WO2008134817A1 - Vecteurs composites pour thérapie par inhalation de poudre sèche - Google Patents

Vecteurs composites pour thérapie par inhalation de poudre sèche Download PDF

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Publication number
WO2008134817A1
WO2008134817A1 PCT/AU2008/000630 AU2008000630W WO2008134817A1 WO 2008134817 A1 WO2008134817 A1 WO 2008134817A1 AU 2008000630 W AU2008000630 W AU 2008000630W WO 2008134817 A1 WO2008134817 A1 WO 2008134817A1
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WO
WIPO (PCT)
Prior art keywords
drug
particle
sub
particles
carrier
Prior art date
Application number
PCT/AU2008/000630
Other languages
English (en)
Inventor
Paul Michael Young
Hak-Kim Chan
Daniela Traini
Original Assignee
The University Of Sydney
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.)
Filing date
Publication date
Priority claimed from AU2007902336A external-priority patent/AU2007902336A0/en
Application filed by The University Of Sydney filed Critical The University Of Sydney
Publication of WO2008134817A1 publication Critical patent/WO2008134817A1/fr

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Classifications

    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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

Definitions

  • the present invention relates to a drug carrier particle that is suitable for aerosolisation, a method of forming a drug carrier particle, and a drug/carrier particle blend for use in dry powder inhalation therapy.
  • DPI Dry powder inhalation
  • DPI therapy depends on a number of factors including the biological aspect of the active ingredient, the physicochemical properties of the formulation, and the performance of the inhaler.
  • the efficiency of dose delivery of dry powders also depends on the particle size, size distribution, shape and surface morphology of the powder.
  • drug particles having a size between 1 and 5 microns have a high surface area to mass ratio and therefore tend to be highly cohesive resulting in poor aerosolisation efficiency and thus respiratory deposition.
  • their delivery into the lung is usually enhanced when they are blended with larger and coarser inert crystalline carrier materials.
  • the aim is for the drug particles to be freed from the carriers and to enter and penetrate the lung while the carriers themselves impact in the upper airways and are ingested.
  • the present invention is directed in part to formation of carrier particles that are suitable for use in dry powder inhalation therapy.
  • the present invention is an inhalable drug carrier particle for carrying at least one drug particle, formed from a plurality of adhered or otherwise co-joined sub-unit particles, wherein the sub-unit particles have an average size of between about 20nm and about 20 microns.
  • the resultant carrier particle may be advantageously used in inhalation therapy.
  • the carrier particle adopts a different surface morphology to a carrier particle formed from crystalline carrier particles of a similar size. It is believed that carrier particles formed from sub-unit particles with the size ranges discussed herein have advantageous properties when compared to carrier particles formed from larger sub-unit particles.
  • inhalable drug carrier particle is intended to encompass any carrier particle that is suitable for inhalation. Such a carrier particle would typically be used in an inhaler.
  • the sub-unit particles are adhered or otherwise co-joined to form the carrier particle.
  • adhered or otherwise co-joined encompasses any form of binding the sub-units together.
  • Various techniques for binding particles together are well known in the art and are encompassed by the present invention, including granulation techniques such as wet granulation.
  • the present invention relates to "average" sizes of particles.
  • the term “average size” can be replaced with the term “average diameter”.
  • the term “average size” can be replaced with the term “median size”.
  • the term “average size” can be replaced with the term “median diameter”.
  • the term "diameter” is a measure of the size of the particle. It is not limited to spherical particles and can be used to measure irregular particles. It may be considered the average length, width and/or height of the particles.
  • the sub-unit particles have an average size of between about 20nm and about 15 microns, for example between about 2 and 15 microns.
  • the sub-unit particles can have an average size of about 3 microns, about 5 microns, about 7 microns, or about 10 microns.
  • the carrier particle can be formed from at least one set of sub-unit particles having an average size of about 3 microns and at least one set of sub-unit particles having an average size of about 5 microns, 7 microns or 10 microns. Other combinations of sets of sub-unit particles can be envisaged.
  • the sub-unit particles can have an average size of between about 1 and 15 microns. In a further embodiment, the sub-unit particles can have an average size of between about 2 and 12 microns. In a further embodiment, the sub-unit particles can have an average size of between about 2 and 10 microns. In a further embodiment, the sub-unit particles can have an average size of between about 2 and 8 microns. In a further embodiment, the sub-unit particles can have an average size of between about 1 and 6 microns. In a further embodiment, the sub-unit particles can have an average size of between about 1 and 4 microns. In a further embodiment, the sub-unit particles can have an average size of between about 2 and 4 microns.
  • the sub-unit particles can have an average size of between about 4 and 6 microns. In a further embodiment, the sub-unit particles can have an average size of between about 6 and 8 microns. In a further embodiment, the sub-unit particles can have an average size of between about 8 and 10 microns.
  • the above numbered values are preferably +/- 1 micron, particularly preferably +/- 0.5 microns, particularly preferably +/- 0.2 microns, particularly preferably +/- 0.1 microns, or particularly preferably +/- 0.05 microns.
  • the sub-unit particles can have an average size of less than about 20 microns, preferably less than about 19 microns, preferably less than about 18 microns, preferably less than about 17 microns, preferably less than about 16 microns, preferably less than about 15 microns, preferably less than about 14 microns, preferably less than about 13 microns, preferably less than about 12 microns, preferably less than about 11 microns, preferably less than about 10 micron, preferably less than about 9 microns, preferably less than about 8 microns, preferably less than about 7 microns, preferably less than about 6 microns, preferably less than about 5 microns, preferably less than about 4 microns, preferably less than about 3 microns, preferably less than about 2 microns, preferably less than about 1 micron, preferably less than about 900nm, preferably less than about 800nm, preferably less than about 700nm, preferably less than about 600nm, preferably less than about 500nm,
  • the sub-unit particles are formed from particles wherein 90% of the particles (do. 9 ) have an average size of less than about 20 microns, preferably less than about 19 microns, preferably less than about 18 microns, preferably less than about 17 microns, preferably less than about 16 microns, preferably less than about 15 microns, preferably less than about 14 microns, preferably less than about 13 microns, preferably less than about 12 microns, preferably less than about 11 microns, preferably less than about 10 microns, preferably less than about 9 microns, preferably less than about 8 microns, preferably less than about 7 microns, preferably less than about 6 microns, preferably less than about 5 microns, preferably less than about 4 microns, preferably less than about 3 microns, preferably less than about 2 microns, preferably less than about 1 micron, preferably less than about 900nm, preferably less than about 800nm, preferably less than about 700n
  • 80% of the particles (do . g), 70% of the particles (d 0 7 ), 60% of the particles (do. 6 ), 50% of the particles (d o . 5 ), 40% of the particles (do. 4 ), 30% of the particles (do. 3 ), 20% of the particles (do. 2 ), or 10% of the particles (d o .i), are less than at least one of the abovementioned sizes.
