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WO2021090013A1 - Nouvelle composition comprenant des particules nanoporeuses de silice amorphe - Google Patents

Nouvelle composition comprenant des particules nanoporeuses de silice amorphe Download PDF

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Publication number
WO2021090013A1
WO2021090013A1 PCT/GB2020/052810 GB2020052810W WO2021090013A1 WO 2021090013 A1 WO2021090013 A1 WO 2021090013A1 GB 2020052810 W GB2020052810 W GB 2020052810W WO 2021090013 A1 WO2021090013 A1 WO 2021090013A1
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Prior art keywords
particles
composition
silica particles
active ingredients
silica
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Inventor
Adam Feiler
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Nanologica AB
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Nanologica AB
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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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5115—Inorganic compounds
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • This invention relates to new pharmaceutical compositions, their use as medicaments and particularly to their administration to the lung to treat lung diseases.
  • Active ingredients need to be formulated in a form that is not only suitable for inhalation, but also for loading into, and administration from, an inhalation device, with a view to enabling efficacy either on a topical basis, or to allow for systemic absorption into plasma following deposition, in the lung.
  • inhaled drug delivery systems present many more difficulties, as the respiratory system is so complex.
  • inhaled active ingredients must not only be efficiently deposited in the right part(s) of the airway, but must also be in a form in which they are able to exert their therapeutic action.
  • the epithelia of the lung comprise a periciliary layer of cells with a luminal mucus layer on top of the cell layer. Any bioactive compound needs to traverse the mucus layer to get into the cell layer.
  • the cell layer In the alveoli in the lower lung, the cell layer is in an aqueous phase and covered by pulmonary surfactant. A bioactive compound needs to traverse the surfactant layer to get to the cell layer underneath.
  • the mucus layer and the surfactant layer are composed of different materials and thus permeation through these layers requires different properties. Therefore, the site of deposition is expected to influence the rate and extent of absorption of a bioactive compound in the lung. Dissolution of bioactive compounds in the mucus or surfactant layer is important for therapeutic effect. Compounds having a lower solubility and/or dissociation constant are less effective in the lung because of low drug exposure. Conversely, low solubility of compounds can be used to prolong drug action because of a longer retention time in the lung.
  • the epithelia of the lung may present differently to healthy tissue and provide a further rate limiting step for a therapeutic effect. Further, as with all modes of drug delivery, effectiveness is based on a combination of dissolution rate and lung mucosal permeation rate and efficiency.
  • Particle size or diameter of either the active ingredient itself or the composition containing it must be below 6 pm in order to reach the lower lung.
  • MMAD mass median aerodynamic diameter
  • density and shape of particles hygroscopicity of particles.
  • hygroscopicity of particles hygroscopicity of particles.
  • MMAD mass median aerodynamic diameter
  • the MMAD should be in the range of 1 and 5 pm. Smaller sized particles are likely to be exhaled and larger sized particles are deposited in the upper airways. Preferably, monodispersed particles are used having a narrow particle size distribution.
  • Suitable pharmaceutical compositions for pulmonary delivery preferably have a controlled particle size and sharp and controllable particle size distribution (PSD), which is beneficial for precise lung deposition. Particle size influences the deposition of particles in the different areas in the lung.
  • PSD particle size distribution
  • deposition of a compound in the different regions of the lungs may also be affected by disorders that give rise to inferior lung function.
  • disorders that give rise to inferior lung function.
  • more drug is deposited in the upper lung compared to healthy volunteers. This results in less drug being deposited in the lower lung and therefore absorbed through the air-blood barrier in the alveoli, which reduces the systemic effect of the drug.
  • compositions that may be employed to carry active ingredients also need to be biocompatible, which means preferably biodegradable and soluble.
  • Suitable pharmaceutical composition for pulmonary delivery of drugs or bioactive compounds include dry powder compositions. Such compositions are often limited to the use of crystalline drugs, because oily or amorphous compounds are extremely difficult to formulate into a dry powder that can be used for consistent and invariable dosing.
  • composition is not sensitive to humidity because that may cause the composition to aggregate and affect the deposition pattern of particles.
  • Inhalation devices that are typically employed to administer active compounds to the lung include metered dose inhalers (MDIs), dry powder inhalers (DPIs) and soft mist inhalers (SMIs). DPIs may be divided into low, medium and high resistant DPIs.
  • MDIs metered dose inhalers
  • DPIs dry powder inhalers
  • SMIs soft mist inhalers
  • the efficiency of DPIs is affected by two main forces 1) an inspiration air flow (IAF), which depends on a flow generated by the patient, and 2) a turbulence produced by the device.
  • IAF inspiration air flow
  • turbulence produced by the device.
  • a balance between these two forces is important for optimal performance of a device. If the IAF is too low, most of the drug is lost in the upper lung, i.e. the throat and the trachea. On the other hand, with most DPI-administered formulations, if the IAF is too high, more drug may be delivered in the lower lung (the bronchi and alveoli), but in a manner where there is often poor disaggregation of particles, and therefore dispersion of the drug in the lung.
  • Typical fixed-dose drug combinations for pulmonary delivery require powder homogeneity to deliver a uniform dose of drug to patients. This is often attempted by a simple blend of micronized drugs with coarse carrier particles.
