceutically active substance which is suitable for delivery by inhalation (which term includes nasal and/or oral inhalation), whether for local administration (eg, an asthma drug intended for local delivery to the lung) or for systemic delivery via the lung.
- inhalation which term includes nasal and/or oral inhalation
- local administration eg, an asthma drug intended for local delivery to the lung
- systemic delivery via the lung e.g, an asthma drug intended for local delivery to the lung
- active substances whatever their intended function (for instance, herbicides, pesticides, foodstuffs, imaging agents, dyes, perfumes, cosmetics and toiletries, detergents, coatings, products for use in the ceramics, photographic or explosives industries, etc..) are embraced by the present invention.
- Examples of pharmaceutically active substances which may be delivered by inhalation include ⁇ 2 - agonists, steroids such as glucocorticosteroids (preferably anti-inflammatories), anti-cholinergics, leukotriene antagonists, leukotriene synthesis inhibitors, pain relief drugs generally such as analgesics and anti-inflammatories (including both steroidal and non-steroidal anti- inflammatories), cardiovascular agents such as cardiac glycosides, respiratory drugs, anti-asthma agents, bronchodilators, anti-cancer agents, alkaloids (eg, ergot alkaloids) or triptans such as can be used in the treatment of migraine, drugs (for instance sulphonyl ureas) useful in the treatment of diabetes and related disorders, sleep inducing drugs including sedatives and hypnotics, psychic energizers, appetite suppressants, anti-arthritics, anti-malarials, anti-epileptics, anti-thrombotics, anti-hypertens
- the active agent may fall into one of a number of structural classes, including but not limited to small molecules (preferably water insoluble small molecules), peptides, polypeptides, proteins, polysaccharides, steroids, nucleotides, oligonucleotides, polynucleotides, fats, electrolytes and the like.
- ⁇ 2 -agonists include the ⁇ 2 -agonists salbutamol (eg, salbutamol sulphate) and salmeterol (eg, salmeterol xinafoate), the steroids budesonide and fluticasone (eg, fluticasone propionate), the cardiac glycoside digoxin, the alkaloid anti-migraine drug dihydroergotamine mesylate and other alkaloid ergotamines, the alkaloid bromocriptine used in the treatment of Parkinson's disease, sumatriptan, zolmatriptan, rizatriptan, naratriptan, frovatriptan, almotriptan, mo ⁇ hine and the mo ⁇ hine analogue fentanyl (eg, fentanyl citrate), glibenclamide (a sulphonyl urea), benzodiazepines such as vallium, triazolam, alprazolam, midazolam and clona
- active agents suitable for practice with the present invention include but are not limited to aspariginase, amdoxovir (DAPD), antide, becaplermin, calcitonins, cyanovirin, denileukin diftitox, erythropoietin (EPO), EPO agonists (eg, peptides from about 10-40 amino acids in length and comprising a particular core sequence as described in WO 96/40749), dornase alpha, erythropoiesis stimulating protein (NESP), coagulation factors such as Factor Vila, Factor Vi ⁇ , Factor IX, von Willebrand factor, ceredase, cerezyme, alpha-glucosidase, collagen, cyclosporin, alpha defensins, beta defensins, exedin-4, granulocyte colony stimulating factor (GCSF), thrombopoietin (TPO), alpha- 1 proteinase inhibitor, elcat
- FSH folli
- Exemplary monoclonal antibodies include etanercept (a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kD TNF receptor linked to the Fc portion of IgGl), abciximab, afeliomomab, basiliximab, daclizumab, infliximab, ibritumomab tiuexetan, mitumomab, muromonab-CD3, iodine 131 tositumomab conjugate, olizumab, rituximab, and trastuzumab (herceptin), amifostine, amiodarone, aminoglutethimide, amsacrine, anagrelide, anastrozole, asparaginase, anthracyclines, bexarotene, bicalutamide, bleomycin, buserelin, busulfan, cabergoline, capecitabine
- exemplary biologically active agents are meant to encompass, where applicable, analogues, agonists, antagonists, inhibitors, isomers, and pharmaceutically acceptable salt forms thereof.
- the invention is intended to encompass synthetic, recombinant, native, glycosylated, non-glycosylated and biologically active fragments and analogs thereof.
- Drugs for which an immediate release into the bloodstream might be particularly desirable include those for use in the treatment of migraine, nausea, insomnia, allergic (including anaphylactic) reactions, neurological or psychiatric disorders (in particular panic attacks and other psychoses or neuroses), erectile dysfunction, diabetes and related disorders and cardiac disorders, anti-convulsants, bronchodilators and drugs for the alleviation of pain or inflammation.
- the active substance may comprise two or more substances formulated together, such as one coated with another, or one dispersed within a matrix of another, or a blend of two or more active substances.
- Common examples of such formulations include pharmaceutically active substances coated with excipients, or solid dispersions of pharmaceutically active substances with excipients, the excipient often being present to modify the release rate and/or to target delivery of the pharmaceutical.
- the active substances of the invention will exhibit the improved flocculation behaviour in the absence of excipients, ie, in the form of the active substance alone (for example in the form of pharmaceutically or nutraceutically active substance(s) without excipients).
- a third aspect of the present invention provides an active substance in particulate form, which is insoluble in the fluid vehicle 1,1,1,2-tetrafluoroethane (HFA 134a) and which when suspended in that vehicle at a concentration of from 0.2 to 5 % w/v exhibits a flocculation volume after 5 minutes which is at least 20 % higher, preferably at least 50 % or 150 % or 200 % or 250 % higher, than that exhibited by the same chemical entity having the same or a similar particle size (typically measured MMAD, "similar” here meaning within 80 to 120 %, preferably within 90 to 110 %, of the measured MMAD) but prepared using a micronisation process.
- HFA 134a 1,1,1,2-tetrafluoroethane
- a fourth aspect provides an active substance in particulate form, which is insoluble in the fluid vehicle 1,1,1,2,3,3,3-heptafluoropropane (HFA 227ea) and which when suspended in that vehicle at a concentration of from 0.2 to 5 % w/v exhibits a flocculation volume after 5 minutes which is at least 20 % higher, preferably at least 50 % or 150 % or 200 % or 250 % higher, than that exhibited by the same chemical entity having the same or a similar particle size (as described above) but prepared using a micronisation process.
- HFA 227ea 1,1,1,2,3,3,3-heptafluoropropane
- micronisation in this context is meant a process involving mechanical means, for instance milling or grinding, to reduce particle size to the micrometer range.
- the active substance preferably exhibits this flocculation behaviour after 6 minutes, more preferably after 8 minutes, still more preferably after 10 minutes, most preferably after 15, 30 or 60 minutes or in some cases after 2, 6, 12 or even 24 hours. It may exhibit this behaviour after only 4, 3, 2 or in some cases 1 minute.