  • the sub-unit particles can have an average size of 2 microns +/- 1 micron, preferably +/- 0.5 micron, particularly preferably +/- 0.2 micron, particularly preferably +/- 0.1 micron. In a further embodiment, the sub-unit particles can have an average size of 4 microns +/- 1 micron, preferably +/- 0.5 micron, particularly preferably +/- 0.2 micron, particularly preferably +/- 0.1 micron. In a further embodiment, the sub-unit particles can have an average size of 6 microns +/- 1 micron, preferably +/- 0.5 micron, particularly preferably +/- 0.2 micron, particularly preferably +/- 0.1 micron.
  • the sub-unit particles can have an average size of 8 microns +/- 1 micron, preferably +/- 0.5 micron, particularly preferably +/- 0.2 micron, particularly preferably +/- 0.1 micron. In a further embodiment, the sub-unit particles can have an average size of 10 microns +/- 1 micron, preferably +/- 0.5 micron, particularly preferably +/- 0.2 micron, particularly preferably +/- 0.1 micron.
  • the present invention encompasses sub-unit particles of various sizes between about 20nm and about 20 microns. These sizes are similar to or smaller than the sizes of the drug particles the carriers are intended to carry.
  • the sub-unit particles may or may not remain the same size.
  • the sub-unit particles may have an average size of between about 20nm and about 20 microns. These sub-unit particles are adhered or otherwise co-joined to form the carrier particle.
  • the carrier particle Once the carrier particle has formed, it may still be possible to identify the individual sub-units from the fused carrier particle. These sub-units may still have an average size of between about 20nm and about 20 microns.
  • the size of the sub-unit particles will change as the carrier particle is formed due to fusing of the sub-units together or some other mechanism. Equally, it may not be possible to distinguish the individual sub-unit particles when viewing the formed carrier particle.
  • the surface properties of the carrier particle will have been, at least in part, affected by the choice of carrier particle.
  • the size of the sub-unit particle will affect aerosolisation efficiency and/or respiratory deposition.
  • At least about 10% of the sub-unit particles forming the drug carrier particle have an average size of between about 20nm and about 20 microns.
  • the drug carrier particle has at least about 20%, preferably about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, about 99%, about 99.5%, about 99.9%, or about
  • sub-unit particles having an average size of between about 20nm and about 20 microns. Equally, these sub-unit particles could have an average size of between about 20nm and 15 microns, about 2 and 12 microns, about 2 and 10 microns, less than about 12 microns, less than about 10 microns or any of the other sizes discussed herein.
  • the present invention includes carrier particles formed exclusively from sub- unit particles as discussed herein and equally carrier particles that have only a percentage of the sub-unit particles being sub-unit particles as discussed herein.
  • the skilled person will choose the amount of sub-unit particle having an average size as discussed herein to achieve the desired properties of the carrier particle.
  • the carrier particle itself may contain other excipients or ingredients as well as the sub-unit particles as discussed herein.
  • the formed drug carrier particle has an average size of between about 50 to about 250 microns, more preferably between about 60 and about 100 microns, and even more preferably between about 63 and about 90 microns.
  • the choice of carrier particle size affects the performance of the aerosolised composition. In general, the size of the carrier particle will affect aerosolisation efficiency and respiratory deposition.
  • an inhalable drug carrier particle formed from a plurality of adhered or otherwise co-joined sub-unit particles, wherein the drug carrier particle has an average size of about 50 and 250 microns, preferably between about 60 and about 100 microns, and more preferably between about 63 and about 90 microns.
  • the carrier particle formed from the plurality of sub-unit particles can have an average size of between about 50 to about 250 microns, and is formed from a plurality of sub-unit particles having an average size of between about 1 and 15 microns, preferably about 2 and 12 microns, about 2 and 10 microns, about 2 and 8 microns, about 1 and 6 microns, about 1 and 4 microns, about 2 and 4 microns, about 4 and 6 microns, about 6 and 8 microns, about 8 and 10 microns, all sizes +/- 1 micron, preferably +/- 0.5 microns, particularly preferably +/- 0.2 microns, particularly preferably +/- 0.1 microns.
  • the carrier particle formed from the plurality of sub-unit particles can have an average size of between about 60 and about 100 microns, and is formed from a plurality of sub-unit particles having an average size of between about 1 and 15 microns, preferably about 2 and 12 microns, about 2 and 10 microns, about 2 and 8 microns, about 1 and 6 microns, about 1 and 4 microns, about 2 and 4 microns, about 4 and 6 microns, about 6 and 8 microns, about 8 and 10 microns, all sizes +/- 1 micron, preferably +/- 0.5 microns, particularly preferably +/- 0.2 microns, particularly preferably +/- 0.1 microns.
  • the carrier particle formed from the plurality of sub-unit particles can have an average size of between about 63 and about 90 microns, and is formed from a plurality of sub-unit particles having an average size of between about 1 and 15 microns, preferably about 2 and 12 microns, about 2 and 10 microns, about 2 and 8 microns, about 1 and 6 microns, about 1 and 4 microns, about 2 and 4 microns, about 4 and 6 microns, about 6 and 8 microns, about 8 and 10 microns, all sizes +/- 1 micron, preferably +/- 0.5 microns, particularly preferably +/- 0.2 microns, particularly preferably +/- 0.1 microns. It should be understood that when considering the size of the sub-unit particle or carrier particle, the bulk powder will contain a range of particle having different sizes.
  • the present invention is concerned with the average size of the particle.
  • the bulk powder will contain some particles of higher and lower sizes.
  • the average particle size will be about 4 microns.
  • some of the formed particles will be considerably smaller or larger than the overall average size. These particles are to be expected and are encompassed by the present invention.
  • the particles are discussed with respect to their average size.
  • the present invention is intended to encompass the "average" particle size.
  • the present invention is intended to cover particles which, on average, have a size of about 10 microns.
  • some variation in particle size is to be expected when forming particles of this size and particles with an average size similar to that of the present invention are intended to fall within the scope of the invention.
  • One measure of average sizes specifically encompassed by the present invention is the median average size.
  • the particle can be formed by fusion of a plurality of sub- unit particles.
  • the carrier particle is formed from sub-unit particles being each of substantially the same size. In another embodiment, the carrier particle is formed from sub-unit particles of different sizes. Still further, the carrier particle can be formed from a first set of sub-unit particles of substantially the same size and second or further sets of sub-unit particles, with each sub-unit particle in a set being of substantially the same size.
  • the properties of the carrier particle can be adjusted by consideration of the choice of sub-unit particle. Either substantially all of the sub-unit particles forming the carrier particles fall within the scope of the present invention, or at least some of the particles do. Therefore, the present invention includes carrier particles formed from two or more sub-unit particles of different sizes, only one or some of which fall within the scope of the invention. In one embodiment, the average size of the sub-unit particles is less than about 300% of the average size of the drug particle.
  • the carrier particle is preferably formed from sub-units having an average size of less than about 18 microns.
  • the sub-unit particles are up to three times as large as the drug particles that are intended to be carried on the carrier particle. Therefore, one could determine the size of the drug particles intended to be carried on the carrier particle and then select sub-unit particles that are up to twice as big as the drug particle.
  • the present invention involves matching the size of the sub-unit particle to the size of the drug particle intended to be carried.
  • the sub-unit particle may be larger, roughly the same size or smaller than the intended drug particle.
  • the size of the drug particle has a direct impact on the choice of carrier particle.
