WO2003090715A2 - Materiaux particulaires - Google Patents

Materiaux particulaires Download PDF

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Publication number
WO2003090715A2
WO2003090715A2 PCT/GB2003/001747 GB0301747W WO03090715A2 WO 2003090715 A2 WO2003090715 A2 WO 2003090715A2 GB 0301747 W GB0301747 W GB 0301747W WO 03090715 A2 WO03090715 A2 WO 03090715A2
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WIPO (PCT)
Prior art keywords
active substance
substance according
seds
particles
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Prior art date
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PCT/GB2003/001747
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English (en)
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WO2003090715A3 (fr
Inventor
Peter York
Boris Yu Shekunov
Mahboob Ur Rehman
Jane Catherine Feeley
Original Assignee
Nektar Therapeutics Uk Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Priority claimed from GB0209402A external-priority patent/GB0209402D0/en
Priority claimed from GB0210268A external-priority patent/GB0210268D0/en
Priority claimed from GB0211086A external-priority patent/GB0211086D0/en
Priority claimed from GBGB0216562.9A external-priority patent/GB0216562D0/en
Application filed by Nektar Therapeutics Uk Ltd filed Critical Nektar Therapeutics Uk Ltd
Priority to AU2003226567A priority Critical patent/AU2003226567A1/en
Priority to EP03747172A priority patent/EP1501483A2/fr
Priority to CA2483218A priority patent/CA2483218C/fr
Publication of WO2003090715A2 publication Critical patent/WO2003090715A2/fr
Publication of WO2003090715A3 publication Critical patent/WO2003090715A3/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
    • A61K9/0012—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
    • A61K9/14—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
    • A61K9/1682—Processes
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61K9/0043—Nose

Definitions

  • the present invention relates to active substances in particulate form, to methods for preparing them and to their uses.
  • 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.
  • Pulmonary delivery by aerosol inhalation has received much attention as an attractive alternative to intravenous, intramuscular, and subcutaneous injection, since this approach eliminates the necessity for injection syringes and needles.
  • Pulmonary delivery also limits irritation to the skin and body mucosa which are common side effects of transdermally, iontophoretically and intranasally delivered drugs, eliminates the need for nasal and skin penetration enhancers (typical components of intranasal and transdermal systems often cause skin irritation/dermatitis), is economically attractive, is amenable to patient self-administration and is often preferred by patients over alternative modes of administration.
  • pulmonary delivery techniques which rely on the inhalation of a pharmaceutical formulation by a patient so that the active drug within the dispersion can reach the distal (alveolar) regions of the lung.
  • aerosolization systems have been proposed to disperse pharmaceutical formulations.
  • US patents nos. 5,785,049 and 5,740,794 the disclosures of which are herein incorporated by reference, describe exemplary active powder dispersion devices which utilize a compressed gas to aerosolize a powder.
  • Other types of aerosolization systems include metered dose inhalers (MDIs), which typically have a drug that is stored in a propellant, and nebulizers (which aerosolize liquids using a compressed gas, usually air).
  • MDIs metered dose inhalers
  • nebulizers which aerosolize liquids using a compressed gas, usually air.
  • DPI dry powder inhaler
  • a dry powder inhaler delivers the drug (or a composition containing the drug, for instance together with a pharmaceutically acceptable excipient) in the form of a dry air-borne particulate powder.
  • DPIs include single use inhalers such as those disclosed in US patents nos. 4,069,819, 4,995,385, 3,991,761 and 6,230,707, and in WO-99/45986, WO-99/45987, WO-97/27892 and GB-1 122 284; multi-single dose inhalers such as those disclosed in US patents nos. 6,032,666 and 5,873,360 and in WO-97/25086; and multi-dose inhalers containing powder ui a bulk powder reservoir such as those disclosed in US patent no. 4,524,769.
  • 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. Set., 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, ACS Symp. Ser., 406, p334 (1989).
  • RESS Rapid Expansion of Supercritical Solution - see Tom & Debenedetti, J Aerosol. Set., 22 (5), 555-584 (1991)
  • GAS Gas
  • inhalable drugs can often yield particles which give less than satisfactory performance in DPI and similar delivery devices.
  • dispersion of many prior art dry powder formulations from inhalation devices exhibits a flow rate dependence such that dispersion of the powder from the device increases with the patient's inspiratory effort.
  • many formulations require mixing or blending with larger carrier particles such as lactose in order to deliver the particles effectively to the deep lung.
  • particulate drugs and indeed other active substances which may need to be delivered as dry (ie, without a fluid carrier) powders using a DPI or analogous mechanism, which can demonstrate improved performance in such a context, in particular improved dispersibility and aerosol performance in fluids and especially in gases such as air.
  • the present invention provides particulate powders, such as might be of use for delivery using a DPI or similar delivery device, having properties which may be beneficial to the DPI delivery process. These properties are illustrated in the examples below.
  • the present invention can provide an active substance in particulate form, preferably prepared using a SEDSTM particle formation process as defined below, which exhibits one or more (preferably two or more, more preferably at least three) of the following characteristics:
  • the particles have a low surface energy.
  • they preferably exhibit a low value for the surface energy related parameter ⁇ s D (the dispersive component of surface free energy, as defined in the examples below, which reflects non-polar surface interactions) and/or for the parameter ⁇ G A
  • the specific component of surface free energy of adsorption again as defined in the examples, which reflects polar surface interactions
  • the value for the active substance of the present invention is preferably lower by a factor of at least 1.2, preferably at least 1.4 or 1.5, than that for the corresponding non-SEDSTM-produced substance.
  • the particles exhibit a low surface adhesion and/or cohesiveness (which may be related to their surface energy). , In particular, they may exhibit lower adhesiveness than those of the same active substance produced by a non-SEDSTM particle formation process.
  • the particles show little or no tendency for aggregation (again this may be related to their surface properties such as surface energy and adhesiveness), or at least form less stable aggregates than those of the same active substance produced by a non-SEDSTM particle formation process.
  • the particles have a volume mean aerodynamic diameter of 7 ⁇ m or less, preferably 5 ⁇ m or less, more preferably 4 ⁇ m or 3 ⁇ m or less, such as from 1 to 5 ⁇ m, from 1 to 4 ⁇ m or from 1 to 2 ⁇ m.
  • the particles have a volume mean geometric diameter of 5 ⁇ m or less, preferably 4 ⁇ m or less, more preferably from 1 to 5 ⁇ m, most preferably from 1 to 4 or from 2 to 4 ⁇ m.
  • the particles have a particle size distribution (x 90 ) of 10 ⁇ m or less, preferably also a value for .
  • each of these values will be from 0.5 to 10 ⁇ m.
  • the particles when measured using a cascade impactor technique (at low turbulence), the particles have a particle size spread, defined as (x go - io) / *so, of 1.3 or less, preferably of 1.25 or 1.2 or less, and/or a volume mean diameter of 6 ⁇ m or less, preferably of 5.5 ⁇ m or less, more preferably of 5.2 ⁇ m or less.
  • Their particle size spread under these conditions is preferably at least 5 %, more preferably at least 10 %, still more preferably at least 12 %, smaller than that of the same active substance produced by a non-SEDSTM particle formation process, and their volume mean diameter preferably at least 10 %, more preferably at least 15 %, still more preferably at least 20 %, smaller than that of the non-SEDSTM substance.
  • the particles are crystalline, or substantially so, and in particular are more crystalline than those of the same active substance produced by a non-SEDSTM particle formation process.
  • Their X- ray diffraction patterns thus preferably exhibit reduced diffraction line broadening and/or a higher signal-to-noise ratio than the X-ray diffraction patterns for the same active substance produced by a non-SEDSTM process.
  • the crystalline particles may exhibit reduced crystal lattice imperfections such as strain defects (point defects and/or dislocations) and/or size effects (grains, small-angle boundaries and/or stacking faults), as compared to crystals of the same active substance produced by a non- SEDSTM process - such imperfections tend to be associated with increased line broadening in the X- ray diffraction patterns.
  • the particles may exhibit a lower crystal strain, and/or a higher crystal domain size, than crystals of the same active substance produced by a non-SEDSTM particle formation process.
  • the active substance is capable of existing in two or more different polymorphic forms, the particles consist 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 polymorphic forms. More preferably, the active substance has a higher activation energy for conversion to one or more other polymorphic forms than does a sample of the same active substance prepared using a non-SEDSTM particle formation process.
  • the particles have a lower surface charge (for instance, mean specific charge) than those of the same active substance produced by a non-SEDSTM particle formation process.
  • the particles exhibit superior powder flow properties (which may be related to lower surface charge and/or adhesiveness) as compared to those of the same active substance produced by a non- SEDSTM particle formation process; for instance, they may be more free-flowing and/or they may deaggregate more efficiently when dispersed in a fluid such as in a DPI device, particularly at low turbulence and/or shear stress levels.
  • the particles have a bulk powder density which is lower than that of the same active substance produced by a non-SEDSTM particle formation process. They preferably have a bulk powder density of less than 0.5 g cm 3 , more preferably of 0.4 g/cm 3 or less, most preferably of 0.2 g/cm 3 or less.
  • the particles have a specific surface area which is higher than that of the same active substance produced by a non-SEDSTM particle formation process.
  • the "shape factor" of the particles by which is meant the ratio of (a) their measured specific surface area (ie, surface area per unit volume) to (b) their theoretical specific surface area as calculated from their measured diameters assuming spherical particles, is higher than that of the same active substance produced by a non-SEDSTM particle formation process.