- the flocculation volume is preferably measured at a concentration of above 0.5 % w/v, more preferably from 0.5 to 3 or 4 % w/v, most preferably from 0.5 to 1.5 or 2 % w/v or from 0.8 to 1.3 or 1.5 % w/v, such as 1 % w/v.
- the above described flocculation performance may also be exhibited at lower active substance concentrations, for instance down to 0.15 or even 0.1 % w/v.
- the active substance preferably exhibits this flocculation performance in other nonsolvent fluid vehicles, in particular hydrofluorocarbon propellants.
- a fifth aspect of the present invention provides an active substance in particulate form, which is insoluble in the fluid vehicle 1,1,1,2-tetrafluoroethane (HFA 134a) and which when suspended in that vehicle at a concentration of from 0.2 to 5 % w/v exhibits a rate of change (decrease) in flocculation volume, during the first 60 seconds after thorough mixing of the active substance and vehicle, of 20 % per minute or less.
- HFA 134a 1,1,1,2-tetrafluoroethane
- a sixth aspect provides an active substance in particulate form, which is insoluble in the fluid vehicle 1,1,1,2,3,3,3-heptafluoropropane (HFA 227ea) and which when suspended in that vehicle at a concentration of from 0.2 to 5 % w/v exhibits a rate of change (decrease) in flocculation volume, during the first 60 seconds after thorough mixing of the active substance and vehicle, of 20 % per minute or less.
- HFA 227ea 1,1,1,2,3,3,3-heptafluoropropane
- the rate of change in flocculation volume is preferably 15 % per minute or less, more preferably 10 % per minute or less, most preferably 5 or 3 % per minute or less. Preferably it is within the quoted ranges for the first 90 or 120 seconds after thorough mixing of the active substance and vehicle; certainly it is within those ranges during the first 30 seconds.
- Other preferred features of the active substances of the third to the sixth aspects of the invention, including the manner in which (and concentration at which) their flocculation volumes may be measured, may be as described for those of the first and second aspects.
- the active substances of the present invention can benefit from generally improved stability, in particular relative to their micronised equivalents, during medium to long term storage (for instance, for periods of a week or more, preferably a month or more, most preferably 3 or 6 or 12 or 18 or 24 or 30 or even 36 months or more). They appear to remain more homogeneously dispersed for longer periods of time.
- MMADs may vary by no more than 30 %, preferably no more than 20 % or 10 %, of the starting value during storage as a fluid suspension for a period of a week or more, preferably a month or more, most preferably 3 or 6 or 12 or 18 or 24 or 30 or even 36 months or more.
- the fluid in which, and concentration at which, they are suspended may be as described above in connection with the first to the sixth aspects of the invention; the fluid is preferably either HFA 134a, HFA 227ea or a mixture thereof.
- the active substances of the invention when used in aerosol formulations for use in inhalers (in particular MDIs), can give a more uniform dosing rate throughout the useable life of the inhaler. They can also provide, in this context, greater uniformity in the efficacy of the delivered drug throughout the inhaler life, particle size being relevant to bioavailability and to efficiency of delivery through the lung (in particular the deep lung).
- a typical aerosol canister for example as used in a metered dose inhaler, can often allow the ingress of atmospheric moisture through its delivery mechanism during medium to long term storage. This moisture can reduce the stability of the suspension inside the canister.
- the active substances of the present invention can be significantly more stable than for instance their micronised equivalents under such storage conditions, being less susceptible to particle growth and agglomeration even in the presence of moisture. It has been found that even amo ⁇ hous phase active substances according to the invention can be relatively stable under such conditions, despite the fact that moisture would normally be expected to induce re-crystallisation.
- the stability of the active substances of the invention is therefore of particular use in aerosol formulations in delivery devices such as inhalers, in particular metered dose inhalers.
- an active substance according to the invention is suspended in a fluid vehicle, suitably an aerosol propellant such as HFA 134a or HFA 227ea or a mixture thereof, and delivered in a succession of doses of equal volume using a metered dose inhaler or into a measuring device such as a multistage liquid impinger or more preferably a cascade impactor (eg, an AndersenTM or AndersenTM- type cascade impactor) :
- a cascade impactor eg, an AndersenTM or AndersenTM- type cascade impactor
- the relative standard deviation RSD ie, the standard deviation expressed as a percentage of the mean value
- the RSD is no more than 12 or 10 or 8 or 7 or 6 or 5 or 4 or even 3 %.
- the RSD in the fine particle content (the quantity of delivered active substance having a MMAD in the fine particle range, such as ⁇ 3.5 or 3.3 ⁇ m) of the delivered doses is preferably no more than 15 % over 3, more preferably over 5, most preferably over 10 or 30 or 50 or 70 or 100 or 150 or 200 successive doses. Yet more preferably, the RSD is no more than 9 or 8 or 7 or 6 or 5 or even 2 %.
- the RSD in the fine particle fraction contained in each dose is preferably no more than 17 % over 3, more preferably over 5, most preferably over 10 or 30 or 50 or 70 or 100 or 150 or 200 successive doses. Yet more preferably, the RSD is no more than 15 or 13 or 10 or 8 or 6 or 5 %.
- the RSD in the MMAD of the active substance particles contained in each dose is preferably no more than 9.5 % over 3, more preferably over 5, most preferably over 10 or 30 or 50 or 70 or 100 or 150 or 200 successive doses. Yet more preferably, the RSD is no more than 7 or 4 or 3 or 2 %.
- the fine particle fraction contained in each dose is preferably at least 25 %, more preferably at least 26 or 27 %, most preferably at least 30 or even 35 % over 3, more preferably over 5, most preferably over 10 or 30 or 50 or 70 or 100 or 150 or 200 successive doses.
- the MMAD of the particles delivered in each dose is preferably 4 ⁇ m or less, more preferably 3.8 or 3.5 ⁇ m or less, again suitably over 3, more preferably over 5, most preferably over 10 or 30 or 50 or 70 or 100 or 150 or 200 successive doses.
- the delivery or measuring device is ideally operated in the standard way, according to the manufacturer's instructions, which will typically for instance involve agitating the aerosol formulation before delivering each dose.
- Suitable measurement methods are those described in Examples 9 to 13 below, and typically involve the use of a cascade impactor such as an AndersenTM-type cascade impactor.
- a cascade impactor such as an AndersenTM-type cascade impactor.
- an aerosol can containing the formulation under test may be coupled to a cascade impactor via a standard adaptor and USP induction port ("throat"), and the contents of the can dispensed into the impactor via a conventional aerosol valve (typically crimped into the top of the can) and actuator.
- the relevant number of doses, over which the parameter in question is measured may be delivered over a period of up to 1, 3, 6, 12, 18, 24 or even 30 or 36 months, although under laboratory test conditions may be delivered over a period of for instance from 30 minutes to 12 hours, more typically from 30 minutes to 4 or 5 hours, most typically from 2 to 3 hours (eg, with an interval of from 15 to 120 seconds, preferably from 30 to 60 seconds, between doses).