  • an inhalable drug carrier particle for carrying at least one drug particle, said drug carrier particle formed from a plurality of adhered or otherwise co-joined sub-unit particles, wherein the average size of the sub-unit particles is less than about 300% of the average size of the drug particle.
  • the average size of the sub-unit particles is less than about 290% of the average size of the drug particle, preferably about 280%, 270%, 260%, 250%, 240%, 230%, 220%, 210%, 200%, 190%, 180%, 170%, 160%, 150%, 140%, 130%, 120%, 1 10%, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% or about 10%.
  • the average size of the sub-unit particles is approximately the same as the average size of the drug particle.
  • the average size of the sub-unit particles is less than the average size of the drug particle.
  • the average size of the sub-unit particles is smaller than the average size of the drug particle. In one embodiment, the average size of the sub-unit particles is 2 times smaller than the average size of the drug particle, preferably 3 times smaller, preferably 4 times smaller, preferably 5 times smaller, preferably 10 times smaller, preferably 20 times smaller, preferably 30 times smaller, preferably 50 times smaller, preferably 100 times smaller than the average size of the drug particle.
  • the drug particle has an average size of less than about 7 microns, preferably, about 1 micron, about 2 microns, about 3 microns, about 4 microns, about 5 microns, about 6 microns or about 7 microns.
  • the carrier particle can have a substantially homogeneous surface.
  • the surface of the present invention may be more homogenous than the prior art particles.
  • homogenous it is meant that overall, there is less variation over the surface of the particle when considering one area compared with another.
  • a given surface may in fact be considerably indented but this indentation is found more regularly over the whole surface of the particle than with prior art particles.
  • a crystalline particle may have very flat surfaces which on the face of it appear homogenous. However, different surfaces will have markedly different electrostatic properties which will affect the adhering ability of the drug particle.
  • the homogeneity of the present invention may help to give a more attractive adherence profile for the carrier particle.
  • the carrier particle can have a relatively increased surface roughness. At least some, the majority, or all of the surface can be indented.
  • the surface morphology may be adjusted for drug adhesion and drug delivery where required.
  • the adhesion of an active pharmaceutical ingredient to the carrier particle can be relatively spatially uniform.
  • the surface morphology can be adjusted to suit the properties of the drug to be adhered.
  • the carrier particle is made up of a plurality of adhered or otherwise co- joined subunit particles, it may contain a large number of indentations, crevices or depressions between adjacent sub-units.
  • the surface of the carrier particle may contain depressions or gaps between each sub-unit. The size of these depressions can be controlled by the size and/or shape of the sub-unit particles. Smaller sub-unit particles will give rise to smaller gaps between adjacent particles whereas larger sub-unit particles will not only giver wider but also deeper indentations.
  • gaps may be useful in modifying the adhesion properties of the drug particle adhered to the carrier particle.
  • a drug particle will have a higher contact area if adhered to a flat uniform surface.
  • the surface contains indentations or gaps, the drug particle will have a lower contact area due to increased void spaces. This affects how strongly the drug particle adheres to the surface of the carrier.
  • a minimum level of adherence is desired' to enable the drug particles to be carried on the carrier particle.
  • the adherence level should not be too high so as to make it difficult for the drug particle to be removed from the carrier particle during respiratory deposition.
  • One way to control this adherence is to modify the gaps between the sub-unit particles. Wider and/or more frequent gaps will result in a lower contact area and adherence value for the carrier particle. Selection of the sub-unit particle size will change the frequency and size of the gaps.
  • an inhalable drug carrier particle for carrying at least one drug particle, said drug carrier particle formed from a plurality of adhered or otherwise co-joined sub-unit particles, wherein the average size of the gaps between the co-joined sub-unit particles on the surface of the drug carrier particle is less than the average size of the drug particle.
  • the average size of the gaps are roughly the same size as the diameter of the drug particle.
  • the gaps are slightly larger than the average size of the drug particle.
  • the average gap size may be thought of as the diameter of the gap, that is the average size from one side of the gap to the other.
  • the drug particles are less likely to be present or fall into these gaps and become stuck or at least relatively more difficult to dislodge.
  • Introducing crevices has been a specific design feature of prior art carrier particles as it was believed that producing crevices on the surface of the carrier particle helped to adhere a greater number of drug particles onto the carrier.
  • many of these drug particles lodged in the crevices remain with the carrier particle and do not reach the lungs of the patient. These crevices were of such a size that drug particles would fall into them and become trapped. It is believed that these drug particles may not be liberated from the carrier.
  • the traditional carrier particles show good adherence for the drug particles, many of these particles will have no clinical benefit for the patient.
  • the drug may particles substantially sit on the surface of the carrier particle rather than fall within crevices formed from prior art particles.
  • the surface of the carrier particle contains fewer crevices that are of a size larger than the drug particles, more drug particles will sit on the surface of the carrier. This is believed to improve performance.
  • about 10%, preferably, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, about 99% or about 99.9% of the gaps on the surface of the carrier particle have an average size less than the average size of the drug particle.
  • about 10%, preferably, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, about 99% or about 99.9% of the gaps on the surface of the carrier particle have an average size of less than about 12 microns, preferably less than about 10 microns, about 8 microns, about 6 microns, about 4 microns, about 2 microns, about 1 microns, about 900nm, about 800nm, about 700nm, about 600nm, about 500nm, about 400nm, about 300nm, about 200nm, about lOOnm, about 50nm, about 20nm, about lOnm or about 5nm.
  • the gaps between the sub-unit particles are preferably about 150%, 140%, 130%, 120%, 110%, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, or 5% the average size of the drug particles.
  • the sub-unit particles as discussed herein preferably give rise to surface gaps on the carrier particle substantially as described above.
  • a theoretical smooth carrier surface would give a high contact area between the carrier particle and the drug particle. Such a carrier would give good uniformity over the surface of the carrier. However, such a carrier would have a high level of adhesion and would therefore give poor drug liberation. Such a theoretical carrier is difficult to produce commercially.
  • Typical commercial grade carriers have a highly varied carrier surface and are typically low cost. However, there is considerable variation in contact area over the surface of the particle which results in considerable drug liberation variation. In addition, it is not possible to tailor the surface properties.
  • the carrier surface has regular indentations it will give a more uniform surface since the surface will be similar over the entire particle. This contrasts with commercial carriers and would give a consistent adhesion profile and uniformity. However, if the indentations are significantly larger than the drug particle individual drug particles will still have high contact with the carrier since they effectively "see” a smooth surface. The surface can be thought of as rolling hills with drug particles adhered over the entire surface of the carrier. This may give rise to high adhesion between the drug and the carrier and poor drug liberation.
  • the surface contains uniform gaps and the gaps are smaller than the drug particles then the surface will be uniform giving a consistent adhesion.
  • the gaps create void spaces which reduce the contact area. This can help to increase drug liberation.
  • Such a surface is ideal as the contact area and adhesion profile is uniform and controllable.
  • the carrier particles have a granular surface morphology.
  • the carrier particle has a substantially uniform surface roughness.
  • a measure of surface roughness is the root mean square roughness (RR MS ). This is calculated using Equation 1.