  • this shape factor is at least 2, more preferably at least 3, most preferably at least 3.5.
  • the "shape coefficient" ⁇ s ,v of the particles determined from image (eg, SEM) analysis and as defined in the following equation:
  • this shape coefficient is higher than that of the same active substance produced by a non-SEDSTM particle formation process, preferably at least 1.5 times as great, more preferably at least twice as great.
  • this shape coefficient is at least 10, more preferably at least 15, most preferably at least 18 or at least 20. It may alternatively be calculated from specific surface area measurements, laser diffraction particle size measurements and the theoretical crystal density, as defined in the following equation :
  • the "aerodynamic shape factor" of the particles, ⁇ is greater than that for the same active substance produced by a non-SEDSTM particle formation process, preferably at least 20 % greater, more preferably at least 30 % or at least 40 % greater, ⁇ is the ratio of the drag force on a. particle to the drag force on the particle volume-equivalent sphere at the same velocity, and may be calculated as described in the following equation:
  • a product according to the invention may be 1.4 or greater, preferably 1.5 or greater, most preferably 1.7 or 1.8 or greater.
  • the particles have reduced surface roughness compared to those of the same active substance produced by a non-SEDSTM particle formation process.
  • non-SEDSTM particle formation process is meant a particle formation process other than the SEDSTM process defined below, for example one involving micronisation, granulation and/or solvent crystallisation under sub-critical conditions, and in particular one involving micronisation.
  • comparisons between substances according to the invention and those made by non-SEDSTM techniques are suitably made using in each case particles of the same or a comparable size (eg, no more than 30 % or even than 20 % different in size) and/or shape.
  • Fig. 1 depicts the percentage dissolution against time for particles processed according to the invention compared to micronised.
  • Fig. 2 depicts an AFM analysis of material process according to this invention.
  • Fig. 3 is a graph showing RMS surface roughness data for materials processed according to the invention.
  • Fig. 4 is a schematic of the SEDS process.
  • Figs. 5 a-f are SEMs of particles produces according to the invention.
  • Figs. 6 a - c depict X-ray powder patterns illustrating the crystallinity of micronised and samples produced according to the invention.
  • Fig. 7 depicts the heat flow ( ⁇ W) for both micronised and SEDSTM powders of terbutaline sulphate.
  • Fig. 8 depicts the strange attractor plots for terbutaline supphate analysed at high (100 seconds per revolution) rotation speed.
  • Fig. 9 depicts the strange attractor plots for TBS analysed at medium (145 seconds per revolution) rotation speed.
  • Fig. 10 and 11 compare the in vitro performance of micronised and SEDSTM processed terbutaline sulphate analysed in a lactose blend as well as pure drug alone.
  • particulate active substances having one or more of the above properties tend to exhibit improved performance, in particular good dispersibility- in delivery devices such as inhalers, especially dry powder inhalers and more especially passive dry powder inhalers.
  • improved performance in particular good dispersibility- in delivery devices such as inhalers, especially dry powder inhalers and more especially passive dry powder inhalers.
  • lower particle surface energy and improved DPI performance lower strain, higher crystallinity and higher polymorphic purity have been associated with reduced agglomeration and particle adhesion, and with lower electrostatic charge, again properties which lead to improved DPI performance.
  • Higher specific surface areas, and higher shape factors have also been found to accompany improved DPI performance.
  • products according to the invention can demonstrate significantly better performance in passive dry powder inhalers than products made by conventional techniques such as spray drying, freeze drying, granulation and in particular micronisation.
  • the active substance of the invention when used in a passive dry powder inhaler or analogous delivery device (for example the commercially available ClickhalerTM), preferably yields a fine particle fraction in the emitted dose of 20 % or greater, preferably 26 % or greater, more preferably 31 % or greater, in cases 35 % or 40 % or 50 % or even 55 % or greater.
  • its fine particle fraction may be at least 20 % greater, preferably at least 25 % or 30 % or 40 % or 50 % or 60 % or 80 % or 100 % greater, more preferably at least 110 % or 120 % or 130 % or 140 % greater, than that of the same active substance produced by a non-SEDSTM particle formation process and having the same or a smaller volume mean diameter.
  • the active substance is preferably in a substantially (eg, 95 % w/w, preferably 98 % or 99 % 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). In particular residual solvent levels in the bulk particles, as opposed to merely at their surfaces, are likely to be lower than in particles of the same active substance produced by a non-SEDSTM process.
  • the fine particle fraction yielded by an active substance according to the invention may be up to 150 % or 175 % or even 200 % or 250 % or 280 % of that of the same active substance produced by a non-SEDSTM process.
  • Such improvements may often be exhibited even if the particle size of the substance of the invention is significantly greater (eg, at least 30 % or, 50 % or 75 % or 90 % greater) than that of the non-SEDSTM-produced substance. They can also be exhibited in the absence of dispersion enhancing additives such as surfactants, in the absence of excipient/carrier materials and/or in unimodal (with respect to particle size) systems.
  • Particular improvements (with respect to substances made by non-SEDSTM processes) may be seen where the active substance is used alone as opposed to in a blend with an excipient such as lactose.
  • the total emitted dose for a substance according to the invention may also, in this context, be at least 10 % greater, preferably at least 15 % greater, more preferably at least 20 % or 25 % or 30 % greater, than that for the same active substance made by a non-SEDSTM process, either with or without excipient(s).
  • the substances of the invention may deposit on the impactor stages with a narrower distribution (typically weighted more to the lower stages such as 1 to 3) than for those made by non-SEDSTM processes.
  • an active substance according to the invention At relatively low dispersing pressures, for instance 2 bar or less, an active substance according to the invention has been found capable of yielding a significantly higher proportion of primary particles in the respirable size range than the same active substance produced by a non-SEDSTM process, the latter often tending to form stable (ie, not dispersible at these pressures) agglomerates above the preferred 5 ⁇ m limit. This again indicates reduced particle cohesiveness and/or reduced inter-particulate contact area in an active substance according to the invention.
  • the volume mean particle diameter d 4 .
  • 3 of the particles of the invention may thus appear larger than that for non-SEDSTM-produced particles when dispersed at pressures of 2 bar and above, but smaller at pressures below 2 bar,, for instance 1.8 bar or below, where the dispersion (or deaggregation) ability of the particles plays a more dominant role.
  • particles according to the invention exhibit volume mean diameters lower than those of their non-SEDSTM equivalents at lower viscous shear stresses, for instance below 20 Nm '2 or even up to 30 or 40 Nm "2 .
  • particles according to the invention appear to undergo significantly less aggregation, or to form significantly less stable aggregates, than those produced by a non-SEDSTM process which may produce stable aggregates well outside the 5 ⁇ m respirable limit.
  • the particles of the invention, at these shear stress levels can produce a large fraction of primary particles in the respiratory size range, preferably having a volume mean diameter of less than 6 or more preferably less than 5 ⁇ m.
  • the volume mean particle diameter of an active substance according to the invention may be at least 10 % smaller, preferably at least 15 % or at least 20 % smaller, than that of the same active substance produced by a non-SEDSTM particle formation technique, even where its volume mean diameter measured at higher dispersions using another technique such as laser diffraction or time-of-flight is greater than (for instance, up to 30 % or 50 % or even 100 % greater than) that of the non-SEDSTM substance.
  • another technique such as laser diffraction or time-of-flight is greater than (for instance, up to 30 % or 50 % or even 100 % greater than) that of the non-SEDSTM substance.
  • particulate active substances of the present invention may be particularly advantageous for use with passive dry powder inhalers which operate in the lower region of turbulent stresses when dispersing the powder they contain.
  • a passive dry powder inhaler is a device for use in delivering a powdered active substance to a patient, in which the patient's inspiratory effort is used as the sole powder dispersing means.
  • the powder is not delivered in a pressurised fluid as in many metered dose inhalers, and nor does its delivery require the use of a rotating impeller or other mechanical means.
  • a second aspect of the present invention provides a method for selecting a particulate active substance for use in a dry powder inhaler, in particular a passive dry powder inhaler, which method involves the assessment of, and selection on the basis of, one or more (preferably two or more, more preferably three or more) of the above described properties of active substances according to the first aspect of the invention.
  • a third aspect provides the use of an active substance according to the first aspect, in a dry powder inhaler and in particular in a passive dry powder inhaler, for the purpose of achieving improved active substance delivery.
  • Improved delivery in this context may involve improved powder dispersion, more accurate dosage delivery, more consistent dosage delivery and/or a higher fine particle fraction in the emitted dose, in particular at relatively low dispersing pressures such as 2 bar or less or 1.8 bar or less.
  • Particle surface energies may be measured using inverse gas chromatography (IGC), for instance using a gas chromatograph from the Hewlett PackardTM series.
  • IQC inverse gas chromatography
  • Surface energy measurements ideally take account of the dispersive component of the surface free energy, ⁇ s D , the specific component of the surface free energy of adsorption, ⁇ G A , the acid-base parameters and or the total (Hildebrand) solubility parameter, which takes into account dispersive, polar and hydrogen-bonding interactions on particle surfaces and thus reflects the inter-particle adhesion.
  • the dispersive component ⁇ s D may be assessed using non-polar probes such as alkanes, and the specific component ⁇ G A may be assessed using data from both polar and non-polar probes, the former having both dispersive and specific components of surface free energy of adsorption.
  • gas chromatography measurements suitably involve the use of both non-polar and polar probes, examples of the former being alkanes such as pentane, hexane, heptane, octane and nonane and of the latter being diethyl ether, toluene, acetone, ethyl acetate, chloroform, dioxane, dichloromethane and tetrahydrofuran.