- a suitable dose volume might be from 20 to 100 ⁇ l, more typically from 45 to 70 ⁇ l such as from 50 to 65 ⁇ l.
- Preferred features of the formulated suspensions, such as the vehicle type, the active substance concentration and the nature and quantity of additives (preferably none), may all be as described in connection with the first to the sixth aspects of " the invention.
- RSD values referred to in (a) to (d) above are typically lower than (preferably at least 5 % or 10 % or 20 % lower than) those obtained when a micronised form of the same chemical entity, having the same or a similar MMAD, is subjected to the same test(s). In each case, uniformity of dosing characteristics is expected to be improved over any given period of use by using an active substance in accordance with the invention.
- the active substances of the invention preferably exhibit the flocculation performance and/or stability described above when stored during the relevant measurement period, in suspension in a fluid vehicle (whether or not within a delivery device such as an inhaler), at ambient temperature (eg, from 18 to 25 °C, or from 20 to 23 °C, such as about 22 °C, or at the accepted industrial standard temperature of 25 °C). More preferably, they exhibit that behaviour and/or stability even if subjected during the measurement period to fluctuations of up to ⁇ 5 °C or ⁇ 10 or 15 °C.
- Measurements for example, of MMAD or fine particle fraction or dose content may be taken both before and after a period of storage under given conditions, or both before and after thermal cycling, and the recorded values and RSDs between the two measurements or sets of measurements are preferably as described under points (a) to (f) above.
- an active substance according to the present invention may be a pharmaceutically active substance or a pharmaceutically acceptable excipient (preferably a substance suitable for and/or intended for delivery by inhalation) other than salmeterol xinafoate (alone or coformulated with hydroxypropyl cellulose); ⁇ -lactose monohydrate; R-TEM ⁇ -lactamase; maltose; trehalose; sucrose; budesonide; salbutamol sulphate; nicotinic acid; paracetamol (alone or coformulated with salmeterol xinafoate, L-poly(lactic acid), ethyl cellulose (EC), hydroxypropyl methyl cellulose (HPMC) or poly vinyl pyrrolidone (PVP)); ibuprofen; ketoprofen (alone or coformulated with EC, HPMC or PVP); salicylic acid; either indomethacin, carbamazepine, theophylline, ascor
- particulate active substances which exhibit the improved flocculation behaviour described in connection with the first to the sixth aspects of this invention can be produced using the so-called SEDSTM ("Solution Enhanced Dispersion by Supercritical fluid") process (now known as the NektarTM SCF process), which is a version of the GAS process referred to above.
- SEDSTM Solution Enhanced Dispersion by Supercritical fluid
- NektarTM SCF process is a version of the GAS process referred to above.
- the NektarTM SCF process is a process for forming particles of a "target" substance. It is a GAS process and so involves contacting a solution or suspension of the target substance in a fluid vehicle (the “target solution/suspension") with a compressed fluid (generally a supercritical or near-critical fluid) anti-solvent under conditions which allow the anti-solvent to extract the vehicle from the target solution/suspension and to cause particles of the target substance to precipitate from it.
- the conditions are such that the fluid mixture formed between the anti-solvent and the extracted vehicle is still in a compressed (generally supercritical or near-critical) state.
- the anti-solvent fluid should be a nonsolvent for the target substance and be miscible with the fluid vehicle.
- Carrying out a SEDSTM process specifically involves using the anti-solvent fluid simultaneously both to extract the vehicle from, and to disperse, the target solution/suspension.
- the fluids are contacted with one another in such a manner that the mechanical (kinetic) energy of the anti-solvent can act to disperse the target solution/suspension at the same time as it extracts the vehicle.
- "Disperse” in this context refers generally to the transfer of kinetic energy from one fluid to another, usually implying the formation of droplets, or of other analogous fluid elements, of the fluid to which the kinetic energy is transferred.
- Suitable SEDSTM processes are described in WO-95/01221, WO-96/00610, WO-98/36825, WO- 99/44733, WO-99/59710, WO-01/03821, WO-01/15664, WO-02/38127 and WO-03/008082.
- the target solution suspension and the anti-solvent are preferably contacted with one another in the manner described in WO-95/01221 and/or WO-96/00610, being co-introduced into a particle formation vessel using a fluid inlet means which allows the mechanical energy (typically the shearing action) of the anti-solvent flow to facilitate intimate mixing and dispersion of the fluids at the point where they meet.
- the target solution/suspension and the anti-solvent preferably meet and enter the particle formation vessel at substantially the same point, for instance via separate passages of a multi-passage coaxial nozzle.
- the SEDSTM process may be of the type described in WO-03/008082, in which the anti-solvent velocity as it enters the particle formation vessel is near-sonic, sonic or supersonic and the target solution suspension and the anti-solvent enter the vessel at separate, although close, locations.
- Such a process is described for instance in Example la below, in connection with the preparation of sample B .
- a particulate active substance according to the present invention is preferably prepared using a GAS process, and more preferably using a SEDSTM process, such as one or a combination of those described in the above documents. Preferred features of the process may be as described below in connection with the seventh aspect of the invention.
- the active substance may thus be insoluble or only sparingly soluble in water. It is preferably insoluble or only sparingly soluble in compressed (eg, supercritical or near-critical) carbon dioxide.
- compressed (eg, supercritical or near-critical) carbon dioxide Such materials lend themselves particularly well to SEDSTM processing and indeed are often difficult to process using other parti ⁇ le formation techniques such as spray drying or freeze drying.
- SEDSTM can yield particulate products with controlled physicochemical characteristics such as particle size, size distribution and mo ⁇ hology, it has not previously been recognised that products of the SEDSTM process could exhibit such an improvement in flocculation performance compared to the corresponding substances produced by other particle formation techniques.
- SEDSTM is known to give the improved product properties described above, and in addition is a relatively efficient, safe, easily scaleable, controlled and reproducible process. It can be used to prepare a wide range of substances including water insoluble materials which cannot for instance easily be prepared by spray drying, materials which are insoluble in supercritical C0 2 which cannot easily be prepared by RESS, and temperature- or otherwise-sensitive materials for which other conventional particle formation processes might be inappropriate. SEDSTM can also yield products which are highly crystalline in nature, and/or high in purity (including polymo ⁇ hic purity) with low residual solvent content.
- a seventh aspect of the present invention provides the use of a SEDSTM process, as described above, to produce an active substance in particulate form, for the pu ⁇ ose of improving the flocculation performance of the substance.
- the process is preferably carried out using supercritical, near-critical or liquid, more preferably supercritical, C0 2 as the anti-solvent.
- supercritical, near-critical or liquid more preferably supercritical, C0 2 as the anti-solvent.