  • the carrier particle has an R RMS of about >0.1nm, preferably >0.2nm, preferably >0.3nm, preferably >0.4nm, preferably >0.5nm, preferably >0.6nm, preferably >0.7nm.
  • the carrier particle has an adhesion value
  • ⁇ 110nN preferably about ⁇ 100nN, more preferably about ⁇ 90nN, more preferably about ⁇ 80nN, more preferably about ⁇ 70nN, more preferably about ⁇ 60nN, more preferably about ⁇ 50nN, more preferably about ⁇ 40nN, more preferably about ⁇ 30nN, more preferably about ⁇ 20nN, more preferably about ⁇ 10nN.
  • the carrier particle has an adhesion value (average force value fo .5 ) of between about 1OnN and about HOnN, preferably between about 1OnN and 9OnN, preferably between about 2OnN and 7OnN, preferably between about 2OnN and 6OnN, preferably between about 2OnN and 5OnN, preferably between about 2OnN and 4OnN, preferably between about 3OnN and 5OnN.
  • adhesion value average force value fo .5
  • f ⁇ are the respective percentile force values for the lognormal distribution.
  • the carrier particle has a GSD value of about ⁇ 1.88, preferably about ⁇ 1.85, preferably about ⁇ 1.80, preferably about ⁇ 1.78, preferably about ⁇ 1.76, preferably about ⁇ 1.75, preferably about ⁇ 1.73, preferably about ⁇ 1.71, preferably about ⁇ 1.69, preferably about ⁇ 1.68, preferably about ⁇ 1.67.
  • the GSD value is ⁇ 1.6, preferably ⁇ 1.5, preferably ⁇ 1.4, preferably ⁇ 1.3, preferably ⁇ 1.2 or preferably ⁇ 1.1.
  • the coefficient of variation (CV) of the GSD is less than about 10%, preferably less than about 8%, preferably less than about 7%, preferably less than about 6%, preferably less than about 5%, preferably less than about 4%, preferably less than about 3%.
  • the carrier particle may give improved aerosolisation efficiency.
  • the carrier particle gives rise to a fine particle fraction (FPF) of greater than about 20%, preferably greater than about 22%, preferably greater than about 24%, preferably greater than about 26%, preferably greater than about 28%, preferably greater than about 30%, preferably greater than about 32%, preferably greater than about 34%.
  • the carrier particle gives rise to a fine particle fraction (FPF) of greater than about 40%, preferably greater than about 50%, preferably greater than about 60%, preferably greater than about 70%, preferably greater than about 80%, preferably greater than about 90%, preferably greater than about 95%, preferably greater than about 98%, preferably greater than about 99%.
  • the carrier particle gives rise to a reduced contact geometry for the adhered drug.
  • an inhalable drug carrier particle formed from a plurality of adhered or otherwise co-joined particle engineered sub-unit particles.
  • the sizes, surface properties and other features as discussed herein are applicable to these sub-unit particles and drug carrier particles.
  • at least about 10% of the particles forming the drug carrier particle are particle engineered sub- unit particles.
  • at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, about 99%, about 99.5%, about 99.9%, or about 99.99% of the particles forming the drug carrier particle are particle engineered sub-unit particles.
  • These sub-unit particles could have an average size of between about 20nm - 15 micron, 2-12 micron, 2-10 micron, less than 12 micron, less than 10 micron or any of the other sizes discussed herein.
  • a drug/carrier particle blend formed from drug carrier particles as discussed herein.
  • the carrier particles may be composed of any pharmacologically inert material or combination of materials which is acceptable for inhalation. They are suitably composed of one or more sugars including monosaccharides, disaccharides, polysaccharides such as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, dextran, starches and sugar alcohols such as mannitol or sorbitol and mixtures of two or more thereof.
  • a preferred diluent or carrier is lactose, particularly in the form of the monohydrate.
  • An alternate carrier is mannitol.
  • a plurality of carrier particles can be loaded with a drug or active pharmaceutical ingredient to form a drug/carrier particle blend.
  • a quantity of such a blend can then be loaded into a capsule or any container ready for aerosolisation and delivery to the respiratory tract of a patient.
  • Other pharmaceutically acceptable excipients, diluents and/or adjuvants can be added to the capsule or container if desired.
  • the adhesion between the drug and the carrier particle is preferably such to ensure a stable ordered mix of the blend whilst being low enough to allow drug liberation during inhalation.
  • drugs which can be used with the carrier particle of the present invention include beta-2 agonists, anticholinergics, mast cell stabilisers, steroids, methylxanthines, inhaled corticosteroids, cromolyn and nedocromil, theophylline, leukotriene modifiers long-acting beta-2 agonists, short-acting beta-2 agonists and/or systemic corticosteroids.
  • “Drugs”, for the purposes of the invention, include a variety of pharmaceutically active ingredients, such as, for example, those which are useful in inhalation therapy.
  • the term “drug” is to be broadly construed and include, without limitation, actives, drugs and bioactive agents, as well as biopharmaceuticals.
  • drug is interchangeable with the term medicament.
  • Various embodiments may include drugs present in micronized form or soluble form.
  • Appropriate drugs may thus be selected from, for example, analgesics, (e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine); anginal preparations, (e.g., diltiazem); anti-allergies, (e.g., cromoglicate, ketotifen or nedocromil); antiinfectives (e.g., cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine); antihistamines, (e.g., methapyrilene); antiinflammatories, (e.g., anti-inflammatory steroids, beclomethasone (e.g.
  • beclomethasone dipropionate fluticasone (e.g. fluticasone propionate), flunisolide, budesonide, rofleponide, mometasone (e.g. mometasone furoate), ciclesonide, triamcinolone (e.g.
  • the medicaments may be used in the form of salts, (e.g., as alkali metal or amine salts or as acid addition salts) or as esters (e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimize the activity and/or stability of the medicament.
  • the medicaments may be used in the form of a pure isomer, for example, R-salbutamol or R-formoterol.
  • Particular medicaments for administration using pharmaceutical formulations in accordance with the invention include anti-allergies, bronchodilators, beta agonists (e.g., long-acting beta agonists), and anti-inflammatory steroids of use in the treatment of respiratory conditions, as defined herein, by inhalation therapy, for example, cromoglicate (e.g. as the sodium salt), salbutamol (e.g. as the free base or the sulphate salt), salmeterol (e.g. as the xinafoate salt), bitolterol, formoterol (e.g. as the fumarate salt), terbutaline (e.g. as the sulphate salt), 3-(4- ⁇ [6-( ⁇ (2R)-2-hydroxy-2-[4-hydroxy-3-
  • cromoglicate e.g. as the sodium salt
  • salbutamol e.g. as the free base or the sulphate salt
  • salmeterol e.g. as the xinafoate
  • a beclomethasone ester e.g. the dipropionate
  • a fluticasone ester e.g. the propionate
  • a mometasone ester e.g., the furoate
  • budesonide dexamethasone, flunisolide, triamcinolone, tripredane, (22R)-6 ⁇ ,9 ⁇ - difluoro-11 ⁇ , 21 - dihydroxy- 16 ⁇ , 17 ⁇ -propylmethylenedioxy-4-pregnen-3,20-dione.