  • the value for the active substance of the present invention is preferably at least 5 % lower, more preferably at least 10 % lower, most preferably at least 12 % or 15 % or 20 % or 30 % lower, than that for the same active substance made by a non-SEDSTM particle formation process.
  • the value for the active substance of the present invention is preferably at least 10 % lower, more preferably at least 15 % lower, most preferably at least 20 % or 30 % or 50 % or 80 % lower, than that for the same active substance made by a non-SEDSTM particle formation process.
  • the value for the active substance of the present invention is preferably at least 5 % lower, more preferably at least 8 % lower, most preferably at least 10 % lower, than that for the same active substance made by a non-SEDSTM particle formation process.
  • particulate active substances according to the present invention tend to have lower surface activity (for example with respect to solvent adsorption) and greater surface stability than those produced by non-SEDSTM particle formation processes, with a more ordered surface structure.
  • Their lower surface energy may be manifested by a lower value for K A and/or K D , for instance as measured in Example 2, indicative of weaker acidic and/or basic interactions respectively at the particle surfaces.
  • K A may be at least 5 %, preferably at least 10 % or at least 12 %, lower than that of the same active substance made by a non-SEDSTM particle formation process
  • K D may be at least 30 %, preferably at least 50 % or at least 60 % lower.
  • ⁇ is the Hildebrand solubility parameter
  • ⁇ s, v is the shape coefficient
  • ⁇ is the molecular volume is preferably at least 10 %, more preferably at least 20 %, still more preferably at least 30 % or 40 %, lower than that of the same active substance produced by a non-SEDSTM particle formation process, and might typically be 100 mJ/m 2 or lower, more preferably 90 or 80 or 70 mJ/m 2 or lower.
  • a lower aggregation tendency in particles according to the invention may be reflected in a lower theoretical aggregate tensile strength ⁇ , which may be calculated as described in the following equation:
  • the ratio of ⁇ for particles of the invention to that for particles of the same active substance produced by a non-SEDSTM process is 0.8 or lower, more preferably 0.5 or lower, most preferably 0.3 or 0.2 or 0.1 or lower, especially when polar interactions are taken into account.
  • the aerodynamic stress required to disperse aggregates of particles according to the invention is typically lower than that required to disperse aggregates of the same active substance prepared by a non-SEDSTM particle formation process.
  • the ratio of the two stresses (SEDSTM product : non-SEDSTM product) is 0.8 or lower, more preferably 0.5 or lower, most preferably 0.3 or 0.2 or lower. Inter-particle aggregation can be particularly relevant to DPI performance since such aggregates tend to survive the pre-separation stage.
  • Aggregation tendencies can also be relevant when an active substance is blended with a carrier such as lactose, where dispersion may depend on the break-up of active-carrier aggregates - again, typically, substances according to the invention may tend to form less stable aggregates with carrier particles.
  • a carrier such as lactose
  • Particle sizes may be measured for instance using (a) an AeroSizerTM time-of-flight instrument (which gives a mass mean aerodynamic equivalent particle diameter, MMAD, measured at Reynolds numbers greater than 1) or (b) a laser diffraction sensor such as the HelosTM system (which provides a geometric projection equivalent mass median diameter). Volume mean aerodynamic and geometric diameters respectively may be obtained from these measurements using commercially available software packages.
  • the aerodynamic diameter d. of a particulate active substance according to the invention is preferably 2 ⁇ m or below, more preferably 1.8 ⁇ m or below, most preferably 1.6 ⁇ m or below.
  • Particle size distributions may be measured using laser diffraction and or time-of-flight measurements, for instance using an AeroSizerTM time-of-flight instrument equipped with an AeroDisperserTM (TSI Inc, Minneapolis, USA) and/or a HelosTM laser diffraction sensor with RodosTM dry powder air dispersion system (Sympatec GmbH, Germany). Volume particle size distributions based on aerodynamic equivalent particle diameters are preferred. Ideally time-of-flight measurements are gathered at high shear forces, high deaggregation levels and/or low feed rates, in order to facilitate production of primary aerosol particles.
  • Particle size distribution (PSD) data in particular obtained by laser diffraction measurements, may also be used to calculate the shape coefficient a s ,v of particles in the manner described above.
  • An active substance according to the invention will suitably have a cumulative particle size distribution such that more than 98 % of the particles are within the respirable particle size range from 0.5 to 10 ⁇ m.
  • Scanning electron microscopy may also be used to measure characteristic particle dimensions and thus characteristics such as particle aspect ratios and shape factors.
  • Crystallinity of a particulate material may be determined using X-ray powder diffraction, preferably high resolution X-ray powder diffraction such as using a synchrotron radiation source. Using commercially available software, X-ray diffraction data may be employed to assess the distribution of crystalline domain sizes and the degree of strain in the crystals.
  • X-ray diffraction line broadening can provide an indication of crystal lattice imperfections such as strain defects (point defects or dislocations) and size effects (grains, small-angle boundaries or stacking faults).
  • the active substance of the invention exhibits a FWHM which is at least 20 % lower, more preferably at least 25 % lower, most preferably at least 30 % or 40 % or 50 % lower, than that of the corresponding peak (ie, the peak for the same crystal plane) in the X-ray diffraction pattern of the same substance produced by a non-SEDSTM particle formation process.
  • the FWHM of at least one, ideally of at least two or three or even of all, peaks is preferably 0.1° or less, more preferably 0.09° or less, most preferably 0.08° or less.
  • the active substance of the invention preferably exhibits an integral breadth ⁇ * which is at least 20 % lower, more preferably at least 25 % lower, most preferably at least 30 % or 40 % or 45 % lower, than that of the corresponding peak in the X-ray diffraction pattern of the same substance produced by a non-SEDSTM particle formation process.
  • the integral breadth of at least one, ideally of at least two or three or even of all, peaks is preferably 0.11° or less, more preferably 0.1° or less.
  • 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 diffraction peaks.
  • This may be associated with a decrease in crystal -i-spacing (Ad/d) of 0.5 % or more, typically 1 % or more, such as from 1 to 2 %, in the product of the invention, and with a corresponding reduction in crystal volume, ⁇ V/V, of 0.5 % or more, typically 1 % or more, such as from 1 to 2 %.
  • Crystal lattice imperfections may also be assessed with reference to the crystal domain sizes and/or the crystal strain. Domain sizes are typically significantly greater for products according to the invention, compared to the same active substance produced using a non-SEDSTM particle formation process, and crystal strain is typically significantly lower. Such parameters may be calculated from X- ray diffraction patterns, for instance by analysing the diffraction peak profiles as a convolution of Cauchy and Gauss integral breadths containing size and strain (distortion) contributions, as known in the art. This allows calculation of for example surface-weighted (D s ) and/or volume weighted (D v ) domain sizes, and of a mean-square (Gaussian) strain, ⁇ , which is the total strain averaged over infinite distance.
  • D s surface-weighted
  • D v volume weighted
  • ⁇ mean-square
  • the active substance of the invention exhibits a surface-weighted domain size D s which is at least 15 % higher, more preferably at least 20 % higher, most preferably at least 30 % or 35 % higher, than that of the same substance produced by a non-SEDSTM particle formation process. It preferably exhibits a volume-weighted domain size Dv which is at least 10 % higher, more preferably at least 15 % higher, most preferably at least 20 % or 25 % higher, than that of the same substance produced by a non-SEDSTM particle formation process. D s may for example be 400 A or greater, and 7- may be 700 A or greater, in an active substance according to the invention.
  • the active substance of the invention exhibits a total strain ⁇ which is at least 30 % lower, more preferably at least 35 % lower, most preferably at least 40 % or 45 % lower, than that of the same substance produced by a non-SEDSTM particle formation process. Its total strain may for instance be 0.7 x 10 "3 or lower, preferably 0.6 x 10 "3 or lower, most preferably 0.5 x 10 "3 or lower. Domain size and strain may alternatively be calculated from the X-ray diffraction data by Le Bail diffraction profile fitting.
  • an active substance according to the invention preferably exhibits a volume-weighted domain size which is at least 50 % higher, more preferably at least 80 % higher, most preferably at least 90 % higher, than that of the same substance produced by a non-SEDSTM particle formation process. It preferably exhibits a strain which is at least 40 % lower, more preferably at least 50 % lower, most preferably at least 60 % lower, than that of the same substance produced by a non-SEDSTM particle formation process.
  • An active substance according to the invention may have an amorphous content of less than 5 % w/w, preferably less than 2 % w/w, more preferably less than 1 or even than 0.5 or 0.2 % w/w. Ideally its amo ⁇ hous phase content is at least 10 times, preferably at least 20 or even 40 or 50 times, lower than that of the same active substance produced by a non-SEDSTM particle formation process.
  • a higher bulk crystallinity, in an active substance according to the invention may be manifested by a lower moisture uptake at any given temperature and humidity, and/or by a thermal activity profile with no exothermic or endothermic peaks, for instance as measured in the examples below.
  • 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
  • An active substance according to the invention is preferably more stable, with respect to polymo ⁇ hic transitions, than a sample of the same active substance prepared using a non-SEDSTM particle formation process; it will thus typically have a higher activation energy for conversion to one or more other polymo ⁇ hic forms than will the non-SEDSTM sample for the same polymo ⁇ hic transition. More preferably, when heated at a rate of 10 °C per minute or greater at atmospheric pressure, the active substance of the invention will not alter its polymo ⁇ hic form. Instead or in addition, the time required for formation of one or more other polymo ⁇ hs of the active substance, calculated for instance from X-ray diffraction and thermal analysis data, is preferably 80 seconds or greater, more preferably 90 seconds or greater.