- the choice of operating conditions such as temperature, pressure and fluid flow rates, and the choice of solvent and of anti-solvent modifier if necessary, will depend on the nature of the active substance, for instance its solubility in the fluids present and, if it can exist in different polymo ⁇ hic forms, which form is to be precipitated.
- the conditions should be chosen to minimise particle sizes - this will usually mean selecting a higher relative anti-solvent flow rate (eg, a target solution/suspension : anti-solvent flow rate ratio (at or immediately prior to the two fluids coming into contact with one another) of 0.03 or less, preferably 0.02 or less or even 0.01 or less), and/or a higher operating temperature (eg, from 50 to 100 °C, preferably from 70 to 90 °C), and/or a higher operating pressure (eg, from 80 to 210 bar, preferably from 90 to 200 bar).
- a higher relative anti-solvent flow rate eg, a target solution/suspension : anti-solvent flow rate ratio (at or immediately prior to the two fluids coming into contact with one another) of 0.03 or less, preferably 0.02 or less or even 0.01 or less
- a higher operating temperature eg, from 50 to 100 °C, preferably from 70 to 90 °C
- a higher operating pressure eg, from 80 to 210
- the SEDSTM processing conditions are also preferably selected to reduce residual solvent levels and/or generally to increase the product purity (including if applicable its polymo ⁇ hic purity). They may be selected to increase the crystallinity of the product, in which case a lower relative anti-solvent flow rate may be preferred (for example, a target solution/suspension : anti-solvent flow rate ratio of 0.01 or greater, preferably 0.015 or 0.02 or greater) so as to slow down the solvent extraction process.
- the product of the seventh aspect of the invention is preferably a product according to one of the first to the sixth aspects.
- “Improving the flocculation performance” in this context means increasing the flocculation volume exhibited by the substance in the relevant vehicle at a given concentration after a given period of time. It may include improving the performance (in particular, the uniformity in performance and/or storage stability) of fluid suspensions of the active substance in delivery devices such as metered dose inhalers.
- the SEDSTM process is preferably used so as to achieve flocculation behaviour, and/or stability, and or performance in a delivery device, of the types described above in connection with the first, second, third, fourth, fifth and/or sixth aspects of the invention.
- Such changes in peformance and attributes may be as compared to those of the substance prior to the SEDSTM processing, and/or of the same substance (preferably having the same particle size or a particle size no more than 10 % or 20 % different) when produced using another particle formation process such as micronising or spray drying.
- Flocculation volume sometimes referred to as "sedimentation volume" can be measured by a conventional and relatively simple method.
- the substance under test in particulate form, is suspended in the desired fluid vehicle at a suitable concentration.
- the mixture should be well agitated (typically, simply by shaking) to ensure a uniform dispersion of particles in the fluid at the start of measurement. Immediately after agitation ceases, timing begins.
- the mixture is left to stand, usually under ambient conditions, and the degree of settling or creaming of the solid observed over time.
- the flocculation volume of the mixture at a given point in time is the volume of fluid which is still occupied by the particulate dispersion, expressed as a percentage of the total fluid volume. A higher flocculation volume thus indicates less settling/creaming, which indicates improved performance.
- the active substance should be insoluble in the chosen fluid vehicle, at least to an extent sufficient to allow suspension of the active substance as solid particles in the fluid.
- the solubility of the substance in the vehicle is preferably less than 10 "5 % w/v.
- surfactants and/or other dispersion enhancing or stabilising additives may be used in order to achieve sufficient dispersion at the start of the test - these include many systems in which the vehicle is water or another aqueous fluid.
- SEDSTM products have been found to exhibit the desired flocculation behaviour even in the absence of such additives, particularly in non-aqueous vehicles.
- an active substance for use in a method of surgery, therapy or diagnosis practised on a human or animal body, in which method the substance is delivered to a patient in suspension in a nonsolvent fluid vehicle in which the flocculation performance of the substance is as defined above in relation to any one of the first to the sixth aspects of the invention.
- a ninth aspect of the invention provides the use of an active substance in the manufacture of a medicament which comprises a suspension of that substance in a nonsolvent fluid vehicle, in which suspension the flocculation performance of the active substance is as defined above in relation to any one of the first to the sixth aspects of the invention.
- the medicament may be for use in a method of surgery, therapy or diagnosis practised on a human or animal body, and is preferably suitable for delivery by inhalation.
- a tenth aspect provides the use of an active substance according to any one of the first to the sixth aspects, in suspension in a nonsolvent fluid vehicle at a concentration of at least 0.2 % w/v, preferably at least 0.5 % w/v, and more preferably the suspension containing no, or less than 0.1 % w/w based on the weight of the active substance, preferably less than 0.01 % w/w or less than 0.001 or 0.0001 % w/w, dispersion enhancing or stabilising additives such as surfactants.
- the suspension preferably contains no cosolvents or lubricity enhancing additives.
- the active substance is preferably an active substance according to one of the first to the sixth aspects. It is preferably a pharmaceutically active substance, more preferably one which is suitable for delivery by inhalation.
- the medical method in which it may ultimately be used may involve the treatment of any of the conditions mentioned in connection with the active substances of the invention.
- the suspension is preferably an aerosol formulation in an aerosol propellant fluid, in particular in a hydrofluorocarbon propellant such as HFA 134a and/or HFA 227ea, and is preferably suitable for delivery to a patient by inhalation.
- a hydrofluorocarbon propellant such as HFA 134a and/or HFA 227ea
- An eleventh aspect of the invention provides a formulation, typically an aerosol formulation, containing an active substance according to any one of the first to the sixth aspects suspended in a nonsolvent fluid vehicle.
- the active substance is preferably a pharmaceutically active substance, although it may alternatively be a nutraceutical, a cosmetic or toiletry or any other active substance suitable for delivery in a nonsolvent propellant fluid.
- the fluid vehicle is preferably an aerosol propellant fluid such as those described above. It is preferably free of chlorofluorocarbon propellants, and more preferably comprises a hydrofluorocarbon propellant such as HFA 134a, HFA 227a, 1,1,2,2,3-pentafluoropropane or a mixture of any thereof.
- a hydrofluorocarbon propellant such as HFA 134a, HFA 227a, 1,1,2,2,3-pentafluoropropane or a mixture of any thereof.
- Other suitable vehicles include other Ci to C 4 hydrofluorocarbons such as CHF 2 CHF 2 , CF 3 CH 2 F, CHF 2 CH 3 and CF 3 CHFCF 3 , and perfluorocarbons such as CF 3 CF 3 and CF 3 CF 2 CF 3 .
- the vehicle is preferably of a pharmaceutically acceptable grade.
- the vehicle is HFA 134a, HFA 227a or a mixture thereof- such propellants are available, for instance, from DuPont Fluoroproducts, Wilmington, DE. It may be water or another aqueous fluid, although the active substance should be insoluble in the chosen vehicle at least to an extent sufficient to allow its suspension as solid particles.
- a fluid vehicle may comprise a mixture of two or more fluids.