  • Medicaments useful in erectile dysfunction treatment e.g., PDE-V inhibitors such as vardenafil hydrochloride, along with alprostadil and sildenafil citrate
  • PDE-V inhibitors such as vardenafil hydrochloride, along with alprostadil and sildenafil citrate
  • alprostadil and sildenafil citrate may also be employed.
  • the drugs that may be used in conjunction with the inhaler are not limited to those described herein.
  • Salmeterol especially salmeterol xinafoate, salbutamol, fluticasone propionate, formoterol, budesonide, beclomethasone dipropionate and physiologically acceptable salts and solvates thereof are especially preferred.
  • formulations according to the invention may, if desired, contain a combination of two or more of any of the above drugs.
  • formulations containing two active ingredients are known for the treatment and/or prophylaxis of respiratory disorders such as those described herein, for example, formoterol (e.g. as the fumarate) and budesonide, salmeterol (e.g. as the xinafoate salt) and fluticasone (e.g. as the propionate ester), salbutamol (e.g. as free base or sulphate salt) and beclomethasone (as the dipropionate ester) are preferred.
  • the present invention is a method of forming an inhalable drug carrier particle comprising: a) particle engineering a substance to form sub-unit particles; b) adhering or otherwise co-joining the sub-unit particles to form the drug carrier particle.
  • particle engineering we mean processes of forming sub-unit particles of a particular size. In one embodiment, we mean processes of reducing the size of particles into smaller sub-units, i.e. particle size reduction.
  • Particle engineering processes includes spray drying, micronisation, freeze drying, crystallisation through sonication, high gravity precipitation, impinging jet precipitation, spray freeze drying, and supercritical fluid precipitation among others.
  • particle engineering is intended to cover any process by which small particles are formed.
  • the particles preferably end up with an average size of between about 20nm and about 20 microns although the term encompasses all of the sizes discussed herein in relation to sub-unit particles.
  • Examples of particle engineering include using a spray drying process using a spray dryer in which solutions of the material making up the particles are spray dried.
  • sub-unit particle manufacture including crystallisation, micronisation, or any suitable method for producing micro and/or nanoparticles.
  • the present invention is a method of forming an inhalable drug carrier particle for carrying at least one drug particle, said method comprising: a) using sub-unit particles with an average size of less than about 200% of the average size of the drug particle; b) adhering or otherwise co-joining the sub-unit particles to form the drug carrier particle.
  • the methods discussed herein can preferably use the sub-unit particles discussed herein. Furthermore, the methods discussed herein preferably form drug carrier particles with at least one of the properties discussed herein.
  • a method of forming a drug carrier particle comprising preparing sub-unit particles as discussed herein and binding or fusing the particles together to form the carrier particle.
  • the sub-unit particles can be formed using a spray drying process using a spray dryer in which solutions of the material making up the particles are spray dried.
  • Alternative methods of sub-unit particle manufacture can be used, including crystallisation, micronisation, or any suitable method for producing micro and/or nanoparticles.
  • the carrier particle is formed from sub-unit particles being each of substantially the same size.
  • the carrier particle is formed from sub-unit particles of different sizes.
  • the carrier particle can be formed from a first set of sub-unit particles of substantially the same size and second or further sets of sub-unit particles, with each sub-unit particle in a set being of substantially the same size.
  • the different sub-unit particle sizes can be obtained through control of the process used to form the particles, including the processes defined herein.
  • control can include controlling such features as the concentration of the solution, the inlet temperature at the spray dryer, the aspirator speed, the liquid flow rate and the atomisation pressure.
  • the sub-unit particles can have an average size of between about 20nm and about 15 microns, for example between about 2 and about 15 microns. In one embodiment, the sub-unit particles can have an average size of about 3 microns, about 5 microns, about 7 microns, or about 10 microns. In a further embodiment, the carrier particle can be formed from at least one set of sub-unit particles having an average size of about 3 microns and at least one set of sub-unit particles having an average size of about 5 microns, 7 microns or 10 microns. In a further embodiment, the sub-unit particles can be any of the sizes discussed herein (particularly as discussed on pages 3-6).
  • the carrier particles can be formed from a slurry containing a saturated solution of sub-unit particles. Techniques such as spheronisation, spray drying and granulation can be used to form the carrier particles. For example, the slurry can be dried in an oven and fractionated through a series of sieves to form carrier particles having a desired size.
  • the carrier particles formed from the plurality of sub-unit particles can have an average size of between about 50 to about 250 microns, more preferably between about 60 and about 100 microns, and even more preferably between about 63 and about 90 microns.
  • the formed carrier particle can have a substantially homogeneous surface.
  • the carrier particle can have a relatively increased surface roughness. At least some, the majority or all of the surface can be indented.
  • the surface morphology can be suitable for drug adhesion and drug delivery when required.
  • the adhesion of an active pharmaceutical ingredient to the carrier particle can be relatively spatially uniform. Where required, the surface morphology can be adjusted to suit the properties of the drug to be adhered to the carrier particle.
  • the carrier particle can be formed of sub-unit particles of any suitable material, including mannitol, lactose, and other sugars.
  • a mixing process can be used to load the formed carrier particles with the selected drug.
  • the drug can be micronised prior to mixing with the carrier particles to form a drug/carrier particle blend.
  • One example of a drug/carrier particle blend can be formed using salbutamol sulphate in a ratio of about 67.5:1 carrie ⁇ drug.
  • the drug/carrier particle blend can be loaded into a suitable capsule or container, such as a gelatine capsule.
  • the capsule can also be loaded if required with other pharmaceutically acceptable excipients, diluents and/or adjuvants.
  • the adhesion between the drug and the carrier particle is preferably such to ensure a stable ordered mix of the blend whilst being low enough to allow drug liberation during inhalation.
  • the present invention is a method of delivering a drug to a patient requiring the drug comprising forming a drug/carrier particle blend as defined herein and aerosolising the blend such that it is suitable for inhalation by the patient.
  • a plurality of carrier particles are loadable with a drug to form a drug/carrier particle blend.
  • the present invention is a drug/carrier particle blend formed from carrier particles as defined herein.
  • the drug/carrier particle blend can be formed using the method as defined herein.
  • the present invention comprises a method of delivering a drug to a patient requiring the drug, the method comprising forming a drug/carrier particle blend as defined herein and aerosolising the blend such that it is suitable for inhalation by the patient.
  • a drug herein, the present invention encompasses a plurality of drugs.
  • the present invention comprises a method of treating a patient having a respiratory or non-respiratory condition, said method comprising administering the drug/carrier particle blend as defined herein.
  • Respiratory conditions include, COPD, bronchitis, allergy, rhinitis, cystic fibrosis, pulmonary infection and asthma.
  • the present invention comprises use of the drug/carrier particle blend as defined herein in the manufacture of a medicament for treatment of a respiratory or non-respiratory condition of a patient.
  • the respiratory condition can be COPD, bronchitis, allergy, rhinitis, cystic fibrosis, pulmonary infection and asthma.
  • the medicament can be manufactured using the methods as defined herein.