  • the active substance preferably contains no detectable seed nuclei of polymo ⁇ hic forms other than that desired to be present.
  • Enhanced crystallinity and/or polymo ⁇ hic purity in active substances according to the invention are believed to contribute to an overall higher physical stability as compared to the same active substances prepared using non-SEDSTM particle formation techniques.
  • Surface electric charge may be assessed as specific charge.
  • the electrostatic charge carried by a particulate material may be measured for instance in a Faraday well.
  • the particulate material may for instance be subjected to triboelectrification by agitating it against an electrically conductive contact surface, for example in a turbula mixer or cyclone separator, and its charge and mass determined both before and after triboelectrification, suitably using an electrometer, to give a value for specific charge.
  • This process may also be used to give a measure of the adhesion properties of the particles, by measuring the mass of the original sample and that removable from the mixer/separator in which it was agitated and calculating the weight percentage of the sample lost by adhesion to the contact surface(s) of the vessel.
  • Adhesion may also be assessed using a simple test of the type described in Examples 3 below, in which a sample is agitated in a container, and the non-adhering material then removed from the container and weighed, to allow calculation of the percentage of the original sample adhering to the container surfaces.
  • an active substance according to the invention preferably has a mean specific charge of from -5 to +5 nCg "1 , more preferably from -1 to +1 nCg "1 , and/or a mean specific charge which is at least 50 %, preferably at least 70 %, most preferably at least 80 % or 90 % or 95 %, lower than that of the same active substance produced by a non-SEDSTM particle formation process.
  • an active substance according to the invention preferably has a mean specific charge which is at least 30 % lower, more preferably at least 50 % lower, most preferably at least 75 % or 80 % or 90 % or 95 % lower, than that of the same active substance produced by a non-SEDSTM process.
  • an active substance according to the invention preferably has a mean specific charge which is at least 30 % lower, more preferably at least 50 % lower, most preferably at least 75 % or 80 % or 85 % lower, than that of the same active substance produced by a non-SEDSTM process.
  • the mean adhesion fraction (ie, the fraction of adhered material) assessed in the manner described above following triboelectrification in a turbula mixer, is preferably 20 % w/w or less, more preferably 10 % w/w or less, most preferably 5 % or 2 % w/w or less, for an active substance according to the invention. It is preferably at least 50 % lower, more preferably at least 75 % lower, most preferably at least 80 % or 90 % lower, for an active substance according to the invention than for the same active substance produced by a non-SEDSTM process.
  • the mean adhesion fraction assessed in the manner described above following triboelectrification in a cyclone separator, is preferably 20 % w/w or less, more preferably 10 % w/w or less, most preferably 5 % w/w or less, for an active substance according to the invention. It is preferably at least 40 % lower, more preferably at least 50 % lower, most preferably at least 60 % or 65 % lower, for an active substance according to the invention than for the same active substance produced by a non-SEDSTM process.
  • an active substance produced by a non-SEDSTM process may exhibit at least 5 times as much adhesion as the same active substance produced by a SEDSTM process, preferably at least 8 times or at least 10 times or at least 15 times that of the SEDSTM substance.
  • the adhesion force per unit area to a highly oriented pyrolytic graphite substrate assessed using atomic force microscopy in the manner described above is preferably less than 60% of, more preferably less than 30% of, most preferably less than 15% of that for particles of the same active substance produced by a non-SEDSTM process.
  • Powder flow properties may be assessed by analysing the dynamic avalanching behaviour of a particulate product, such as using an AeroflowTM powder avalanching apparatus (Amherst Process Instruments, Amherst, USA), for instance as described in the Examples below.
  • AeroflowTM powder avalanching apparatus Amherst Process Instruments, Amherst, USA
  • Superior powder flow properties, in an active substance according to the invention, may be manifested by a strange attractor plot which is closer to the origin and/or has a smaller spread than that for the same active substance produced by a non-SEDSTM process.
  • a strange attractor plot may be obtained, again as described in the examples below, from powder avalanching data (in particular, time intervals between avalanches) using the method of Kaye et al, Part. Charact, 12 (1995), 197-201.
  • Substances according to the invention tend to exhibit lower mean avalanche times (for example at least 5 % or even 8 % lower at 100 s/rev, at least 10 % or even 14 % lower at 145 s/rev) than corresponding products of non-SEDSTM processes.
  • They may show a lower irregularity of flow (for example at least 5 % or even 8 % lower at 100 s/rev, at least 8 % or even 10 % lower at 145 s/rev) than corresponding non-SEDSTM products, irregularity of flow being assessed in terms of avalanche scatter.
  • the bulk powder density of an active substance according to the invention may be measured in conventional manner, for example using a volumetric cylinder, and is preferably at least 20 % lower, more preferably at least 50 % lower, most preferably at least 60 % or 70 % or 80 % lower, than that of the same active substance produced by a non-SEDSTM process. Its aerosolised powder bulk densityis preferably at least 10 %, more preferably at least 20 %, lower. It has been found that active substances according to the invention may, su ⁇ risingly, have both relatively low bulk powder densities yet also good powder flow properties in particular lower cohesiveness and adhesiveness and or a lower tendency to accumulate static charge.
  • Specific surface area of particles may be determined by conventional surface area measuring techniques such as low temperature physical adso ⁇ tion of nitrogen (eg, BET nitrogen adso ⁇ tion using a Surface Area Analyser CoulterTM SA 3100 (Coulter Co ⁇ ., Miami, USA)).
  • the specific surface area of a particulate active substance according to the invention is at least 1.2 or 1.5 times, more preferably at least twice, still more preferably at least 3 times, most preferably at least 4 or 4.5 times, that of the same active substance produced by a non-SEDSTM process.
  • an active substance according to the invention might have a specific surface area of at least 10 m 2 /g, preferably at least 15 or 20 or 25 m 2 /g, and/or a surface-to-volume ratio of at least twice, preferably at least 2.5 times, that of spherical particles of the same volume diameter.
  • An active substance preferably has a shape factor /which is at least 20 %, more preferably at least 30 %, larger than that of the same active substance (suitably having the same or a comparable crystal shape and particle size) produced by a non-SEDSTM particle formation process.
  • particles of an active substance according to the invention preferably have a higher available surface area than particles of the same active substance made by a non-SEDSTM process - where for instance the particles are in the form of platelets or needles, those of the present invention may thus be thinner than those produced by non-SEDSTM techniques.
  • a typical shape factor /for a particulate active substance according to the invention might for instance be 3 or greater, preferably 3.2 or greater, more preferably 3.5 or greater, most preferably 3.7 or greater.
  • a higher specific surface area and/or shape factor appears, in an active substance according to the invention, to accompany improved dissolution performance as compared to the same active substance produced by a non-SEDSTM particle formation process.
  • a product according to the invention may dissolve more rapidly in any given solvent and with greater efficiency, for instance with at least 40 % higher dissolution, more preferably at least 50 % higher dissolution than the non- SEDSTM product after a period of 150 or even 300 minutes, ideally the SEDSTM product achieving complete dissolution after a period of 50 minutes or less.
  • Such improved dissolution is particularly advantageous for poorly soluble (generally poorly aqueous soluble) materials.
  • Particles of an active substance according to the invention preferably have a RMS roughness, measured using AFM, of 0.5 nm or less, preferably 0.3 or 0.2 nm or less. Their RMS roughness is preferably at least 70 % lower, more preferably at least 80 % or 90 % lower, than that of the same active substance prepared by a non-SEDSTM particle formation process.
  • Deposition properties of an active substance may be measured using the cascade impactor technique, for instance using an AndersenTM-type cascade impactor (Copley Scientific Ltd, Nottingham, UK). Such devices imitate particle deposition in the lungs from a dry powder inhaler. High fine particle fractions are preferred, with respect to delivery to stages 1 to 5 of the impactor. Thus, fine particle fractions are preferably measured as the mass of particles having an efficient cut-off diameter (ECD) of between 0.5 and 5 ⁇ m, for instance as described in the examples below. From the cascade impactor data, an apparent volume mean diameter may also be calculated as known in the art.
  • ECD efficient cut-off diameter
  • HPLC may be used for quantitative analysis of the active substance content in the material deposited at each stage of the impactor and if applicable in associated apparatus such as pre-separator, throat or mouthpiece.
  • the active substance of the invention may be blended with a suitable excipient, preferably a pharmaceutically acceptable excipient suitable for delivery to the lung, a common example being lactose.
  • a suitable excipient preferably a pharmaceutically acceptable excipient suitable for delivery to the lung, a common example being lactose.
  • Such a blend might typically contain from 1 to 10 % w/w of the active substance, preferably from 2 to 5 % w/w.
  • it tends to be better able to detach from the excipient, under these conditions, than the same active substance prepared by a non-SEDSTM process; in other words, it forms less strong aggregates with the excipient.
  • the active substance of the invention is preferably in the form of solid (eg, as opposed to hollow, porous or at least partially fluid-containing) particles. It is preferably in a crystalline or semi- crystalline (as opposed to amo ⁇ hous) form, more preferably crystalline.