- the mixture may be tailored for instance to minimise the difference in densities between the vehicle and the active substance and thus enhance the overall flocculation performance of the active substance.
- a mixture of the propellants HFA 134a and HFA 227a may be used to minimise the risk of either settling or "creaming" of a suspended active substance.
- the concentration of the active substance in the formulation may be 0.1 % w/v or greater, 0.2 % w/v or greater, or even 0.5 % w/v or 0.6 % w/v or 0.7 % w/v or 0.8 % w/v or 1 % w/v or greater, depending on the dosing level of the active substance. It is preferably from 0.1 or 0.2 to 5 % w/v, more preferably from 0.5 or 0.7 to 1.6 %w/v, most preferably from 0.5 or 0.7 to 1.5 or 1.3 or 1.1 or 0.9 % w/v, although it may be up to 3 % w/v. In cases, therefore, the present invention can allow relatively high concentration formulations to be prepared, of particular use for active substances which need to be delivered in high doses.
- the concentration of the active substance in the formulation may be as low as 0.05 or 0.02 % w/v.
- the active substance generally need not be surface modified (eg, by treatment with a nonsolvent such as a non-polar liquid) prior to inco ⁇ oration in the formulation.
- One or more surfactants, or other dispersion enhancing or stabilising additives may be included in the formulation, typical examples being nonionic surfactants such as those available in the TweenTM series.
- a lubricant may be included to prevent the active substance depositing on the internal surfaces of the aerosol can or other delivery device in which the formulation is to be used.
- the formulation consists essentially of only the active substance and the vehicle, with only low levels (for instance, less than 0.1 % w/w based on the weight of the active substance, preferably less than 0.01 % w/w or less than 0.001 or 0.0001 % w/w) of, or more preferably in the absence of, such additives.
- the formulation conveniently contains no, or only low levels (for instance, less than 0.01 % w/w based on the weight of the fluid vehicle, preferably less than 0.001 % w/w) of cosolvents, typical cosolvents being alcohols such as ethanol.
- the stability of the formulation is preferably as described above in connection with the first to the sixth aspects of the invention, as is its aerosol performance (in particular dosage uniformity) in use in a delivery device such as a metered dose inhaler or when assessed for instance using a cascade impactor.
- the formulation preferably comprises a fine particle fraction (as defined 5 above) of at least 25 %, more preferably at least 30 %, most preferably at least 35 %.
- formulations according to the present invention can be particularly efficient for delivering active substances to the central and in particular to the deep lung, and thus in turn for the systemic delivery of active substances via the lung.
- particles with MMAD from 4 to 6 ⁇ m, more specifically from 4.7 to 5.8 ⁇ m will reach the "central" lung area 10 (trachaea and primary bronchi) whereas only those with MMAD of 3.5, preferably 3.3 ⁇ m or less will penetrate the "deep" lung region (alveoli, and secondary and terminal bronchi).
- the stability of the invented formulations, with respect to flocculation and aggregation of the suspended active substance particles can allow them to deliver active substances having a high bioavailability and an efficient release profile.
- the active substance when a formulation according to the invention is delivered to a hve human or animal patient using a metered dose inhaler or an equivalent delivery device, the active substance may be released more rapidly into the patient's bloodstream, compared for instance to a micronised form of the same active substance (suitably having the same or a similar MMAD) delivered under the same test conditions.
- the bioavailability of the active substance (expressed for example as the
- 20 maximum, or as the total, plasma concentration attained following dose delivery may be higher than, preferably at least 1.5 or 1.8 or 2 or 2.5 times as high as, that of the micronised equivalent.
- active substances according to the invention may perform well in such tests whether with or without excipients such as the polymeric excipients (eg, polyvinyl pyrrolidones or polyethylene glycols) traditionally used to improve the bioavailability and/or release rate of for
- a formulation according to the invention may achieve a maximum concentration Cm ax of the active substance in the patient's bloodstream within one hour of administration (typically of inhalation), preferably within 30 minutes, more preferably within 15 minutes of administration. This time to achieve maximum concentration is referred to hereafter as
- the eleventh aspect of the invention may also encompass formulations in which Hie fluid (typically liquid) vehicle is other than an aerpsol propellant, for instance a liquid carrier for a pharmaceutically active substance intended for delivery by injection, orally or by any other suitable administration route.
- Hie fluid typically liquid
- vehicle may be organic or aqueous, it may comprise a mixture of two or more fluids, and it may include materials other than the active substance.
- a twelfth aspect of the present invention provides a drug delivery device, preferably an inhaler, which contains one or more dosage formulations of an active substance according to any one of the first to the sixth aspects, and preferably also a suitable fluid vehicle in which to aerosolise the substance.
- the delivery device may contain, or be able to produce, one or more aerosol formulations according to the eleventh aspect of the invention.
- the delivery device is preferably of the type designed to deliver a predetermined dose of an active substance in a pressurised fluid vehicle, for instance a metered dose inhaler (which term includes pressurised metered dose inhalers (pMDIs)).
- a thirteenth aspect of the invention provides an aerosol can containing an aerosol formulation according to the eleventh aspect of the invention, and which is suitable for use in a delivery device such as a MDI, preferably a device according to the twelfth aspect of the invention.
- the internal surfaces of the aerosol can ie, those surfaces which come into contact with the aerosol formulation during use
- the internal surfaces of the aerosol can ie, those surfaces which come into contact with the aerosol formulation during use
- the capacity of the aerosol can typically be from 10 to 20 ml. It may suitably be made from toughened glass or aluminium. It may comprise a conventional delivery mechanism, such as a metering valve of typical volume 25 to 100 ⁇ l, more typically from 45 to 70 ⁇ l, such as from 50 to 65 ⁇ l, together with a suitable valve actuator.
- a metering valve of typical volume 25 to 100 ⁇ l, more typically from 45 to 70 ⁇ l, such as from 50 to 65 ⁇ l, together with a suitable valve actuator.
- the invention provides a method for delivering an active substance, the method involving charging an aerosol can with an active substance and/or a formulation according to the invention. Subsequent delivery of the can contents may be via a delivery device such as a MDI.
- a fifteenth aspect provides a method of treatment of a human or animal patient, which method involves administering to the patient, preferably using a method according to the fourteenth aspect of the invention, an active substance and/or a formulation according to the invention.
- Both of these methods preferably involve the use of a drug delivery device such as an inhaler, more preferably a delivery device according to the twelfth aspect of the invention.
- the active substance preferably comprises a pharmaceutically active substance suitable for inhalation therapy.
- Figs 1 to 13 are graphs showing changes in flocculation volume with time for the samples tested in Examples 1 to 7 below.
- SEDSTM processes were used to produce a number of drugs in particulate form and their behaviour in typical MDI propellants was then examined.
- the system used to carry out the particle formation was of the general type shown schematically in Fig 1 of WO-95/01221.