  • an inhalation drug carrier particle for carrying at least one drug particle, said drug carrier particle formed from a plurality of adhered or otherwise cojoined sub-unit particles, wherein the average size of the sub- unit particle is selected such that, in use, the: a) surface topography; surface roughness; surface uniformity; surface homogeneity; and/or surface cohesion force of the drug carrier particle; and/or b) the contact geometry; and/or adhesion force of the drug carrier particle relative to the drug particle; and/or c) the fine particle fraction of the drug particle carried on the drug carrier particle; is optimised to enhance the aerosol performance of the drug/carrier particle blend.
  • an inhalation drug carrier particle for carrying at least one drug particle said drug carrier particle formed from a plurality of adhered or otherwise cojoined sub-unit particles comprising selecting an average size of the sub-unit particles such that, in use, the: a) surface topography; surface roughness; surface uniformity; surface homogeneity; and/or surface cohesion force of the drug carrier particle; and/or b) the contact geometry; and/or adhesion force of the drug carrier particle relative to the drug particle; and/or c) the fine particle fraction of the drug particle carried on the drug carrier particle; is optimised to enhance the aerosol performance of the drug/carrier particle blend.
  • Fig. 1 is a graph of particle size distribution of the sub-unit particles formed to manufacture the carrier particles according to the present invention
  • Fig. 2 is a graph of particle size distribution of carrier particles formed from the sub-unit particles defined herein, raw mannitol carrier, and micronised salbutamol sulphate;
  • Fig. 3 depicts X-ray powder diffraction patterns of regular carrier particles (i.e. not formed in accordance with the present invention) and composite carrier particles according to the present invention
  • Fig. 4 depicts scanning electron micrographs of 63-90 micron sieve fractionated (A) raw crystalline mannitol, (B) 3 micron, (C) 5 micron and (D) 10 micron carrier particles;
  • Figs. 5A and 5B are representative atomic force microscope topographic images of a regular carrier and a composite carrier;
  • Fig. 6 depicts the spatial adhesion distribution of salbutamol sulphate drug probe 1 over 10 x 10 ⁇ m areas of a regular and composite carrier;
  • Fig. 7A depicts the cumulative percentage adhesion plot for salbutamol AFM probe 1 measured over a 1O x 10 ⁇ m area on a regular and composite carrier (as in Fig. 5) and Fig. 7B depicts the median separation force of three probes on both carrier substrates;
  • Fig. 8 is a graph of the aerosolisation efficiency of salbutamol sulphate from different drug/carrier particle blends measured as fine particle fraction (FPF);
  • Fig. 9 represents next generation impactor stage deposition of salbutamol sulphate aerosolised from blends containing each of the carriers;
  • Fig. 10 provides high magnification SEM images of (A) regular carrier blend and (B) composite carrier blend with the arrows pointing to likely salbutamol sulphate particulates;
  • Fig. 1 1 is a graph of particle size distributions of the (A) micronised drug samples and primary lactose particles (median) and (B) carrier particles (sieved);
  • Fig. 12 provides scanning electron microscopy images of fractioned (A) regular carrier, (B) 2 ⁇ m based carrier, (C) 6 ⁇ m based carrier and (D) 10 ⁇ m based carrier;
  • Fig. 13 provides representative topographical images of the 63-90 ⁇ m sieve fractioned (A) regular carrier (B) 2 ⁇ m based carrier (C) 6 ⁇ m based carrier and (D) 10 ⁇ m based carrier;
  • Fig. 14 provides X-ray powder difractographs for the (A) primary lactose particles and (B) carriers;
  • Fig. 15 provides differential scanning calorimetry thermograms of (A) primary lactose particles and (B) carriers;
  • Fig. 17 shows the in vitro NGI stage deposition of salbutamol sulphate aerosolised from each of the carriers
  • Fig. 20 provides schematic views of different carrier particle morphologies and the predicted influence of this on drug particle adhesion.
  • carrier particles from a plurality of adhered, fused or otherwise co-joined sub-unit particles of mannitol and lactose. It will be appreciated that other materials, such as other sugars, can be utilised to form suitable carrier particles.
  • the carrier particles as formed herein can be used to form drug/carrier particle blends that are suitable for inhalation by a patient requiring the drug.
  • the drug can be suitable for treating respiratory conditions such as cystic fibrosis, COPD, bronchitis, allergy, rhinitis and asthma. It will also be appreciated that the drug can be suitable for delivery via the lungs and be used to treat non-pulmonary conditions.
  • mannitol sub-unit particles of approximately 3, 5, and 10 micron diameter were prepared by spray drying aqueous mannitol solutions through a laboratory scale Buchi-191 Mini Spray Dryer. The different particle sizes were obtained by carefully controlling the spray drying conditions, including the mannitol concentration, the inlet temperature, the aspirator speed, the liquid flow rate and the atomisation pressure.
  • mannitol particles with a diameter of approximately 3 microns
  • Fig. 1 depicts the particle size distribution of the formed mannitol sub-unit particles.
  • the sub-unit particles were used to form a series of different larger composite carrier particles. As described below, different carrier particle combinations were formed from the different groups of sub-unit particles. It will be appreciated that carrier particles could be formed, if desired, from sub-unit particles of different diameters.
  • composite carriers were produced using a wet granulation method in which different slurries were made. Each was made from only one size of the primary spray-dried mannitol particles. Saturated mannitol was used as the binder and constituted no more than 10% v/w of the total slurry. The slurries were dried and sieve fractionated (e.g. through a 180 microns sieve) to obtain a 63-90 microns diameter carrier particle formulation. The particle size distribution of the composite carrier particles were confirmed by laser diffraction (see Fig. 2).
  • the crystallinity of the carrier particles and a regular carrier not formed according to the method of the present invention were each assessed using X-ray powder diffraction (XRPD, D5000, Siemens, Germany) at room temperature using a Cu Ka radiation at 30 mA and 40 kV, with an angular increment of 0.05°/s and count time of 2s.
  • XRPD X-ray powder diffraction
  • the results of the X-ray diffraction are presented in Fig. 3, with the patterns produced being characteristic of a crystalline material.
  • the particle morphology was investigated optically using a stereo-microscope at
  • Elongation ratios of 2.08 ⁇ 0.56 ⁇ m and 1.95 ⁇ 0.63 ⁇ m for regular and composite carrier particles, respectively were determined.
  • the regular carrier had a higher shape value of 0.56 ⁇ 0.17 ⁇ m which was higher than the composite carrier 0.35 ⁇ 0.11 ⁇ m. This is understood on the basis that the composite carrier has an increased perimeter function as it is made up of many smaller sub-units rather than one crystal plane.
  • Fig. 4 depicts the scanning electron micrographs of 63-90 micron sieve fractionated (A) raw crystalline mannitol (a control), (B) 3 micron, (C) 5 micron and (D) 10 micron composite carrier particles.
  • R RM S surface root mean square roughness
  • the surface roughness of the regular and composite particles was 0.64 ⁇ 0.35 ⁇ m and 0.79 ⁇ 0.09 ⁇ m, respectively.