  • the crystalline form which is significantly longer in one dimension than in at least one other dimension (ie, it has a relatively high aspect ratio); this embraces for example needle-like crystals and also, potentially, wafer-, blade- or plate-like crystals (which are longer in two dimensions than in the third) and elongate prism-shaped crystals. These have been found to show better DPI performance than correspondingly sized particles of other shapes. Needle-like (acicular) or platelet-shaped crystals may be particularly preferred. In the above discussion, "significantly" longer means at least 5 %, preferably at least 10 % or 20 % or
  • particles according to the invention if in the form of platelets or needles are typically thinner than those of the same active substance produced by a non-SEDSTM process (as reflected by for instance a difference in shape factors, shape coefficients and specific surface areas).
  • the particles of the invention can often be seen to have less rounded edges and corners and/or to be less fragmented than those of the non-SEDSTM substance in particular a micronised substance - this may be reflected in a lower surface energy, lower particle adhesion and or lower tendency for aggregation in the product of the invention.
  • the behaviour of an active substance according to the present invention on aerosolisation which in turn affects its suitability for respiratory drug delivery and in particular for DPI delivery, may be assessed and characterised using the techniques outlined in the examples below. These can involve assessing the size, surface characteristics, aerodynamic properties, deagglomeration behaviour and/or solid state properties of the active substance particles. Such techniques may be used for instance in the selection method of the second aspect of the invention.
  • active substance is meant a substance capable of performing some useful function in an end product, whether pharmaceutical, pesticidal or whatever.
  • the term is intended to embrace substances whose function may be as an excipient for another substance.
  • 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, hydrophiHc or hydrophobic. 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 phospholipids and aminolipids, carbohydrates such as polysaccharides, cells and viruses.
  • the active substance preferably comprises (more preferably is) a pharmaceutically or nutriceutically active substance, or a pharmaceutically or nutriceutically acceptable excipient, or a mixture of two or more thereof. More preferably it is a pharmaceutically active substance or mixture thereof which is suitable for delivery by inhalation (which term includes nasal and/or oral inhalation), although in general it may be any active substance which is deliverable as a dry powder, ideally using a passive dry powder inhaler. Many other 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.
  • formulations which achieve a maximum concentration of a pharmaceutically active substance, C max , within 1 hour of administration, preferably within 30 minutes, and most preferably within 15 minutes. This time to achieve maximum concentration of the active substance is referred to herein as T max .
  • Examples of pharmaceutically active substances which may be delivered by inhalation include ⁇ 2 - agonists, steroids such as glucocorticosteroids (preferably anti-iirflammatories), 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
  • the active agent may fall into one of a number of structural classes, including but not limited to small molecules (preferably 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, safmeterol 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, rizatriptan, naratriptan, frovatriptan, almotriptan, zolmatriptan, mo ⁇ hine and the mo ⁇ hme analogue fentanyl (eg, fentanyl citrate), glibenclamide (a sulphonyl urea), benzodiazepines such as vallium, triazolam, alprazolam, midazolam and
  • 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 (e.g., 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 VDI, 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,
  • Patent No. 5,922,675 amylin, C-peptide, sornatostatin, somatostatin analogs including octreotide, vasopressin, follicle stimulating hormone (FSH), influenza vaccine, insulin-like growth factor (IGF), insulintropin, macrophage colony stimulating factor (M-CSF), plasminogen activators such as alteplase, urokinase, reteplase, streptokinase, pamiteplase, lanoteplase, and teneteplase; nerve growth factor (NGF), osteoprotegerin, platelet-derived growth factor, tissue growth factors, transforming growth factor- 1, vascular endothelial growth factor, leukemia inhibiting factor, keratinocyte growth factor (KGF), glial growth factor (GGF), T Cell receptors, CD molecules/antigens, tumor necrosis factor (TNF), monocyte chemoattractant protein-1, endothelial growth factors, parat
  • Exemplary monoclonal antibodies include etanercept (a dirneric 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, capecita
  • 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.
  • the active substance may comprise two or more active substances formulated together, such as one coated with another, or one dispersed within a matrix of another, or a physical mixture (blend) of two or more.
  • Common examples of such formulations include two or more coformulated pharmaceutical actives, or pharmaceutically active substances coated with excipients, or physical mixtures of pharmaceutically active substances with excipients such as in particular lactose, 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 improved dispersibility and DPI performance in the absence of excipients, ie, in the form of the active substance alone (for example in the form of a drug or drugs without excipients).
  • the improved dispersibility and DPI performance is preferably also exhibited in the absence of dispersion-enhancing or stabilising additives, such as surfactants or lubricants.
  • a particulate active substance according to the invention will exhibit improved dispersibility and DPI performance as compared to the same active substance, in particulate form, prepared by a non-SEDSTM particle formation process, in particular micronisation or granulation.
  • micronisation is meant a process involving mechanical means, for instance milling or grinding, to reduce particle size to the micrometer range.
  • the non-SEDSTM substance may comprise particles having the same or a smaller size (for instance, 90 % or less of the size of, or preferably 80 % or 70 % or 60 % or less of the size) than those of the active substance of the invention.
  • 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, ascorbic
  • particulate active substances which exhibit the improved DPI performance and other advantageous properties described above can be produced using the so-called SEDSTM ("Solution Enhanced Dispersion by Supercritical fluid") process, which is a version of the GAS process referred to above.
  • SEDSTM Solution Enhanced Dispersion by Supercritical fluid
  • SEDSTM is a process for forming particles of a ' ⁇ target” substance. It involves contacting a solution or suspension of the target substance in a fluid vehicle (the “target solution/suspension") with an excess of 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 thus formed between the anti-solvent and the extracted vehicle is still in a compressed or 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-
  • 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.
  • a particulate active substance according to the first aspect of the present invention is preferably prepared 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 fourth 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 particle formation techniques such as spray drying or freeze drying.
  • a fourth 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 dispersibility of the substance and/or its performance in a passive dry powder delivery device, and/or for the pu ⁇ ose of achieving one or more of the characteristics (a) to (q), optionally in combination with one or more of the other preferred properties, listed above in connection with the first aspect of the invention.
  • the process is preferably carried out using supercritical or near-critical, 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. Generally, the conditions should be chosen to minimise or reduce particle sizes and/or size distributions - this will generally mean selecting a higher anti-solvent flow rate (eg, a target solution/suspension : anti-solvent flow rate ratio
  • a higher operating temperature e.g, from 50 to 100 °C, preferably from 70 to 90 °C, especially for a C0 2 anti-solvent
  • a higher operating pressure e.g, from 80 to 210 bar, preferably from 90 to 200 bar, again especially for a C0 2 anti-solvent
  • the process conditions are also ideally chosen to maximise or enhance the purity (which may be the polymo ⁇ hic or enantiomeric purity) of the product - this will involve the use of a vehicle, anti- solvent, temperature and pressure suitable to maximise or enhance selectivity of precipitation of the desired substance from those present in the target solution/suspension.
  • the operating conditions for the process are preferably selected, for any particular set of reagents (including the fluid vehicle and anti-solvent) and particle formation vessel and fluid inlet geometry, so as to maximise or enhance the degree of supersaturation in the target solution/suspension flow at its point of contact with the anti-solvent. This may be effected for instance in the manner described in the examples below, using solubility measurements to determine the optimum operating conditions.
  • the product of the fourth aspect of the invention is preferably a particulate active substance according to the first aspect.
  • Improving the performance of a substance in a passive dry powder delivery device will typically mean increasing the fine particle fraction in the emitted dose when the active substance is delivered using a passive dry powder inhaler.
  • the improvement may for instance be as compared to the performance 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 % or 30 % or 40 % different) when produced using another particle formation process such as micronising, granulation or conventional spray drying.
  • 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 using a passive dry powder inhaler or analogous delivery device, wherein the substance has one or more of the properties described above in connection with the first to the fourth aspects of the invention.
  • a sixth aspect of the invention provides the use of an active substance in the manufacture. of a medicament for use in a passive dry powder inhaler or analogous delivery device, wherein the substance has one or more of the properties described above in connection with the first to the fourth aspects of the invention.
  • the active substance is preferably an active substance according to the first aspect, and is preferably prepared using the method of the fourth aspect and/or selected using the method of the second aspect. It is preferably a pharmaceutically or nutriceutically active substance.
  • Other preferred features of the fifth and sixth aspects of the invention may be as described in connection with the first to the fourth aspects.
  • a seventh aspect of the present invention provides a dosage formulation or collection thereof, for use in a drug delivery device such as in particular a dry powder inhaler, the dosage formulation containing a particulate active substance according to the first aspect of the invention.
  • the formulation consists essentially of the active substance, ie, it contains 95 % w/w, preferably 98 % w/w or 99 % w/w, or more of the active substance.
  • it may consist essentially of a pharmaceutically active substance in the absence of excipients and/or of dispersion enhancing or stabilising additives.
  • An eighth aspect of the invention provides an active substance (eg, drug) delivery device, preferably an inhaler, which contains one or more dosage formulations of an active substance according to the first aspect.
  • the delivery device is preferably of the type designed to deliver a predetermined dose of an active substance in a dry (ie, without a fluid carrier) particulate form, for instance a dry powder inhaler and in particular a passive dry powder inhaler. It may contain one or more dosage formulations according to the seventh aspect of the invention.
  • the invention provides a method for delivering an active substance, the method involving charging a delivery device, in particular a device according to the eighth aspect of the invention, with an active substance and/or a formulation according to the invention and/or an active substance selected in accordance with the second aspect of the invention.
  • a tenth aspect provides a method of treatment of a human or animal patient, which method involves administering to the patient, preferably using the method of the ninth aspect of the invention, an active substance and/or a formulation according to the invention and/or an active substance selected in accordance with the second aspect of the invention. Both of these methods preferably involve the use of a delivery device such as an inhaler, more preferably a delivery device according to the eighth aspect of the invention.