- a two-passage coaxial nozzle (see Fig 3 of WO- 95/01221) was used to co-introduce into a 500 ml (except for Examples la) particle formation vessel (i) a solution of the drug in a solvent carrier and (ii) supercritical C0 2 as the anti-solvent.
- the anti-solvent extracted the carrier at the nozzle outlet causing particles to be precipitated.
- the temperature and pressure were controlled within the vessel to ensure the C0 2 remained in supercritical form throughout the process, even when mixed with the carrier.
- the particulate products were all fine, free flowing powders with smooth particle surfaces.
- Flocculation volumes were measured in the general manner described above. 0.4 g of the relevant sample was filled into a 100 ml glass aerospl bottle. The bottle was pressurised with 40 ml of the propellant fluid tp give a 1 % w/v dispersion and then shaken vigorously for 30 seconds to ensure complete dispersion of the powder. After agitation, the bottle was placed on a flat surface and the flocculation volume measured by eye every 15 seconds for the following 10 minutes. Measurements were taken at 22 °C.
- Salmeterol xinafoate (sample A) in its polymo ⁇ hic form I was precipitated from methanol (2 % w/v) using an operating temperature of 60 °C, an operating pressure of 100 bar, a nozzle with a 200 ⁇ m outlet diameter, a particle formation vessel with 50 ml capacity, a salmeterol solution flow rate of 0.4 ml/min and a C0 2 flow rate of 20 ml/min (note: all C0 2 flow rates were measured at the pump head).
- the product had a MMAD of 5.3 ⁇ m (AerosizerTM).
- a further sample (B) of salmeterol xinafoate form I was made by a modified SEDSTM process, as described in WO-03/008082, in which the salmeterol solution and C0 2 were introduced through an inlet tube and a pe ⁇ endicularly orientated nozzle (outlet diameter 200 ⁇ m) respectively, with a C0 2 flow rate sufficient for it to acquire a sonic velocity at the nozzle outlet.
- the salmeterol methanol solution concentration was 3 % w/v, the operating temperature 36 °C, the operating pressure 80 bar, the salmeterol solution flow rate 4 ml min and the C0 2 flow rate 158 ml/min.
- the C0 2 was pre-heated to 90 °C prior to entering the nozzle, to compensate for Joule-Thomson cooling on expansion of the fluid across the nozzle.
- the product had a MMAD of 1.6 ⁇ m (AerosizerTM).
- Example la The flocculation performance of the products of Example la (samples A and B) was tested in the propellants HFA 134a (less dense than salmeterol xinafoate) and HFA 227ea (more dense), in each case over a 10 minute period. Also tested, under the same conditions, was a sample C of salmeterol xinafoate form I (MMAD 1.1 ⁇ m by AerosizerTM) made by a standard micronisation process.
- HFA 134a less dense than salmeterol xinafoate
- HFA 227ea more dense
- Fig 1 shows the time variation in flocculation volume of the three samples in HFA 134a, expressed as a percentage of the initial volume.
- the performance of both SEDSTM produced samples ie, products according to the present invention was clearly superior to that of the micronised sample, which after 3 minutes had a flocculation volume below 40 % and after 10 minutes of only 30 %.
- the SEDSTM samples retained, even after 10 minutes, a flocculation volume of 90 % or greater, in the case of sample B greater than 98 %. Sample B was found to retain a flocculation volume of greater than 98 % even after 24 hours' standing.
- sample B the rate of change was -0.2 % per minute.
- the rate of change was -38 % per minute averaged over the first minute.
- Fig 2 shows how the same samples performed in HFA 227ea. Again the performance of the
- SEDSTM produced samples A and B was superior to that of the micronised sample C, which after 5 minutes had a flocculation volume below 35 %.
- the SEDSTM 1 samples retained a flocculation volume of greater than 40 % after 5 and even 10 minutes.
- Budesonide was precipitated from acetone (2 % w/v) at 70 °C and 100 bar.
- the budesonide solution flow rate was 12.6 ml/min and the C0 2 flow rate 833 mVmin.
- a nozzle with an 800 ⁇ m outlet was used.
- the product MMAD was 1.65 ⁇ m (AerosizerTM).
- Example 2a The flocculation performance of the product of Example 2a was compared, in the propellants HFA 134a (less dense than budesonide) and HFA 227ea (more dense), with that of a micronised budesonide sample (MMD 1.5 ⁇ m).
- Fig 3 shows the results in HFA 134a.
- the performance of the product of the invention was significantly better than that of the micronised sample, which after 2 minutes had a flocculation volume below 40 % and after 6 minutes of less than 30 %.
- the SEDSTM sample even after 10 minutes, still showed a flocculation volume of 80 %. Its rate of change in flocculation volume was -3.5 % per minute averaged over the first 2 minutes.
- the micronised sample exhibited a flocculation rate of -37 % per minute over the first minute.
- Fig 4 shows the results in HFA 227ea, demonstrating significantly higher flocculation volumes for the SEDSTM sample (greater than 50 % after 5 minutes and even after 10 minutes still greater than 40 %) as compared to the micronised one.
- the rate of change in flocculation volume for the SEDSTM sample was -13 % per minute over the first 2 minutes, and for the micronised sample -44 % per minute over the first minute.
- Fig 5 shows the changes in flocculation volume of the three samples over a 10 minute period, expressed as a percentage of the initial volume.
- micronised product despite being smaller in size than both the SEDSTM samples, still does not perform so well in the propellant.
- the rates of change in flocculation volume in HFA 134a were -20 % per minute for sample A and -1 % per minute for sample B, both averaged over the first 2 minutes.
- Sample D exhibited a flocculation rate of -68 % per minute over the first minute.
- Salbutamol sulphate was precipitated from methanol (1 % w/v), using dichloromethane (DCM) as an anti-solvent modifier.
- the operating temperature was 75 °C
- the salbutamol solution flow rate was 42 ml min
- the CO 2 flow rate 633 ml/min was 633 ml/min.
- the nozzle used had a 900 ⁇ m diameter outlet.
- the product was in the form of plate-like crystals with a MMD of 3.95 ⁇ m (SympatecTM).
- Example 4b -flocculation performance of salbutamol sulphate
- the product of Example 4a was compared, in the propellants HFA 134a (less dense than salbutamol sulphate) and HFA 227ea (more dense), with that of a micronised salbutamol sample of MMD 14.5 ⁇ m.
- Fig 7 shows the changes in flocculation volume of the two samples in HFA 134a, over a 10 minute period, expressed as a percentage of the initial volume.
- the product of the invention performed better than the micronised one, the latter having a flocculation volume of less than 20 % after only 2 minutes whereas the SEDSTM product retained a flocculation volume greater than 70 % over the 10 minute test period.
- the flocculation rates were -10 % per minute for the SEDSTM sample, averaged over the first 2 minutes, and -84 % per minute for the micronised sample, averaged over the first minute.