  • the pharmaceutical composition is typically present in a liquid form, as a solution or suspension in a propellant, such as a hydrocarbon, a fluorocarbon or a hydrogen-containing fluorocarbon. In such systems, it is often difficult to prevent dissolution of a bioactive compound from the particle or to prevent leakage of the compound from the drug-containing particle.
  • solvents and/or surfactants are employed with a view to imparting stability to the suspension of drug particles.
  • the compound needs to have a low solubility in the solvents that are used.
  • UK patent application GB 2355711 discloses a method for the preparation of particles, whereby the particles are sized during the manufacturing of the particles.
  • Patlolla et a/, J. Control Release, 144, 233 (2010) discloses the encapsulation of celecoxib in nanostructured lipid carrier nanoparticles and their nebulization prior to administration to mice.
  • US patent application US 2003/0211035 A1 describes the attachment or encapsulation of a biomedical functional material (such as a bioactive agent ligand) to polymeric microspheres.
  • Contreras et al, Mol. Pharm., 12, 2642 (2015) evaluates the difference between oral and pulmonary administration of porous particles formed by spray drying a solution of rifampicin and L-leucine) to guinea pigs.
  • Particles comprising nanoporous (mesoporous) silica materials have been disclosed for use in general pharmaceutical and cosmetic applications in inter alia international patent application WO 2012/035074.
  • poorly soluble active ingredients are incorporated within nanopore channels of the silica particles.
  • the use of similar particles with a specific particle size distribution for delivery of active ingredients to the respiratory tract are disclosed in international patent application WO 2018/202818. See also international patent applications WO 2019/211624 and WO 2020/095042.
  • composition suitable for administration to the lung, which composition comprises a plurality of particles, which particles comprise or consist of one or more active ingredients that is/are suitable for delivery to the lung, and which particles have:
  • MMAD mass median aerodynamic diameter
  • mean particle size that is/are that is between about 0.95 pm and about 6.05 pm
  • compositions of the invention a geometric standard deviation (GSD) that is no more than 1.33, which compositions are hereinafter referred to as 'compositions of the invention'.
  • GSD geometric standard deviation
  • mean particle sizes may be presented as weight-, number-, or volume-, based mean diameters.
  • the term 'weight based mean diameter' will be understood by the skilled person to include that the average particle size is characterised and defined from a particle size distribution by weight, i.e. a distribution where the existing fraction (relative amount) in each size class is defined as the weight fraction, as obtained by e.g. sieving (e.g. wet sieving).
  • volume based mean diameter' is similar in its meaning to weight based mean diameter, but will be understood by the skilled person to include that the average particle size is characterised and defined from a particle size distribution by volume, i.e. a distribution where the existing fraction (relative amount) in each size class is defined as the volume fraction, as measured by e.g. laser diffraction.
  • the term 'number based mean diameter' will be understood by the skilled person to include that the average particle size is characterised and defined from a particle size distribution by number, i.e. a distribution where the existing fraction (relative amount) in each size class is defined as the number fraction, as measured by e.g. microscopy.
  • Mass median aerodynamic diameter will be understood by those skilled in the art to mean the diameter at which 50% of the particles by mass are larger and 50% are smaller over the total delivered dose as determined by any approved device, usually a cascade impactor such as a NGI, Andersen or Marple Miller impactor (see e.g. US Pharmacopeia at ⁇ 601>; and/or www.uspbpep.com/usp31/v31261/usp31nf26sl_c601.asp).
  • MMAD may be readily determined by those skilled in the art, for example by plotting on log probability paper the percentages of mass that is less than the stated aerodynamic diameters versus the aerodynamic diameters. The MMAD is taken as the intersection of the line with the 50% cumulative percent.
  • Particle sizes and/or MMADs of the particles may be varied depending on the preferred and/or intended site of delivery of the active ingredient. Particle sizes and/or MMADs that may be mentioned is/are between about 1 pm and about 5.50 pm. However, it is preferred that the particle size and/or MMAD of particles in compositions of the invention is between about 1.05 pm (e.g.
  • about 1.5 pm and about 5.0 pm such as up to about 4.4 pm, for example up to about 3.0 pm, and for example specifically about 1.6 pm, about 1.7 pm, about 2.9 pm, about 2.8 pm, about 2.7 pm, about 2.6 pm, about 2.5 pm, about 2.4 pm, or about 2.3 pm preferably between about 1.8 pm and about 2.2 pm, such as 1.9 pm or about 2.1 or about 2.0 pm.
  • This will mean that particles will tend to deposit primarily in the bronchioli.
  • GSD will be understood by those skilled in the art to be a measure of the spread of an aerodynamic particle size distribution. It is typically calculated as follows as:
  • d9o/dlo 1/2 wherein d9o and dio represent the diameters at which 90% and 10%, respectively, of the aerosol mass are contained, in diameters less than these diameters.
  • the GSD of particles in compositions of the invention is about less than 1.32, such as less than 1.28 or less than 1.25, including less than 1.23. less than about 1.22, and even less than about 1.21, about 1.20, about 1.19, about 1.18, about 1.17, about 1.16, about 1.15, about 1.14, about 1.13, about 1.12, about 1.11, about 1.10, about 1.09, about 1.08, about 1.07, about 1.06 or about 1.05 or less.