  • the active substance preferably comprises a pharmaceutically active substance suitable for inhalation therapy.
  • the system used to carry out the SEDSTM particle formation processes was of the general type shown schematically in the figures of WO-95/01221.
  • the SEDSTM method described in WO 95/01221 was employed to prepare powders of salmeterol xinafoate (SX, GlaxoSmithKline), terbutaline sulphate (TBS, AstraZeneca) and fenoterol hydrobromide (FHBr, Boehringer Ingelheim).
  • SX salmeterol xinafoate
  • TBS terbutaline sulphate
  • FHBr fenoterol hydrobromide
  • the particle formation vessel of 0.5 L volume was used in all cases.
  • solvents including methanol. Ethanol, acetone and tetrahydrofurane were tested.
  • Typical flow rate of C0 2 was 5 kg/hour.
  • PSD measurements were performed using firstly, AeroSizer time-of-flight instrument equipped with AeroDisperserTM (TSI Inc., Minneapolis. USA) and secondly, laser diffraction sensor Helos with dry- powder air-dispersion system Rodos (Sympatec GmbH. Germany).
  • the volume mean particle diameter, VMD was obtained for both instruments using software options. In the general case of non- spherical particles, these instruments cannot provide the exact value of VMD, however, the time-of- flight technique gives an aerodynamic-equivalent particle diameter, whereas the laser diffraction method provides the geometric projection-equivalent diameter.
  • the deposition behaviour of micronised and supercritically-produced powders were evaluated using an Andersen-type cascade impactor (Copley Scientific Limited, Nottingham. UK). This device is designed to imitate particle deposition in the lungs; the control criterion is that the high fine particle fraction (FPF) of a respirable drug to be delivered to the defined stages (from 1 to 5) of the cascade impactor.
  • the drugs were blended with inhalation grade, DMV Pharmatose® 325M ⁇ - lactose monohydrate, with 3.8% w/w of drug typical for such formulation.
  • the airflow through the apparatus measured at the inlet to the throat, was adjusted to produce a pressure drop of 4 kPa over the inhaler under test (ClickhalerTM) according to compendial guidelines, consistent with the flow rate 49 L/min.
  • the theoretical tensile strength of the particle aggregate, required to separate primary particles, is proportional to the work of particle adhesion (Kendell and Stainton, Powder Technology, 121,223-229, 2001) and can be associated with the specific surface energy defined by the IGC method.
  • Table 2 represents the surface-energy related parameters which reflect the interaction of the non- polar ⁇ s D and polar AG A nature.
  • the reduced magnitude of ⁇ s D for the supercritically-produced powders implies that the surfaces of these particles are less energetic for non-polar, dispersive surface interactions than the micronised materials.
  • the largest changes are however observed for the polar interactions lG ⁇ which are significantly smaller, by a factor of 1.5 on average, for the supercritically-produced powders.
  • the enhanced powder dispersion always correlated well with the reduced surface energy of these materials.
  • Salmeterol xinafoate (GlaxoWellcome, Ware UK) in the form of granulated material (G-SX) used for micronisation and micronised powder (M-SX).
  • HPLC grade solvent was purchased from BDH Chemicals, Leicester, UK. All analytical grade liquid probes used in IGC studies were purchased from Labscan. Dublin, Ireland. Industrial grade (>99.95% pure) C0 2 was supplied by Air Products (Manchester, UK).
  • the SEDSTM method was employed to prepare powders of SX form I (S-SX). This technique is based on mixing between supercritical C02 antisolvent and a drug solution using a twin-fluid nozzle as more fully described in WO 95/01221 cited above. Methanol, acetone and tetrahydrofurane were tested in this work.
  • the particle formation vessel 500 ml volume
  • the temperature in the vessel was monitored by a thermocouple with accuracy ⁇ 0.1 °C and was kept constant at 40°C.
  • Pressure in the vessel was controlled by an air-actuated back-pressure regulator (26-1761 with ER3000 electronic controller, Tescom.
  • IRC Inverse gas chromatography
  • Hewlett Packard Series II 5890 Gas Chromatograph Hewlett Packard, Wilmington, DE, USA
  • Injector and detector temperatures were maintained at 100 and 150°C respectively.
  • Glass columns 60 cm long and 3.5 mm i.d.
  • the columns were deactivated with 5% solution of dimethyldichlorosilane in toluene before being packed with SX powder.
  • the columns were plugged with silanised glass wool at both ends and maintained at 40°C.
  • Data were obtained for a known weight and surface area of the sample using a nitrogen gas (purity > 99.995%) flow at 20.0 ml min.
  • the column was weighed before and after the experiment to ensure no loss of materials during the run. Trace amount of vapour from non-polar and polar probes was injected. The retention times and volumes of the injected probes were measured at infinite dilution and thus were independent of the quantity of probes injected.
  • the non-polar probes employed were pentane, hexane, heptane, octane and nonane: the polar probes were dichloromethane, chloroform, acetone, ethyl acetate, tetrahydrofuran and diethyl ether. Triplicate measurements in separate columns were made for G-SX. M- SX and S-SX powders.
  • Triboelectrification was undertaken against a stainless steel contact surface using either a turbula mixer or a cyclone separator. Triboelectrification in a turbula mixer (Glen Creston, UK) was carried out by agitating a powder sample for 5 minutes at 30 rpm in a 100 ml stainless steel vessel at ambient temperature and relative humidity. A sample was poured in a reproducible manner into a Faraday well connected to an electrometer (Keithley 610, Keithley Instruments, Reading, UK). Charge and mass of sample was then recorded to give specific charge before and after triboelectrification.
  • %w/w adhesion to the inner surface of the mixing vessel was calculated from the original mass of sample and the mass of sample poured into the Faraday well.
  • a powder was fed from a steel vibratory table into a venturi funnel.
  • Compressed air (velocity 8 m/s. relative humidity below 10%, ambient temperature) was used to convey the powder from the venturi along a horizontal pipe into the cyclone separator.
  • the Faraday well and force compensation load cell was fitted at the base of the cyclone and used to collect charged particles.
  • the instrument consisted of laser diffraction sensor HELOS and dry-powder air-dispersion system
  • R is the gas constant.
  • T is the column's absolute temperature
  • a is the probe's surface area.
  • N A is the Avogadro's number
  • ⁇ s D is the dispersive component of surface free energy of a SX powder
  • ⁇ L D is the dispersive component of surface free energy of the solvent probes.
  • Polar probes have both dispersive and specific components of surface free energy of adso ⁇ tion.
  • the specific component of surface free energy of adso ⁇ tion ( ⁇ G ⁇ ) can be estimated from the vertical distance between the alkane reference line and the polar probes of interest. This free energy term can be related to the donor number (DN) and acceptor number (AN*) of the polar solvent by the following equation:
  • DN describes the basicity or electron donor ability of a probe
  • AN* defines the acidity or electron acceptor ability.
  • AN* denotes a correction for the contribution of the dispersive component and the entropy contribution into the surface energy is assumed negligible.
  • the IGC data for the various SX samples analysed by the above approach are summarized in Tables 3 and 4. Comparison between different materials shows that the magnitude of ⁇ s D is 15% smaller for S- SX compounds than for both M-SX and G-SX compounds. In addition, ⁇ G A SP for all polar probes used reduced by at least half for S-SX compound compared to the other two materials. Comparison between M-SX and G-SX materials indicates that, although the ⁇ s D are almost equal within the experimental error, ⁇ G SP for all the polar probes is larger for the granulated material. The specific surface area, a, is twice as small for the S-SX compound compared with both M-SX and G-SX materials indicating that the mean surface -equivalent particle diameter for these compounds is smaller than for S-SX compound.
  • S-SX crystal surfaces have, in relative terms, more exposed basic groups but fewer exposed acidic groups than both G-SX and M-SX compounds. Particles of all three compounds have a similar platelet shape with the dominant ⁇ 001 ⁇ crystal faces. However, S-SX particles have the largest shape factor,/(see Table 3), which means that platelets of G-SX and M-SX are thicker. The other materials have more energetic lateral crystal surfaces as a result of the solution crystallisation procedure (G-SX) and particle breakage on micronisation (M- SX).
  • Table 5 presents results on the charge, Q, and fraction of adhered material, AD.
  • S-SX particles exhibited significantly less (between one and two orders of magnitude) accumulated charge than the micronised powder before and after turbula mixing and also for the non-adhered drug in cyclone separator.
  • the fraction of adhered material is several times smaller for S-SX powder than for M-SX powder in both the turbula mixing and cyclone separator tests.
  • the enhanced dispersability of S-SX powders means a decrease of the inter-particulate contact area and/or reduction of the cohesive forces leading to better performance of S-SX compound in the inhalation devices.
  • the Andersen cascade impactor measurements indicated a greater than two-fold increase (from 25.15 to 57.80%,) of FPF for S-SX powder compared with FPF of M-SX powder.
  • This example measured the surface charge and adhesiveness of particles of the drug salbutamol sulphate produced using a SEDSTM process as compared to that of both the unprocessed starting material and a micronised sample of the drug.
  • a simple adhesion test was devised to examine the observation that the ultra-fine powders prepared by the SEDSTM process exhibited low adhesion to containers and vessel walls, and low adhesive interaction with surfaces in general.
  • a small quantity of powder was weighed into a screw topped glass jar and the jar rotated for 5 minutes. The non-adhering powder was then tipped from the jar and weighed and the percentage powder adhering to the walls of the jar calculated.