- Fig 8 shows the results in HFA 227ea, in which the micronised sample had a flocculation volume of less than 20 % after only 2 minutes whereas the SEDSTM product still had a flocculation volume of greater than 70 % after 8 minutes and greater than 60 % after 10 minutes.
- the flocculation rates were -5 % per minute for the SEDSTM sample, averaged over the first 2 minutes, and -55 % per minute for the micronised sample, averaged over the first minute.
- the polar drug dihydroergotamine mesylate (DHE) was precipitated from methanol (5 % w/v) at 50 °C and 100 bar.
- the DHE solution flow rate was 1 ml/min and the C0 2 flow rate 200 ml/min.
- the process used was the modified SEDSTM process used for salmeterol sample B in Example la, in which the C0 2 had a sonic velocity at the nozzle outlet and was pre-heated to 120 °C prior to entering the nozzle.
- the product had a MMAD of 1.25 ⁇ m (AerosizerTM) and comprised small plate-like crystals.
- Example 5a The flocculation behaviour of the product of Example 5a was tested in the propellant HFA 227ea, which is more dense than DHE. Also tested was the micronised DHE starting material, which had a MMD of 15.1 ⁇ m.
- Fig 9 shows the results for the two samples, the SEDSTM product clearly performing better than the micronised version. After 10 minutes, the SEDSTM product still exhibited a 100 % flocculation volume, whereas after only 1 minute the micronised sample had a flocculation volume of less than 20 % and after 5 minutes of less than 10 %. Even after 24 hours' standing, the SEDSTM sample still exhibited no visible creaming in the HFA 227ea.
- the flocculation rates were 0 % per minute for the SEDSTM sample, averaged over the first 2 minutes, and -90 % per minute for the micronised sample, averaged over the first minute.
- the polar drug risperidone-(9-hydroxy)-palmitate was precipitated from tetrahydrofuran (5 % w/v) at 80 bar.
- Two samples A and B were made using a modified SEDSTM process as for sample B of Example la (sonic velocity CO2; CO2 pre-heated to 90 °C; vessel temperature 36 °C); a third sample C was made using the process as for sample A of Example la, using an operating temperature of 41 ° C and a nozzle outlet diameter of 400 ⁇ m.
- the risperidone solution flow rate was 4 ml/min for sample A and 1 ml/min for samples B and C.
- the CO 2 flow rate was 200 ml/min in all experiments.
- the MMDs (SympatecTM) were 2.95 ⁇ m for sample A, 2.5 ⁇ m for sample B and 3.5 ⁇ m for sample C.
- Example 6a The products of Example 6a were compared with the starting material (MMD 8.1 ⁇ m) in both HFA 134a and HFA 227ea.
- Example 6a In HFA 134a (Fig 10), the Example 6a products clearly out-performed the starting material, having in the case of samples A and B a flocculation volume of 100 % even after 10 minutes. Sample C still had a flocculation volume of greater than 80 % after 10 minutes, compared to the starting material which after only 1 minute had a flocculation volume of less than 20 %.
- the flocculation rates were 0, 0 and -1 % per minute for samples A, B and C respectively, averaged over the first 2 minutes, and -152 % per minute for the micronised sample, averaged over the first minute.
- Compound I an anti-asthma drug, was precipitated from methanol at 80 °C and 200 bar, using a 400 ⁇ m outlet nozzle.
- Two samples A and B were made, using drug solution concentrations of 0.2 and 1.25 % w/v respectively.
- the drug solution flow rate was 10 ml/min and the C0 2 flow rate 100 ml min; for sample B the drug solution flow rate was 4.5 ml/min and the CO 2 flow rate 150 ml min. Needle-like crystals were obtained in both cases; their MMDs (SympatecTM) were 5.7 and 15.1 ⁇ m respectively.
- Example 7a The products of Example 7a were compared with a micronised sample of Compound I (MMD 3.4 ⁇ m) in both HFA 134a and HFA 227ea.
- Example 7a In HFA 134a (Fig 12), the Example 7a products both retained a flocculation volume of 100 % after 10 minutes, whereas the micronised material had a flocculation volume of less than 35 % after the same period.
- the flocculation rates were 0 % per minute for samples A and B, both averaged over the first 2 minutes, and -23 % per minute for the micronised sample, averaged over the first minute.
- Bromocriptine mesylate a polar drug used in the treatment of Parkinson's disease, was precipitated from ethanol (concentration 1.2 % w/v) using a modified SEDSTM process as for sample B of Example la (sonic velocity CO 2 ; CO 2 pre-heated to 90 °C).
- the operating pressure and temperature were 80 bar and 36 °C respectively.
- the drug solution flow rate was 1 ml min for sample A and 4 ml/min for sample B; in both cases the C0 2 flow rate was 200 ml/min.
- the nozzle had a 200 ⁇ m outlet diameter.
- Example B The flocculation performance of the crystalline product (sample B) of Example 8a was tested in both HFA 134a and HFA 227ea.
- HFA 134a the sample retained a flocculation volume of 53 % after 10 minutes. In HFA 227ea, it still had a flocculation volume of 95 % after 10 minutes.
- Crystalline DHE was prepared by the modified SEDSTM process used for salmeterol sample B in Example la.
- the drug was precipitated from a dimethyl formamide/water (9:1 v/v) mixture (5 % w/v) at 50 °C and 100 bar.
- the C0 2 had a sonic velocity at the nozzle outlet and was pre-heated to 112 °C prior to entering the nozzle.
- the nozzle had a 0.2 mm outlet diameter and the particle formation vessel a capacity of 2 litres.
- the C0 2 flow rate was 12 kg/hour, that for the DHE solution 1 ml min.
- the product had the form of thin plate-like particles.
- Aerosol formulations were then prepared in accordance with the invention by suspending the DHE in the propellant HFA 134a (DuPont Fluoroproducts, Wilmington, DE) in 18 ml aluminium pMDI aerosol canisters (Presspart, Cary, NC), at a drug concentration of 0.65 % w/w.
- the canisters were equipped with ValoisTM DF 30/63 RCU 63 ⁇ l metering valves (Valois Pharmaceuticals, Marly-le- Roi, France). (Note that in all aerosol performance tests, unless otherwise specified, active substance samples were stored, formulated and tested under ambient conditions.)
- Unit doses of these formulations were delivered into an AndersenTM cascade impactor fitted with a USP induction port and operated at 28.3 1/min. Their deposition profiles in the various stages of the impactor, and their MMADs, were measured at the beginning (after priming - 5 shots fired to waste) and end of the can life (approximately 100 shots), the aim being to assess the dose uniformity over that period. Standard experimental procedures USP ⁇ 601> and USP ⁇ 905> were followed for the cascade impactor and dose content uniformity tests; DHE levels were assessed by HPLC and reported as ex-valve. The interval between shots was at least 30 seconds, to prevent cooling of the aerosol can and consequent moisture condensation.