  • FPF fine particle fraction
  • the FPF is the proportion of particles that are deposited in lungs which is typically taken as below 5pm.
  • Preferred FPFs are at least about 50%, including at least about 60%, such as at least about 75% (e.g. at least about 80%), including at least about 85%, e.g. at least about 90%, such as at least about 95%, at least about 98%, and up to at least about 99%, at least about 99.9% or about 100%.
  • compositions of the invention comprise or consist of particles that are very small, but have a well-defined particle size distribution.
  • Compositions of the invention may be manufactured in numerous ways, for example as described hereinafter. However they are manufactured, it is essential that they are separated and classified into the particle size ranges disclosed herein by an appropriate process known to those skilled in the art.
  • particles may be separated using cyclonic separation, by way of an air classifier, sedimentation, force-field fractionation, and/or by sieving using one or more sieves or filters to obtain particles within the desired size ranges.
  • particles within the desired size ranges are preferably obtained by elutriation, for example as described hereinafter.
  • Elutriation is a process for separating particles based on their size, shape and density, using flowing liquid in a direction opposite to the direction of sedimentation.
  • the smaller particles rise to the top (overflow) because their terminal sedimentation velocities are lower than the velocity of the rising fluid.
  • Particles within the size range mentioned herein are also often prone to aggregation in air due to the large surface area to volume ratio.
  • particle aggregation is a serious hurdle for pulmonary delivery, given that the particle size is critical to ensure correct distribution of the particles in the lung. Aggregation of particles would be expected to lead to accumulation in the throat and upper airways thereby limiting the effectiveness of the formulation. Additionally, aggregation of particles or sticking of particles in the capsules during inhalation is a severe limitation. Given that, in the field of inhalation of dry powders, active ingredients are typically administered in the form of micronized particles (of a size between about 1 pm and about 6 pm). The problem of aggregation is typically solved by either suspending micronized particles of active ingredient in a propellant (e.g.
  • HFA HFA
  • other excipients such as mannitol, lactose, sorbitol, etc.
  • inactive excipient e.g. mannitol or lactose
  • monodisperse porous particles within this size range may be made on a bench scale by various routine methods, such as precipitation, seeded and controlled growth, emulsification and microfluidics techniques, it is very difficult or very costly to manufacture porous particles on a larger, industrially-relevant scale with a perfectly uniform particle size without the creation of fine particles or sub-micron particles.
  • Spray drying is technique that is used on an industrial scale but this produces particles with a broad particle size distribution and creates fine particles.
  • composition suitable for administration to the lung, which composition consists essentially of a plurality of particles, which particles comprise or consist of one or more active ingredient that is suitable for delivery to the lung, and which particles have:
  • a MMAD and/or a mean (or an absolute) particle size, that is/are between about 0.95 pm and about 6.05 pm;
  • the phase 'consisting essentially of includes that the composition of the invention is substantially free of any excipients that are added and either do act, or are intended to act, as a lubricant.
  • the phrase 'consisting essentially of includes that the composition comprises less that about 1%, such as less than about 0.5%, including less than about 0.1%, or less than about 0.01%, or even less than about 0.001%, of such excipients by total weight of a composition of the invention.
  • compositions of the invention allow for the removal of fines, and thereafter the production of compositions of the invention on an industrial scale, which compositions are provided in the form of handleable powders that can be administered to patients using conventional devices in a manner that provides effective therapy in a reproducible manner, in view of the fact that aggregation is not a problem.
  • compositions of the invention may comprise or consist of one or more active ingredients that is/are suitable for delivery to the lung in the form of a dry powder.
  • Dry powders are typically administered to the lung by employing one or more of the devices mentioned hereinbefore (MDIs, SMIs and DPIs).
  • compositions of the invention comprise one or more active ingredients that is/are suitable for delivery to the lung, they may further comprise excipients that may be termed 'carrier particles', which carrier particles are associated in some way with said active ingredient in a pulmonary drug delivery composition.
  • excipient and/or carrier particles that may be employed in compositions of the invention may thus comprise one or more of the materials that are presently employed in the delivery of active ingredients to the lung in the form of dry powders.
  • Such materials may be presented in the form of a simple and/or random mixture with active ingredients, as part of an interactive mixture, in which, for example, smaller particles of active ingredients are adhered to carrier particle surfaces, and/or as porous materials, in which active ingredients are loaded into the pores of such particles.
  • excipients that are typically employed in MDI inhalation technology in which active ingredients administered as a pressurized suspension of micronized particles distributed in a propellant (e.g. HFA) include mannitol, lactose, sorbitol, etc.).
  • active ingredients are administered in the form of micronized drug particles, either alone or blended with inactive excipient of larger particle size (e.g. mannitol or lactose), inside a capsule, which may be pre-loaded or manually loaded into a device.
  • Inhalation from a DPI may de-aggregate the medication particles and disperse them within the airways.
  • active ingredient(s) is/are loaded into the pores of amorphous nanoporous (mesoporous) silica particles.
  • Such silica particles of the compositions of the invention may also have a mass density that is less than about 0.6 g/cm 3 , such as about 0.4 g/cm 3 , for example between about 0.15 and about 0.35 g/cm 3 .