  • This example measured the specific surface area (by low temperature physical adso ⁇ tion of nitrogen) of a poorly aqueous soluble drug produced using a SEDSTM process, as compared to a micronised sample of the same drug.
  • the specific surface area of the micronised sample was 5.6 m 2 /g, whereas that of the SEDSTM sample was 27.8 m 2 /g.
  • Fig. 1 plots the percentage dissolution against time.
  • the ultra-fine particulate products of the invention clearly dissolves much more rapidly and efficiently than the micronised version of the same substance, exhibiting much faster dissolution profiles to complete dissolution.
  • a further advantage of the SEDSTM products is the consistency of their dissolution profiles between repeat batches.
  • the properties of a micronised sample of salbutamol sulphate were compared with those of a SEDSTM- processed sample of the same drug.
  • the SEDS " TM sample was prepared from a 10 % w/v solution of salbutamol sulphate in acetone, using a 568 ml particle formation vessel, a two-passage concentric nozzle with a 0.1 mm internal diameter orifice, a processing temperature of 50 °C and pressure of 150 bar, a drug solution flow rate of 0.04 ml/min and a supercritical carbon dioxide anti-solvent flowing at
  • the mean amo ⁇ hous content of the micronised sample determined by the dynamic moisture so ⁇ tion method, was 6.92 % w/w (standard deviation 1.10). That of the SEDSTM sample in contrast was only 0.13 %w/w (SD 0.05).
  • ⁇ s D the dispersive component of surface free energy, determined by IGC
  • ⁇ s D the dispersive component of surface free energy, determined by IGC
  • blends of salbutamol sulphate with lactose were tested in an Andersen-type cascade impactor with a ClickhalerTM DPI device.
  • the fine particle fraction of the emitted dose was measured as 11.86 % for the micronised sample and 33.57 % for the SEDSTM one.
  • the respiratory drug terbutaline suplphate (TBS) was prepared by SEDSTM process and its properties and DPI performance compared to those of a micronised sample of the same drug.
  • the DPI performance of blends of TBS with the carrier alpha-lactose monohydrate was also investigated, since the drug-carrier adhesion and hence the particulate (especially surface) properties of the drug and carrier, can significantly influence their dispersibilty in DPI systems.
  • the material studied was supplied as micronised powder of terbutaline sulphate (AstraZeneca R & D, Lund, Sweden), ⁇ -lactose monohydrate (Pharmatose 325 M inhalation grade DMV International, Veghel, The Netherlands) was used as a carrier for the cascade impaction studies.
  • Carbon dioxide (BOC Ltd, UK) was 99.9 % pure and methanol, ethanol and water were of HPLC grade (Fischer Scientific Limited, Loughborough, UK).
  • SEDS TM Solution Enhanced Dispersion by Supercritical Fluids
  • the SEDSTM process was modified in such a way that an additional extraction vessel packed with TBS powder was placed in an oven and pure ethanol was pumped through the vessel. This enhanced extraction of TBS and resulted in product yield > 85 %w/w (see Figure 4, vessel position indicated by dotted lines). All other experiments were conducted in a SEDSTM apparatus as disclosed in WO 95/01221 consisting of a stainless steel particle formation vessel (50 ml) positioned in an air assisted heated oven with a specially designed two flow coaxial nozzle capable of withstanding a pressure of 500 bar. Pressure in the system was maintained within + 1 bar by an automated back-pressure regulator (Tescom, Japan).
  • Drug solution (2 % w/v) was delivered by a separate reciprocating HPLC pump (Jasco PU-980, Japan) and varied between 0.1 and 4.8 ml/min.
  • Liquid C0 2 (-10 °C) was pumped by a water-cooled Dosapro Milton Roy pump (Type: MB 112S (L) 10M 480/J W2, Pont- Saint-Pierre, France) and flow was varied between 4.5 and 80 ml min.
  • the C0 2 passed through a heat exchanger to ensure that it was supercritical before entering the nozzle, which consisted of two concentric tubes and a small premixing chamber. Two nozzle diameters, 0.1 and 0.2 mm were used in the study.
  • the powder typically about 200 mg a batch) was collected from the vessel and analysed. A range of operating temperatures (35 - 80 °C) and pressures (80 - 250 bar) were applied to produce drug powder using the SEDSTM process.
  • TBS powder was analysed using a laser diffraction RODOS/VIBRI dispersing system (HELOS/RODOS, Sympatec GmbH, Clausthal-Zellerfeld, Germany).
  • the instrument consisted of a laser sensor HELOS and a RODOS dry-powder air-dispersion system (Sympatec
  • the TBS samples were also analysed using an AeroSizerTM (Amherst Process Instruments, Amherst,
  • AeroDisperserTM pulse jet disperser
  • the measurement range of the AeroSizerTM is nominally from 0.2 to 200 ⁇ m of aerodynamic diameter with the standard 750 ⁇ m diameter tapered nozzle.
  • SEDSTM TBS samples were analysed for 300 seconds in triplicate using normal deagglomeration conditions, feed rate (5000 particles per second ) and medium shear force (0.5 psi).
  • SEM Scanning Electron Microscopy
  • DSC Differential Scanning Calorimetry
  • a chiller unit was used in conjunction with the calorimeter to attain the lower temperatures.
  • Dynamic Vapour Sorption (DVS) VFS
  • a Thermal Activity Monitor (TAM, model 2277; Thermometric AB, Jarfalla, Sweden) was used to measure the calorimetric heat flow ( ⁇ W) vs. % RH profile of each sample.
  • TAM Thermal Activity Monitor
  • the TAM measures the total heat flow in power, P, produced from either a physical or chemical reaction.
  • the calorimetric power is proportional to the rate of moisture so ⁇ tion or deso ⁇ tion, crystallization, ' and/or other processes. Exothermic events are measured as a deflection in the positive y-axis direction. Although crystallization is an exothermic process, it can be observed as a net endothermic process. During crystallization, there is an exotherm due to crystallization and a simultaneous endotherm due to deso ⁇ tion of previously sorbed moisture.
  • the TAM profile gives the resultant of these processes.
  • the TAM profile can be an exothermic peak only, an endothermic peak only or a sequential combination of both exothermic and endothermic peaks.
  • Hewlett Packard 6890 Series Gas Chromatograph (GC) Hewlett Packard, Penna, USA
  • the 6890 GC data acquisition system was used to record data from a thermal conductivity detector (TCD) and flame ionisation detector (FID) with the instrument modified for IGC by Surface Measurement Systems
  • SMS iGC Controller vl.3 The whole system was fully automated by control software (SMS iGC Controller vl.3) and the data analysed using SMS iGC Analysis macros. Prior to analysis, each column was equilibrated at 30 °C and 0 % relative humidity (RH) for 5 hours by passing dry helium gas through the column. Helium gas was also used as the carrier gas. Hydrogen and compressed air flow rates were set at 40 and 450 ml min "1 respectively for the FID.
  • the chromatograph injection port was maintained at 80 °C, TCD detector at 150 °C and the FED detector at 150 °C. Column temperature was set at 30 °C throughout analysis.
  • AeroflowTM powder avalanching apparatus (Amherst Process Instruments, API, Amherst, USA) was employed to analyse the dynamic avalanching behaviour of micronised and SC processed TBS samp es.
  • e ero ow appara us consis s o a ran mecanic ro a ng rum w t a po at t e ont.
  • white light source is positioned in front of the drum and a masked array of photocells is behind the drum.
  • 50ml of the drug powder was added to the drum, which is about 15 % of its total volume to ensure good powder mixing during the operation. As the drum rotates, the powder bed is carried upwards until an unstable state is reached and an avalanche occurs.
  • the time between successive avalanches was recorded by the projection of the light beam through the drum onto the photocell array.
  • the photocells generated a voltage dependent on the amount of light falling on the cells and the area of unmasked photocells shielded from the light source by the powder.
  • the voltage output was recorded by a computer, which translates the output as powder movement using a technique disclosed in B.H. Kaye. Characterising the flowability of a powder using the concepts of fractal geometry and chaos theory, Part. Part. Charact. 14: 53-66 (1997).
  • Each TBS sample was tested in duplicate and mean avalanche time and irregularity (scatter) of avalanches were recorded.
  • Powder Dispersion by Cascade Impaction An Andersen Cascade Impactor (1 ACFM Eight Stage Non Viable Andersen Cascade Impactor, Copley Ltd, Nottingham, UK) was used to determine the dispersability and fine particle fraction (FPF) of each powder/carrier blend and pure drug alone through a dry powder inhaler device (Clickhaler®, Innovata Biomed, St. Albans, UK).
  • a dry powder inhaler device Clickhaler®, Innovata Biomed, St. Albans, UK.
  • the eight metal plates of the impactor were coated with a thin layer of silicone spray and left to dry for 30 minutes.
  • a pre- separator was attached to the top of the impactor to prevent large particles or aggregates from reaching the stages.
  • the air flow through the apparatus was adjusted to generate a pressure drop of 4 kPa over the inhaler under test and a duration consistent with the flow of 4 litres min "1 according to compendia! guidelines (Pharm Forum, 22: 3049-3095 (1996). These conditions are consistent with a flow rate of 49 1 min "1 and 4.9 s duration.
  • Ten doses were discharged into the apparatus and each determination was carried out at least twice. After each determination, the powder on each impaction stage was collected by rinsing with mobile phase and the resulting solutions were analysed by HPLC. The amount of drug deposited in the throat piece and the pre- separator was also determined.
  • the Andersen cascade impactor is traditionally calibrated at 28.3 1 min "1 but may be operated at higher flow rates, which are thought to more closely approximate a patient's capabilities (F.