  • the composite carrier had a higher mean R RMS , statistical analysis suggested no significant difference between the two carriers existed (Students t test, p ⁇ 0.05). It is likely that this lack of significance between the surface roughnesses of the two carriers is due to the increased variability in sample morphology of the regular carrier. Such variation can be observed by comparing the relative standard deviations (RSD) of the R RMS values, where the regular carrier exhibited a variance of 55%, in comparison to 11 % for the composite carrier.
  • RSS relative standard deviations
  • the projected topographical surface area of each image was divided by the sample image area (i.e. lO ⁇ m x lO ⁇ m) to obtain a projected surface area per square micron (A proj ).
  • Statistical analysis of the A pr qj suggested, significant differences between the two carriers (students t test, p ⁇ 0.05).
  • the force of cohesion between individual micronised salbutamol particles and carrier particles was assessed using colloid probe microscopy. Individual particles of micronised salbutamol sulphate were mounted onto the apex of nominal 0.58 N/m tipless AFM cantilevers (NP-OW, Veeco, Cambridge, United Kingdom). Particles of each carrier were mounted on carbon sticky tabs, attached to AFM sample stubs. The force of cohesion between each drug probe and both regular and composite carrier were investigated in force volume mode. 4096 individual force curves were conducted over 10 ⁇ m x 10 ⁇ m areas of each substrate using the following settings: approach-retraction cycle, 2 ⁇ m, cycle rate, 8.33 Hz, and constant compliance region of 60 nm.
  • FIG. 6 A spatial adhesion plot of salbutamol sulphate particle adhesion with both regular and composite carriers is shown in Fig. 6. From this figure it can be seen that the adhesion of salbutamol sulphate to the regular carrier was greater than for the composite carrier, with greater variation in maximum and minimum force values. To further investigate this, the particle adhesion values were processed to produce a probability histogram.
  • Fig. 7 A shows the cumulative separation force distribution of salbutamol sulphate drug probe 1 with both regular and composite carrier particles.
  • the different formed carrier particles were mixed with micronised salbutamol sulphate in a ratio of 67.5:1 w/w to achieve a dose of 400 ⁇ g salbutamol sulphate per every 30mg of final blend.
  • a further blend using raw crystallised mannitol was also formed.
  • Other drugs and ratios can be envisaged.
  • gelatine capsules Size three, Capsugel, Sydney, Australia
  • a quantity of blend 33 ⁇ 3 mg
  • Containers other than capsules can be envisaged as being suitable for the invention.
  • a next generation impactor (NGI) (British Pharmacopoeia) was then used to characterise the aerosolisation efficiency.
  • the drug deposited on specific stages of the NGI were investigated.
  • the drug deposition in all stages of the NGI is shown in Fig. 9.
  • the drug deposited on stage 3 filter of the NGI is plotted along with its percentage represented as a function of the total loaded and emitted dose (referred to as the fine particle fraction of the loaded (FPF LD ) and emitted (FPF ED ) dose, respectively).
  • These fractions (stage 3-filter) represent particles with an aerodynamic diameter of less than 4.46 ⁇ m, which would most likely penetrate the respiratory tract upon inhalation.
  • the micron-sized particulates appear to have a high contact area with the planar surface of the carrier material. Furthermore, many particulates appear to be adhered in areas of potentially high adhesion (such as crevice features).
  • identification of salbutamol sulphate drug particles in the composite blend is easier, since the needle-like morphology is a stark comparison to the spherical geometry of the carrier. From Fig. 9B it can be seen that the contact geometry between the drug particles is reduced due to each particle making contact with multiple mannitol sub-units. It envisaged that this formulation would result in reduced adhesion (as observed by AFM) and increased aerosolisation efficiency (as observed in the in vitro deposition studies).
  • Lactose monohydrate (Lactochem® crystals) was supplied by Friesland Foods
  • Domo (Zwolle, The Netherlands).
  • the model drug, micronised salbutamol sulphate was supplied by 3M (St. Paul, MN, USA). Water was purified by reverse osmosis
  • a series of primary micron-sized lactose particles were prepared by spray drying an aqueous solution of lactose using a Mini Spray Dryer (B ⁇ chi, B-191, Switzerland).
  • Target particle size Inlet Measured outlet Aspiration Atomising air Liquid feed rate Aqueous lactose temperature temperature (%) flow (L.h 1 ) (ml.min ') solution (g.r 1 )
  • the prepared powders were stored in a tightly sealed container with silica gel for a 5 minimum of 24 hours prior to composite formation.
  • the primary lactose particles were mixed with a 10% v/w saturated lactose aqueous slurry and passed through a 180 ⁇ m sieve.
  • the resultant aggregates were dried at 150 °C for 1.5 hours in a mini fluid bed dryer (Umang Pharmatech Ltd. Easton, PA, USA).
  • the composite powders were collected and stored for 24 hours as before, prior to sieving through a
  • the morphology of the carrier particles were investigated using scanning electron microscopy (SEM). Samples were prepared by depositing on a carbon sticky
  • the carrier particles were imaged at 10 keV using a field emission SEM (FESEM).
  • each carrier was studied with conventional Tapping Mode® atomic force microscopy (AFM) (Multimode AFM, nanoscope HIa controller, Veeco Inc., California, USA). Samples were mounted on carbon sticky tabs and imaged with a high aspect ratio silicon probe (MicroMasch tips, Group Scientific Ltd, Sydney, Australia) at a scan rate of 1.0 Hz. Three 10 ⁇ m x 10 ⁇ m areas were studied for each
  • the particle size distributions of the micronised salbutamol sulphate, primary lactose particles and carriers were investigated using laser diffraction. Samples were analysed using the Malvern Mastersizer 2000 with Scirocco dry powder feeder (Malvern, UK). The micron-sized powders were analysed using a 400 kPa pressure differential while the carrier systems were analysed at 100 kPa. Samples were repeated in triplicate at an obscuration between 0.3-10.0%. Refractive indices of 1.540 and 1.553 were used for lactose and salbutamol sulphate samples, respectively.
  • the crystalline properties of the primary lactose particles and four carriers were investigated using X-ray powder diffraction. Samples were analysed at room temperature with a XRPD D5000 (Siemens, Kunststoff, Germany) using CuKa radiation at 30mA and 40 kV. An angular increment of 0.05 0 S. "1 and count time of 2 s was used.
  • DSC differential scanning calorimetry
  • Colloid probe microscopy was used to measure the force of adhesion between individual salbutamol sulphate particles and each carrier. Individual particles of micronised salbutamol sulphate were mounted onto the apex of 0.58 N.m "1 spring constant tipless AFM cantilevers (NP-OW, Veeco, Cambridge UK), using methods and validation described elsewhere. Prior to measurement, particles of each carrier were mounted on carbon sticky tabs and attached to AFM sample stubs. The force of cohesion between each drug probe and both regular and composite carrier was investigated in Force Volume mode, where 4096 individual force curves were conducted over 10 ⁇ m x 10 ⁇ m.
  • HPLC High performance liquid chromatography
  • the aerosol performance of micronised salbutamol sulphate from each drug- carrier formulation was investigated using the next generation impactor (NGI).
  • NGI next generation impactor
  • the NGI (Apparatus E, British Pharmacopeia, Appendix XXI F) is an 8-stage inertial impactor that separates an aerosol cloud into discrete size ranges based on aerodynamic diameter.