  • the silica particles that may be employed in compositions of the invention may have a pore size that is between about 1 nm (e.g. about 2 nm) and about 100 nm (e.g. about 50 nm).
  • Porous silica particles preferably have an average pore size that is in the range of about 2 nm (e.g. about 3 nm, such as about 4 nm, including about 5 nm and about 8 nm) up to about 30 nm (e.g. about 20 nm, such as about 16 nm (e.g. about 15 nm), including about 13 nm, such as about 12 nm (e.g. about 10 nm).
  • Specific average pore sizes that may be mentioned include about 4.5 nm, about 5.0 nm, about 5.5 nm, about 6.5 nm, about 7.0 nm, about 7.5 nm, about 8.0 nm, about 8.5 nm, about 9.0 nm, about 9.5 nm, about 10 nm, about 11 nm, about 12 nm, about 13 nm, or about 14 nm.
  • Such particles may also possess a pore volume that is between about 0.05 cm 3 /g, such as about 0.08 cm 3 /g, including about 0.09 cm 3 /g (e.g.
  • about 0.1 cm 3 /g such as about 0.2 cm 3 /g, or about 2 cm 3 /g
  • 3 cm 3 /g such as about 2.5 cm 3 /g, including about 2.0 cm 3 /g (e.g. about 1.5 cm 3 /g or about 1.0 cm 3 /g), and/or may preferably possess a surface area that is in the range of about 35 m 2 /g, e.g.
  • m 2 /g or about 50 m 2 /g (such as about 100 m 2 /g, including about 150 m 2 /g or about 200 m 2 /g) up to about and about 1,200 m 2 /g, such as about 450 m 2 /g, including about 350 m 2 /g, e.g. about 300 m 2 /g. All of these parameters may be determined by routine techniques, such as nitrogen adsorption isotherm (Brunauer, Emmett and Teller (BET)), mercury inclusion, and Barrett, Joyner and Halenda (BJH), methods.
  • BET Brunauer, Emmett and Teller
  • BJH Barrett, Joyner and Halenda
  • Shapes of the mesoporous silica particles may be controlled by the process of manufacture. Shape may be important for the incorporation and dissolution of the active ingredient. Thus, although silica particles may potentially be any shape (e.g. gyroids, rods, fibres, pseudo-spheres, cylinders, core-shells) in compositions of the invention, they are preferably essentially spherical.
  • essentially spherical we mean that they may possess an aspect ratio smaller than about 20, more preferably less than about 10, such as less than about 4, and especially less than about 2, and/or may possess a variation in radii (measured from the centre of gravity to the particle surface), in at least about 90% of the particles that is no more than about 20% of the average value, such as no more than about 10% of that value, for example no more than about 5% of that value.
  • Porous silica particles may be loaded with one or more active ingredients by any suitable process known to those skilled in the art.
  • particles may be loaded by way of a solvent evaporation technique, for example as described hereinafter, impregnation, for example using a melt, use of supercritical CO2, shear mixing, co-grinding, spray-drying or freeze-drying.
  • Well known equipment such as a fluidized bed may be used.
  • a preferred technique is solvent evaporation.
  • active ingredients may be manufactured as nanocrystals and adsorbed onto silica particles.
  • Loading the active ingredient into silica particles means that it is loaded into the nanopores of the particles. It is preferred that the pores of the silica particles are loaded, such that between about 0.1 and about 60%, preferably up to about 50%, such as up to about 45%, including up to about 40%, such as up to about 35% or up to about 30%, including up to about 25% (e.g. about 20%, or about 10%) of the total weight of the loaded particles is active ingredient and, optionally, other pharmaceutical excipients, diluents or additives. In the alternative, it is preferred that up to about 60%, including up to about 70%, or up to about 80%, such as up to about 90%, e.g.
  • the pores of the silica particles are loaded with active ingredient and, optionally, other pharmaceutical excipients, diluents or additives.
  • active ingredient up to about 100% of the pores of the silica particles are loaded with active ingredient and, optionally, other pharmaceutical excipients, diluents or additives.
  • the entire mass of active ingredient does not have to be loaded into the pores of the particles and may otherwise be attached to the surfaces of the particle.
  • Active ingredients may be loaded into such silica particles in a manner that is independent of the morphology of the drug compound.
  • Crystalline, oily and amorphous compounds may be attached to, or loaded into, the particles.
  • active ingredients may be presented within the pores of the particles of compositions of the invention in an essentially crystalline state.
  • crystalline we mean that the active ingredient is at least about 95%, such as at least about 98%, for example at least about 99%, e.g. at least about 99.5%, and preferably at least about 99.9%, such as at least about 99.99%, crystalline, which may be detected by standard techniques, such as PXRD.
  • the active ingredient may be presented within the pores of the particles of compositions of the invention in an essentially amorphous state.
  • essentially amorphous we mean that the active ingredient is no more than about 5%, such as no more than about 2%, for example no more than about 1%, e.g. no more than about 0.5%, and preferably no more than about 0.1% crystalline, which, again, may be detected by standard techniques, such as PXRD.
  • Presenting active ingredient in a crystalline or in an amorphous state within the pores of the particles of compositions of the invention means that the latter are capable of delivering a consistent and/or uniform dose of active ingredient, which is independent of solubility, after administration to the lung.