  • ECDs effective cut-off diameters
  • ECDp2 is the ECD at the alternative flow rate
  • ECD 2S.3 is the manufacturer's flow rate (28.3 1 min “1 )
  • F2 is the alternative flow rate in 1 min "1 .
  • the alternative flow rate used in this study was
  • TBS was produced using the SEDSTM process.
  • Different solvents such as pure methanol, methanol water, pure water and pure ethanol were used to dissolve drug material between 1-10 % w/v in concentration.
  • concentration of the drug concentration of the drug, drug solution flow rate, C0 2 flow rate, temperature and pressure of the system were manipulated.
  • SEDSTM products such as a hydrated crystal, amo ⁇ hous material, and two previously reported polymo ⁇ hs A and B were produced using different solvents and experimental conditions, as seen in Figures 5 a-f.
  • Particles in the smaller 50 ml vessel were exposed to partially mixed ethanol-rich phase which exist in the core of high velocity jet (BY. Shekunov, J. Baldyga, and P. York. Particle formation by mixing with supercritical antisolvent at high Reynolds numbers, Chem. Eng. Sci., 56: 2421-2433 (2001)), whereas the particles in the large 500 ml vessel were accumulated in well mixed C0 2 -rich phase.
  • Figures 5 a-f The use of different solvents such as pure methanol and methanol/water resulted in needle-like as well as spherical amo ⁇ hous particles respectively, jfaracies ooiamcu u->m ⁇ m. methanol, pure ethanol and pure water have revealed well-defined crystal edges compared to micronised particles.
  • the average particle size by volume determined by laser diffraction for a typical batch of TBS 1 and TBS2 was between 3.2 and 3.4 ⁇ m with 90 % less than 7 ⁇ m in comparison to 3.0 ⁇ m microparticles of micronised terbutaline sulphate with 90 % less than 5 ⁇ m. This method showed good reproducibility and therefore, was used for the quality control assessment.
  • the sampling procedures in the AeroSizerTM nozzle may produce discrepancies in time-of- flight measurements at large particle number densities, which is the case of small amo ⁇ hous particles in Figure 5e. Therefore, the reproducibility of results for this technique was lower than for the laser diffraction method.
  • the X-ray powder patterns in Figures 6 a - c illustrate the crystallinity of micronised and TBSl and TBS2 samples, which is assessed on the basis of the sha ⁇ ness of the major ⁇ jffraction peaks. From the results it can be seen that there is no significant difference in the XRPD profiles of micronised and TBS 1 samples. However, based on XRPD data, theTBS2 sample has shown lower bulk crystallinity in comparison to the micronised sample. The DSC profiles (Table 8) confirm this conclusion; the fusion enthalpy for TBS2 batch is considerably lower than for both micronised and TBS 1 batches, thus the crystallinity for TBS 1 being higher than that for the micronised material.
  • the sample may be deliquescing at high RH.
  • the heat flow ( ⁇ W) for both micronised and SEDSTM powders of TBS are normalised to 1 mg for comparison.
  • the endothermic peak for micronised TBS is most likely due to crystallisation of the amo ⁇ hous fraction that was previously induced by micronisation.
  • the TAM profile for TBS2 sample of TBS has an incomplete exothermic peak between 85 and 90 % RH because the RH ramping experiment (3 % RH/hr from 0 % to 90 % RH) ended before the event was completed. No exothermic or endothermic peaks were observed in the TAM profile of TBS 1 sample of TBS, which is typical for a highly crystalline material.
  • the TAM results show that the micronised TBS has an event at about 79% RH, probably due to crystallisation.
  • the results also show that TBS2 sample has an exothermic event at about 85 % RH.
  • TBSl materials show very similar surface energetics with marginally lower non-polar, dispersive surface interaction ( ⁇ s ) and slightly higher specific interaction (- ⁇ G A SP ) for polar, amphoteric and basic probes.
  • ⁇ s non-polar, dispersive surface interaction
  • - ⁇ G A SP slightly higher specific interaction
  • the TBS2 sample indicated significantly less energetic, both dispersive and specific, interactions (Table 9).
  • comparison of the K A and K D values of TBS2 and micronised samples indicates the weakest, both acidic and basic interactions for this supercritically processed material.
  • the SEDSTM material has less exposed energetic acidic and basic groups.
  • TBS2 particles may have a more ordered structure than that for micronised material, despite the fact that the bulk structure determined using X-ray diffraction and DSC techniques appeared more ordered for the micronised particles.
  • Micronised material is sometimes conditioned before being used for a DPI formulation, by passing a saturated ethanol vapour through the powder bed.
  • TBSl material was produced with an excess of ethanol solvent. Therefore, it is possible that the surface structure was modified after particle formation for micronised and TBS 1 materials and disorganised compared to the crystal structure in the bulk.
  • TBS2 sample Enhanced flow properties of TBS2 sample are consistent with lower energetics and lower cohesiveness of this material as indicated by the IGC measurements and the following ACI studies.
  • FIGS 10 and 11 compare the in vitro performance of micronised and SEDSTM processed TBS analysed in a lactose blend as well as pure drug alone.
  • the ACI measurements demonstrated that the TBS2 batch in both cases produced a significantly higher FPF in comparison to both micronised and TBS 1 material. For this material, a high proportion of fine particle mass with a narrow distribution was collected on stage 1-3 in contrast to the broad distribution across stages 1-5 for the micronised material.
  • the SC processed TBS2 material also demonstrated an increased fine particle fraction (FPF) in both lactose blend and drug alone compared to micronised powders (38.6 % vs 30.7 %, and 29.6 % vs 17.7 %) and increased emitted dose (see Table 12). Since the lactose particles are large and cannot penetrate beyond the pre-separator stage, this indicates that dispersion between pure drug particles and formation of loose aggregates plays a major role in defining the deposition profile.
  • Table 12 Since the lactose particles are
  • the main factor responsible for better performance of supercritically processed TBS powder in the ACI is possibly related to the dispersibility of this powder at low air flow rates.
  • the enhanced dispersibility is particularly significant for DPI devices where the performance strongly depends on powder deaggregation at relatively low dispersion forces.
  • high turbulence is favourable for dispersion but it inevitably leads to high pressure differentials which may be unacceptable for correct functioning of many devices.
  • the example assessed the force of adhesion of particles of salbutamol sulphate produced using a SEDSTM processes compared to the same compound in micronised form.
  • Conventional AFM analysis was used. Particles of the samples were mounted onto AFM probes and the adhesion force per unit area to a freshly cleaved highly oriented pyrolytic graphite substrate (HOP G, Agar Scientific, Essex, UK) in a liquid (2H 3H perf-uoropentane) environment was determined. The contact area involved in the interaction was assessed and related to the force measurements.
  • HOP G highly oriented pyrolytic graphite substrate
  • the initial forces for individual particles of the micronised and SEDSTM- produced materials were 15.77nN (SD 4.55nN) and 4.2 InN (SD 0.71nN) respectively.
  • the aerosol performance of a SEDSTM processed sample of bromocriptine mesylate was assessed in a unit-dose passive inhaler device (Turbospin PH & T (Italy)), at a peak inspiratory flow rate (PFIR) of 28.3 LPM and 60 LPM.
  • PFIR peak inspiratory flow rate
  • Bromocriptine dispersed well at high flow rates (ED>80%) regardless of full weight. Moreover, it exhibited minimal flow rate defendence, as ED drops were minimal (8-20%) following emptying of the capsules.

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Abstract

La présente invention concerne des substances actives se présentant sous forme particulaire, des procédés de préparation et d'utilisation de ces dernières. L'invention se rapporte à des poudres particulaires, telles que celles pouvant être utilisées pour l'apport au moyen d'un inhalateur de poudre sèche ou d'un dispositif d'apport similaire, présentant des propriétés qui peuvent être bénéfiques pour le processus d'apport de l'inhalateur de poudre sèche.
PCT/GB2003/001747 2002-04-25 2003-04-24 Materiaux particulaires WO2003090715A2 (fr)

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WO2004069253A1 (fr) * 2003-02-10 2004-08-19 Bayer Healthcare Ag Traitement de maladies bacteriennes des organes respiratoires par application locale de fluoroquinolones
WO2009103035A3 (fr) * 2008-02-13 2009-11-12 Board Of Regents, The University Of Texas System Flocons ouverts divisés de particules anisotropes pour une administration aux poumons améliorée
CN106163598A (zh) * 2014-04-28 2016-11-23 菲利普莫里斯生产公司 尼古丁粉末吸入器
CN106170313A (zh) * 2014-04-28 2016-11-30 菲利普莫里斯生产公司 带香味尼古丁粉末吸入器
EP3838264A1 (fr) * 2015-06-04 2021-06-23 Crititech, Inc. Particules de taxane et leur utilisation
US11160754B2 (en) 2017-06-14 2021-11-02 Crititech, Inc. Methods for treating lung disorders
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US11458133B2 (en) 2016-04-04 2022-10-04 Crititech, Inc. Methods for solid tumor treatment
US11523983B2 (en) 2017-06-09 2022-12-13 Crititech, Inc. Treatment of epithelial cysts by intracystic injection of antineoplastic particles
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US11160754B2 (en) 2017-06-14 2021-11-02 Crititech, Inc. Methods for treating lung disorders
US11583499B2 (en) 2017-10-03 2023-02-21 Crititech, Inc. Local delivery of antineoplastic particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer
US11918691B2 (en) 2017-10-03 2024-03-05 Crititech, Inc. Local delivery of antineoplastic particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer
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