  • the method followed that specified for DPIs in the pharmacopoeia (Appendix XXI F). All in vitro measurements were conducted at 60 l.min “1 , (obtained using a Rotary vein pump and solenoid valve timer (Erweka GmbH, Germany) which was set using a calibrated flow meter (TSI 3063, TSI instruments Ltd., Buckinghamshire, UK).
  • Size distributions of the primary particles and salbutamol sulphate are shown in fig 1 1 A, while the engineered carriers are shown in Fig 11 B.
  • the salbutamol sulphate particle size distribution had a median diameter (d o . 5 ) of 1.39 ⁇ m ⁇ 0.05 ⁇ m with 90% of particles (do.9) less than 2.71 ⁇ m ⁇ 0.14 ⁇ m, suggesting the micronised drug to be of a suitable size for inhalation.
  • the spray dried primary lactose particles, used to engineer the composite carriers had d.05 diameters of 2.27 ⁇ m ⁇ 0.12 ⁇ m, 6.15 ⁇ m ⁇ 0.50 ⁇ m and 10.75 ⁇ m ⁇ 0.09 ⁇ m.
  • Fig 12 A Representative scanning electron micrographs of the sieve fractioned composite and regular carrier particles are shown in Fig 12. All carriers appeared to have similar macroscopic morphology and size distributions. This is expected since all carriers were processed through a 63-90 ⁇ m sieve fraction. Higher resolution images showed distinct variations between the regular carrier (Fig 12 A) and the composite carriers (Fig 12 B- C). In general, the regular carrier particles were formed as discrete singular crystals of the sieve fractioned range whereas the composite carriers were macroscopically similar in dimension to the regular carrier, but were composed of multiple micron-sized particles appearing crystalline in nature. In addition, qualitative analysis of the composite carriers suggested an increase in micro-particle morphology between the 2 ⁇ m and 10 ⁇ m based composite carriers, respectively.
  • X-ray powder diffractograms of the primary lactose particles and carriers are shown in Fig 14 A and B, respectively.
  • the diffuse diffraction patterns for the primary lactose particles (Fig 14 A) are indicative of an amorphous material.
  • the diffraction patterns for the carrier materials had intensity patterns characteristic of crystalline material.
  • the diffraction patterns for the carrier materials (Fig 14 B) were similar and had peaks characteristic of ⁇ -lactose monohydrate at 12.4° 2 ⁇ .
  • the composite carrier diffraction patterns had intensities less than that of the regular carrier, most likely due to the significant difference in the primary crystal size (2-10 ⁇ m in comparison to 63-90 ⁇ m).
  • the composite carriers had an additional peak at 10.6° 2 ⁇ , suggesting the presence of ⁇ -lactose which is produced due to the mutarotation of the ⁇ -form during the drying process.
  • Fig 15 A and B Differential scanning thermograms for the four primary lactose particles and four carriers are shown in Fig 15 A and B, respectively.
  • the thermal response for the primary particles was indicative of an amorphous material.
  • an exothermic peak for each powder was observed with an onset between 130-140°C.
  • the onset increased with increasing median particle temperature. It is suggested that this increase is due to an increase in heat capacity and reduction in surface area to mass ratio.
  • the thermal response of the carrier materials (Fig 15 B) were characteristic of crystalline material.
  • Equation 2 GSD - Where f x are the respective percentile force values for the lognormal distribution. Essentially a GSD of 1 would be a monomodal, monodispersed force distribution.
  • the drug recovered from all components of the NGI and device was measured by HPLC as previously described and the data was processed to produce various descriptors of aerosolisation efficiency. These were the total recovered dose from the device and all NGI components (TD); the emitted dose (ED), representing TD excluding capsule and device components; the fine particle dose (FPD) representing drug recovered from stage 3 to 8 of the NGI (equivalent to the mass of particles with an aerodynamic diameter ⁇ 4.46 ⁇ m).
  • the percentage drug deposited on each stage was calculated for each formulation and is plotted in Fig 17. Analysis of the total TD and ED suggested no significant differences with recoveries of 514.9 ⁇ m ⁇ 44.8 ⁇ m and 431.7 ⁇ m ⁇ 32.5 ⁇ m being observed across all formulations.
  • FIG. 20 A schematic of the likely influence of morphology on the relative contact area between drug and carrier is shown in Fig. 20.
  • a carrier containing a surface constructed of smaller units allows control of the surface morphology.
  • Specific inter-particular 'gaps' between the individual components of the composite may result in variations in geometry and surface roughness. This can subsequently influence the contact geometry between drug and carrier; thus influencing adhesion and aerosol performance.
  • the degree of adhesion may be tailored to the specific drug particles used.
  • the use of smaller sub-units to make up the carrier results in a morphology which is more consistent on the micro and nanoscopic levels

Abstract

L'invention concerne de nouvelles particules vecteurs formées à partir d'une pluralité de particules sous-unitaires agglomérées ou unies d'une quelconque manière, aptes à l'aérosolisation. L'invention se rapporte aussi à des procédés de formation de particules vecteurs de médicament, et à des mélanges de particules vecteurs et de médicaments destinés à la thérapie par inhalation de poudre sèche.
PCT/AU2008/000630 2007-05-03 2008-05-05 Vecteurs composites pour thérapie par inhalation de poudre sèche WO2008134817A1 (fr)

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AU2007902336A AU2007902336A0 (en) 2007-05-03 Composite carriers for dry powder inhalation therapy
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AU2007903179A AU2007903179A0 (en) 2007-06-13 Composite carriers for dry powder inhalation therapy

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011069197A1 (fr) * 2009-12-08 2011-06-16 The University Of Sydney Formulations inhalables

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6103270A (en) * 1996-06-07 2000-08-15 Inhale Therapeutic Systems Methods and system for processing dispersible fine powders
US6153224A (en) * 1995-01-31 2000-11-28 Co-Ordinated Drug Development Limited Carrier particles for use in dry powder inhalers
US6309623B1 (en) * 1997-09-29 2001-10-30 Inhale Therapeutic Systems, Inc. Stabilized preparations for use in metered dose inhalers
WO2002045682A1 (fr) * 2000-12-08 2002-06-13 School Of Pharmacy, University Of London Support d'inhalation particulaire
WO2004017914A2 (fr) * 2002-08-21 2004-03-04 Ivax Corporation Compositions a inhaler

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6153224A (en) * 1995-01-31 2000-11-28 Co-Ordinated Drug Development Limited Carrier particles for use in dry powder inhalers
US6103270A (en) * 1996-06-07 2000-08-15 Inhale Therapeutic Systems Methods and system for processing dispersible fine powders
US6309623B1 (en) * 1997-09-29 2001-10-30 Inhale Therapeutic Systems, Inc. Stabilized preparations for use in metered dose inhalers
WO2002045682A1 (fr) * 2000-12-08 2002-06-13 School Of Pharmacy, University Of London Support d'inhalation particulaire
WO2004017914A2 (fr) * 2002-08-21 2004-03-04 Ivax Corporation Compositions a inhaler

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011069197A1 (fr) * 2009-12-08 2011-06-16 The University Of Sydney Formulations inhalables

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