  • the active ingredient may remain in the same physical state (e.g. crystalline or amorphous), during and after manufacture, under normal storage conditions, and during use.
  • active ingredient can be transformed from one solid state form to another, resulting in changes in adhesive forces, which will, in turn, affect the performance of the formulation to be inhaled.
  • formulators have often presented microparticulate active ingredients in a crystalline form in such prior art formulations. This has often led to difficulties in achieving reproducibly, because micronization or milling are often used to reduce particle size of the active ingredient, which can lead to high energy particles in amorphous form.
  • the loading of active ingredients into the pores of the silica particles in accordance with the invention can physically stabilize the drug in an essentially crystalline and/or or an essentially amorphous form, and prevents it from undergoing solid state transformation, such that the physio-chemical properties of the drug do not change over time.
  • the active ingredient can be stored in the form, or as part, of a composition of the invention, optionally in admixture with pharmaceutically acceptable carriers, diluents or adjuvants, under normal storage conditions, with an insignificant degree of solid state transformation (e.g. crystallisation, recrystallisation, loss of crystallinity, solid state phase transition, hydration, dehydration, solvatisation or desolvatisation).
  • solid state transformation e.g. crystallisation, recrystallisation, loss of crystallinity, solid state phase transition, hydration, dehydration, solvatisation or desolvatisation.
  • the active ingredient may be stored in this form under normal storage conditions, with an insignificant degree of chemical degradation or decomposition.
  • Examples of 'normal storage conditions' include temperatures of between minus 80 and plus 50°C (preferably between 0 and 40°C and more preferably ambient temperature, such as between 15 and 30°C), pressures of between 0.1 and 2 bars (preferably atmospheric pressure), relative humidities of between 5 and 95% (preferably 10 to 60%), and/or exposure to 460 lux of UV/visible light, for prolonged periods (i.e. greater than or equal to six months).
  • active ingredient may be found to be less than about 15%, more preferably less than about 10%, and especially less than about 5%, solid-state transformed.
  • the skilled person will appreciate that the above-mentioned upper and lower limits for temperature and pressure represent extremes of normal storage conditions, and that certain combinations of these extremes will not be experienced during normal storage (e.g. a temperature of 50°C and a pressure of 0.1 bar).
  • the amorphous porous silica particles are biodegradable mesoporous silica.
  • the term 'biodegradable' means that the silica particles are dissolvable. Accordingly, a preferred embodiment of the invention is that the silica is a synthetic amorphous silica.
  • the silica particles of the compositions of the invention must be amorphous and therefore entirely non-crystalline (and remain so under normal storage conditions as hereinbefore defined), by which we mean that no crystallinity is detectable by standard techniques, such as PXRD.
  • Amorphous silica is less sensitive to humidity when compared to dry crystalline powder compositions that are typically used in pulmonary delivery of active ingredients.
  • Amorphous silica particles may be manufactured by processes known in the art.
  • porous particles may be manufactured by cooperative self- assembly of silica species and organic templates such as cationic surfactants such as alkyltrimethylammonium templates with varying carbon chain lengths, and counterions such as cetyltrimethylammonium chloride (CTA+CI- or CTAC) or cetyltrimethylammonium bromide (CTA+Br- or CTAB), or non-ionic species such as diblock and triblock polymer species, such as copolymers of polyethylene oxide and polypropylene oxide for example Pluronic 123 surfactant.
  • organic templates such as cationic surfactants such as alkyltrimethylammonium templates with varying carbon chain lengths, and counterions such as cetyltrimethylammonium chloride (CTA+CI- or CTAC) or cetyltrimethylammonium bromide (CTA+Br- or CTAB), or non-ionic species such as diblock and triblock polymer species, such
  • mesoporous silica particles occurs following the hydrolysis and condensation of silica precursors which can include alkylsilicates such as tetraethylorthosilcate (TEOS) or tetramethylorthosilicate (TMOS) in solution or sodium silicate solution.
  • TEOS tetraethylorthosilcate
  • TMOS tetramethylorthosilicate
  • the mesoporous silica particle size can be controlled by adding suitable additive agents, e.g. inorganic bases, alcohols including methanol, ethanol, propanol, and other organic solvents, such as acetone, which affect the hydrolysis and condensation of silica species.
  • Pore size may not only be influenced by hydrothermal treatment of the reaction mixture such as heating up to 100°C or even above and also with the addition of swelling agents in the form of organic oils and liquids that expand the surfactant micelle template, but also, after condensation of the silica matrix, removing the templating surfactant by calcination typically at temperatures from about 500°C to about 650°C, or alternatively from 650°C up to about 750°C, in each case for e.g. several hours.
  • Calcination at the higher of the above two temperature ranges not only burns away the organic template resulting in a porous matrix of silica (which the lower of the above two temperature ranges will also achieve), but also creates particles with one or more of the smaller average pore sizes mentioned hereinbefore (e.g. about 2 nm to about 14 nm, about 3 nm to about 13 nm and/or about 4 nm to about 12 nm (e.g. about 10 nm)), pore volumes (e.g. about 0.05 cm 3 /g to about 2.5 cm 3 /g, including about 0.08 cm 3 /g (e.g.