- the CI measurements and calculated values are shown in Table 2 for (a) the MMAD, (b) the fine particle dose (weight of delivered drug with MMAD ⁇ 3.3 ⁇ m) and (c) the fine particle fraction FPF (percentage of delivered drug particles with MMAD ⁇ 3.3 ⁇ m).
- the "% difference” is the difference between the start and end of test values expressed as a percentage of the mean.
- Dose content uniformity was assessed using a Thiel apparatus following the USP method. Again three cans were tested. Measurements for total DHE content in the delivered dose were taken at the start, middle and end of the delivery period, corresponding approximately (after valve priming) to delivered doses 1, 50 and 100. Two priming shots were fired immediately prior to collection of an analytical shot. Mean and % RSD values were calculated across these three measurements, for each can.
- the stability of aerosol formulations according to the invention was assessed using a thermal cycling treatment designed to simulate a longer term storage period under ambient conditions.
- Crystalline samples of the drug DHE prepared as described in Examples 9 (VMD 2.8 ⁇ m by SympatecTM; bulk powder density 0.14 g/ml), were suspended in HFA 134a in standard pMDI aerosol canisters, as in Examples 9 and 10.
- Two formulations were prepared, 11A having a DHE concentration of 8 mg/ml and 1 IB a DHE concentration of 16 mg/ml.
- the canisters were subjected to temperature cycling consisting of three 3 or 4 hour cycles between -20 °C and 40 °C for four weeks. Two samples were removed at each of the 1, 2 and 4 week timepoints, and tested for particle size distribution (AndersenTM cascade impaction (ACI), beginning of can life). Dose content uniformity (beginning, middle and end of can life) was assessed at the 1 and 4 week timepoints. The methodology was as in Examples 9. Three samples were also tested pre-thermal cycling (time zero); here particle sizes were assessed at both the beginning and end (100 th shot after priming) of the can Ufe to obtain an average MMAD for all 6 measurements.
- the particle size (ACI) results are shown in Table 6 for formulation 11A and in Table 7 for formulation 1 IB.
- the fine particle fraction FPF is again the fraction having MMAD ⁇ 3.3 ⁇ m.
- the high crystallinity of the DHE of the invention contributes to its improved stability in aerosol formulations.
- Amo ⁇ hous phase regions have a greater tendency to dissolve in a propellant fluid over time, particularly if (as often happens) atmospheric moisture enters the aerosol canister through the valve mechanism. Following this dissolution, the active substance can then re-crystallise around the still suspended particles, leading to particle growth and/or aggregation and a resultant change in the MMAD as well as in the ultimate aerosol performance.
- the DHE formulations of the invention appear to have a high degree of stability in this respect, even under conditions representing extended storage periods.
- Aerosol formulations 12A and 12B containing the bromocriptine samples A and B respectively suspended in HFA 227ea, were prepared in 19 ml aluminium aerosol canisters (Presspart Inc, Gary, NC) equipped with 50 ⁇ l metering valves (Valois Pharmaceuticals, Marly-le-Roi, France). The suspension concentrations were 0.7 % w/w for formulation 12A and 0.69 % w/w for 12B.
- a control formulation 12C was prepared containing 0.74 % w/w micronised bromocriptine. In each case the powder was dispersed in the propellant by first sonicating the canisters for 10-15 seconds in a bath sonicator and then placing them on a wrist-action shaker for about 30 minutes. Each canister was then primed by wasting the first 5 shots.
- the formulations were tested on an AndersenTM cascade impactor to determine their aerodynamic particle properties.
- the cascade impactor was operated at 28.3 1/min and fitted with a USP induction port ( ⁇ USP 601> Pharmacopeial Previews 22, 3065 (1995)).
- USP 601> Pharmacopeial Previews 22, 3065 (1995) The particle size distributions were fractionated into mass of drug deposited on the pMDI actuator, USP induction port, eight stages and terminal filter. Five shots were actuated per test, with an interval of at least 30 seconds between shots to prevent cooling of the can and resultant moisture condensation!
- the bromocriptine content in each sample was determined by HPLC.
- the percentage of the total dose deposited from stage 4 to the terminal filter (corresponding to particles of MMAD less than 3.3 ⁇ m) was considered to be the fine particle fraction.
- Table 11 shows the mean dose contents across three aerosol cans for each formulation, determined at the start, middle and end of the can life. Also shown is the overall mean dose content for each formulation, together with the calculated % RSD which gives an indication of the variation in dose content through the can life. Again all measurements (apart from the RSD percentages) are in ⁇ g of delivered drug.
- the data for formulations 12A and 12B show good uniformity in dose content over the test period, in particular compared to formulation 12C containing the micronised drug.
- the active substance is present in the amo ⁇ hous phase, it appears to have extremely good suspension stability in HFA 227ea, which in turn indicates improved stability against re-crystallisation - this is thought to be due to increased purity, and in particular to reduced residual solvent levels, when an active substance is prepared in accordance with the invention as opposed to by a conventional route such as crystallisation followed by micronisation.
Abstract
Description
Claims
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AU2003229913A AU2003229913B2 (en) | 2002-04-17 | 2003-04-15 | Aerosol containing a particulate active substance |
CA2482499A CA2482499C (en) | 2002-04-17 | 2003-04-15 | Aerosol containing a particulate active substance |
MXPA04010018A MXPA04010018A (en) | 2002-04-17 | 2003-04-15 | Aerosol containing a particulate active substance. |
JP2003585697A JP2005529115A (en) | 2002-04-17 | 2003-04-15 | Aerosols containing particulate active substances |
SI200332518A SI1496857T1 (en) | 2002-04-17 | 2003-04-15 | Aerosol containing a particulate active substance |
EP03722750.1A EP1496857B1 (en) | 2002-04-17 | 2003-04-15 | Aerosol containing a particulate active substance |
DK03722750.1T DK1496857T3 (en) | 2002-04-17 | 2003-04-15 | AEROSOL CONTAINING A PARTICULAR ACTIVE CONNECTION |
ES03722750.1T ES2619573T3 (en) | 2002-04-17 | 2003-04-15 | AEROSOL CONTAINING AN ACTIVE SUBSTANCE IN THE FORM OF PARTICLES |
CY20171100362T CY1119242T1 (en) | 2002-04-17 | 2017-03-22 | AEROLA Contains A Particulate Active Substance |
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- 2003-04-15 ES ES03722750.1T patent/ES2619573T3/en not_active Expired - Lifetime
- 2003-04-15 EP EP03722750.1A patent/EP1496857B1/en not_active Expired - Lifetime
- 2003-04-15 WO PCT/GB2003/001665 patent/WO2003088945A1/en active Application Filing
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- 2003-04-15 DK DK03722750.1T patent/DK1496857T3/en active
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2004
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2009
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2011
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2013
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2014
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