  • the template may alternatively be removed by extraction and washing with suitable solvents such as organic solvents or acidic of basic solutions.
  • the porous silica particles may be manufactured by a sol-gel method comprising a condensation reaction between a silica precursor solution, such as sodium silicate or an aqueous suspension of silica nanoparticles as an emulsion, in either case with a non-miscible organic solution (such as benzyl alcohol), an oil, or a liquid polymer.
  • a silica precursor solution such as sodium silicate or an aqueous suspension of silica nanoparticles as an emulsion
  • a non-miscible organic solution such as benzyl alcohol
  • droplets are formed by, for example, stirring or spraying the solution.
  • Gelation of the silica may be carried out by means of changing pH, which may be carried out during or after the condensation step, and/or evaporation of the aqueous phase.
  • the porosity of the particles here are formed either by exclusion due to the presence of the non-miscible secondary phase or by the jamming of the silica nanoparticles during evaporation.
  • Such particles may further be treated by washing to remove the non-miscible secondary phase and heating to induce condensation of the silica matrix. Furthermore, the particles may be treated by calcination as hereinbefore described to strengthen the silica matrix.
  • the porous particles may be manufactured as porous glass through a process of phase separation in borosilicate glasses (such as Si02-B203-Na20), followed by liquid extraction of one of the formed phases through the sol-gel process, or simply by sintering glass powder.
  • borosilicate glasses such as Si02-B203-Na20
  • a thermal treatment typically between 500°C and 760°C, an interpenetration structure is generated, which results from a spinodal decomposition of the sodium-rich borate phase and the silica phase.
  • the porous particles may also be manufactured using a fumed process.
  • fumed silica is produced by burning silicon tetrachloride in an oxygen- hydrogen flame producing microscopic droplets of molten silica which fuse into amorphous silica particles in three-dimensional secondary particles which then agglomerate into tertiary particles.
  • the resulting powder has an extremely low bulk density and high surface area.
  • the silica particles may be modified prior to separation according to size and/or prior to loading with active ingredient.
  • Surface modifying may include chemical surface modifying, e.g. etching. This results in an altered surface of the silica particles and may be useful to prevent to particles from aggregating, whilst not having an influence on the dissolution rate of the active ingredient compound from the particles.
  • a further step of surface modifying the particles by coating after manufacturing and/or after loading may be carried out.
  • Coating may not only be used to assist with the adherence of a bioactive compound to the surface of particles, but may also be used to provide an electrical charge on the surface of the particles and, in doing so, further prevent aggregation of the particles.
  • Particles may be coated with a functionalizing agent, such as a surfactant or an amino acid selected from the group L-lysine, L-alanine, glycine, leucine and L- tyrosine. Coating may be done to block the pores in the particle or coating may be done without blocking the pores of the particle.
  • a functionalizing agent such as a surfactant or an amino acid selected from the group L-lysine, L-alanine, glycine, leucine and L- tyrosine.
  • silica particles prior to loading with active ingredient, may be surface modified by chemical reaction of free silanol groups with a reagent that provides at least one organic group. This can be achieved by surface modification of silica particles by reaction with an alkoxysilane, and/or an alkylhalosilane, many of which are commercially available, for example as described hereinafter.
  • reagents are capable of forming 1 to 3 Si-O-Si links to the surface by way of a condensation reaction with surface silanol groups.
  • Typical functionalising reagents that may be employed to achieve this include 3-aminopropyl triethoxysilane, 3-mercaptopropyl trimethoxysilane and various PEG-silanes.
  • a functionalising reagent that may be mentioned is an alkylhalosilane, which alkylhalosilane may be an alkylchlorosilane containing up to 4 (e.g. 3) alkyl groups, such as between 1 and 4 (e.g. 3) linear or branched C 1-24 alkyl groups, such as Ci-is alkyl groups, including Ci-io alkyl groups, e.g. a di- or tri-C alkylchlorosilane, such as tripropylchlorosilane, triethylchlorosilane or trimethylchlorosilane.
  • Alternative (and/or preferred) functionalising reagents include reactive species that comprise only one alkyl chain, such as alkyl esters of halocarboxylic acids (e.g. alkylchloroformates) or haloalkanes, for example as described hereinafter.
  • Preferred reagents include those containing linear or branched Ci-24 alkyl groups, such as Ci-is alkyl groups, including Ci-10 alkyl groups, such as Ci-4 alkyl groups, e.g. methylchloroformate or methyliodide, propylchloroformate or propyl iodide or, more preferably, ethylchloroformate or ethyliodide.
  • Surface modifications of this type may be carried out by reacting said functionalising reagent with silica particles, optionally in the presence of an appropriate solvent (e.g. toluene or tetrahydrofuran) and/or an appropriate base (e.g. imidazole, N-methylmorpholine or sodium carbonate), for example as described hereinafter, or alternatively as described in Zhao and Li, J. Phys. Chem., 102, 1556 (1998), Taib etal, Int. J. Chem., 3, 2 (2011), or Chmielowiec and Morrow, J. Colloid Interface Sci., 94, 319 (1983).
  • an appropriate solvent e.g. toluene or tetrahydrofuran
  • an appropriate base e.g. imidazole, N-methylmorpholine or sodium carbonate
  • functionalisation of silica is preferably achieved with a low conversion (i.e. only functionalising a portion of the surface -OH groups).
  • the choice of the functionalising reagent, solvent and temperature enables a functionalisation method to obtain the desired surface coverage with organic (e.g. alkyl) groups and therefore the desired properties.
  • Longer alkyl chains e.g. ethyl groups and higher
  • functionalization with ethyl groups is preferred as it will liberate only ethanol in the body.
  • the loaded silica particles may be admixed with one or more fatty acid- or lipid-based surfactants.
  • Such admixing is preferably done by dry mixing said surfactant with said loaded particles, more preferably by way of a high energy mixing process.
  • Appropriate high energy mixing equipment may include, for example, intensive mechanical processors (e.g. the Nobilita- 130 Unit Mechanofusion System (Hosokawa Micron Corporation, Osaka, Japan) or Laboratory Mixer Granulator P 1-6 (DIOSNA Dierks & Sohne GmbH, Osnabruck, Germany)), for example under appropriate mixing conditions, such as those described hereinafter and/or in Zhou et a/, J. Pharm. Sc/., 99, 969 (2010).
  • intensive mechanical processors e.g. the Nobilita- 130 Unit Mechanofusion System (Hosokawa Micron Corporation, Osaka, Japan) or Laboratory Mixer Granulator P 1-6 (DIOSNA Dierks
  • Admixing may also be achieved by other techniques known to those skilled in the art, including spraying a solution or a suspension of said surfactant onto the surfaces of said particles by a suitable means, such as using a fluidized bed and/or a jet mill.
  • fatty acid- or lipid-based surfactant' will be understood to include any surfactant comprising a long (Cs-24) hydrocarbon chain.
  • Surfactants comprising such hydrocarbon chains are or may be derived from oilseeds (e.g. palm, palm kernel, coconut, etc.), and may be saturated, branched, linear and/or aromatic.
  • Surfactants based on lipids or fatty acids may be non-ionic, but are preferably ionic.
  • Ionic surfactants may include those with a cationic head group (e.g. primary, secondary, or tertiary amines; primary and secondary amines and quaternary ammonium salts); Zwitterionic (amphoteric) surfactants (e.g. sultaines, betaines and phospholipids); but more preferably include anionic surfactants, such as salts of sulfate esters (e.g. ammonium lauryl sulfate and sodium lauryl sulfate), sulfonate esters and phosphate esters or, more preferably, carboxylate esters.
  • a cationic head group e.g. primary, secondary, or tertiary amines; primary and secondary amines and quaternary ammonium salts
  • Zwitterionic (amphoteric) surfactants e.g. sultaines, betaines and phospholipids
  • anionic surfactants such as salts of sul
  • Anionic surfactants based on carboxylate esters include carboxylate salts (soaps), which surfactants comprises an alkali, or an alkaline earth, metal ion (e.g. sodium, potassium, calcium or magnesium) and one or more fatty acid chain with at least 10, such as at least 12, including at least 14, such as at least 16, carbon atoms.
  • Preferred specific anionic surfactants in this class include sodium stearate, sodium lauroyl sarcosinate and carboxylate-based fluorosurfactants, such as perfluorononanoate and perfluorooctanoate.
  • the surfactant that is employed in compositions of the invention is magnesium stearate.
  • the amount of surfactant that may be employed in compositions of the invention is in the range of about 0.1% to about 12% by weight of the composition, such as about 0.2% to about 11%. Preferred amounts are in the range of about 1%, such as about 2%, including about 3%, up to about 10% by weight of the composition. Specific amounts that may be included are thus about 0.5%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, about 5.0%, about 5.5%, about 6.0%, about 6.5%, about 7.0%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, about 10.0% and about 10.5%.
  • a process for the production of a composition of the invention comprises separating particles by an appropriate method as described herein to obtain particles having an MMAD and a GSD within the ranges specified herein.
  • step (f) optionally, admixing the loaded particles from step (e) with a fatty acid- or lipid-based- surfactant as described herein.
  • the process described herein for production of compositions of the invention has the advantage that it allows the production of particles with sizes that enable better control of the site of deposition of the particles in the lung, so enabling accurate tailoring of site-specific lung delivery (e.g. improved delivery to the deep lung) compared to prior art inhalation formulations comprising other drugs.
  • the process described herein also reduces manufacturing costs compared to processes in which separation is conducted after loading particles with a bioactive compound, and, as described hereinbefore, is a scalable process. This may improve the yield and efficiency of the manufacturing process.
  • the process also potentially provides for a higher drug loading of the bioactive compounds in final dosage forms comprising compositions of the invention.
  • compositions of the invention are useful as medicaments/pharmaceuticals. Their unexpectedly good flow properties renders them suitable for pulmonary delivery.
  • compositions of the invention may be used to deliver a wide variety of active ingredients that are suitable for administration, and/or it desirable to administer, to the lung.
  • active ingredients include biologically-, pharmaceutically- and/or medicinally-active compounds that have a therapeutic or a prophylactic effect on a disease, including those diseases mentioned hereinafter.
  • Active ingredients may thus comprise one or more antiallergic agent, bronchodilator, pulmonary lung surfactant, analgesic, antibiotic, anti infective, leukotriene inhibitor or leukotriene antagonist, antihistamine, antiinflammatory agent, antineoplastic agent, anticancer agent, anticholinergic, anaesthetic, antitubercular, cardiovascular agent, 32-adrenergic receptor agonist, corticosteroid, nonsteroidal, anti-inflammatory agent, antibiotic, anticholinergic agent, antiviral agent, mucolytic agent, prostacyclin, beta-blocker, anti- infective agent, smoking cessation agent, angiotensin II receptor antagonist, enzyme, steroid, genetic material, viral vector, antisense agent, protein or peptide (such as a tripeptide, a growth factors or an oligon
  • 32-adrenergic receptor agonists include formoterol, salbutamol, pirbuterol, metaproterenol sulfate, clenbuterol, metaproterenol, terbutaline, salmeterol, pirbuterol, procaterol, reproterol, bitolterol, fenoterol, tulobuterol and atenolol.
  • corticosteroids include beclomethasone, ciclesonide, budesonide, fluticasone, funisolide, fluocotin butyl, triamcinolone acetonide and mometasone.
  • nonsteroidal anti-inflammatory agents include cromolyn sodium, nedocromil, amlexanox and diclofenac (sodium).
  • antibiotics include tobramycin, colistin, aztreonam and tobramycin.
  • anticholinergics include tiotropium bromide, ipratropium bromide, enalaprilat and enalapril.
  • antiviral agents include zanamivir, ribavirin, ipratropium bromide and particularly remdesivir.
  • mucolytics include N-acetyl cysteine.
  • leukotriene receptor antagonists include pranlukast.
  • prostacyclin analogues examples include iloprost.
  • beta-blockers examples include metoprolol and propranolol.
  • anti- infective agents examples include pentamidine.
  • smoking cessation agents include nicotine.
  • anesthetics include sevoflurane, desflurane, enflurane, halothane and isoflurane.
  • anti-cancer agents include gefitinib, dasatinib, imatinib and bosutinib.
  • the active ingredient may also be selected from the group felodipine, indapamide, itraconazole, losartan, quetiapine, clofazimine, OSU-03021 and folic acid.
  • compositions of the invention find utility in the pulmonary treatment of various disorders, including local and/or systemic disorders of the respiratory system and/or lungs.
  • disorders may include one or more of infection, inflammation, COPD, asthma, tuberculosis, severe acute respiratory syndrome, respiratory syncytial virus, influenza, smallpox, drug resistant respiratory infection and/or cancer.
  • composition of the invention for use in the treatment of a respiratory disorder by pulmonary administration as well as the use of a composition of the invention for the manufacture of a medicament for the treatment of a respiratory disorder by pulmonary administration.
  • a method of treatment of respiratory disorder comprises the pulmonary administration of a pharmacologically-effective amount of an active ingredient that is useful in the treatment of said respiratory disorder in the form of a composition of the invention to a patient in need of such treatment.
  • 'Patients' include mammalian (particularly human) patients.
  • Human patients include both adult patients as well as paedeatric patients, the latter including patients up to about 24 months of age, patients between about 2 to about 12 years of age, and patients between about 12 to about 16 years of age. Patients older than about 16 years of age may be considered adults for purposes of the present invention. These different patient populations may be given different doses of active ingredient.
  • Active ingredients may be administered in the form of racemates, single enantiomers and/or pharmaceutically-acceptable salts.
  • salts of active ingredients include base addition salts and preferably acid addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or, preferably, free base form of an active ingredient with one or more equivalents of an appropriate acid or base as appropriate, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of an active ingredient in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • Pulmonary delivery means compositions of the invention are adapted for delivery to the lungs by direct inhalation, and thereby giving rise to either the direct topical treatment by the aforementioned lung diseases, or systemic absorption of active ingredients through lung mucosa.
  • Administration of active ingredient is preferably intermittent.
  • the mode of administration may also be determined by the timing and frequency of administration, but is also dependent, in the case of the treatment of the relevant condition, on its severity.
  • compositions of the invention may also impart, or may be modified to impart, an immediate, or a modified, release of active ingredients.
  • compositions of the invention may be combined with other excipients that are well known to those skilled in the art for pulmonary delivery of active ingredients.
  • excipients may include propellants; surfactants, such as poloxamers; sugars or sugar alcohols, such as lactose, glucose, mannitol or trehalose; lipids, such as DPPC, DSPC, DMPC, cholesterol; amino acids, such as leucine or trileucine; cyclodextrins, hydroxypropylated chitosan, poly-lactic-co-glycolic acid (PLGA); antioxidants; humidity regulators and the like, though such are by no means essential. Indeed, we have found that, in the pulmonary delivery of compositions of the invention, fewer additional excipients are needed, which may reduce cost of manufacture.
  • Inhalation devices that may be employed to administer compositions of the invention to the lung include MDIs, SMIs and DPIs, including low, medium and high resistant DPIs.
  • compositions of the invention may form stable compound suspensions when suspended in solvents that are typically employed in MDIs.
  • Loaded silica particles in particular may be well-dispersed in different solvents and may be further modified to prevent dissolution or leakage of drug into the solvent before delivery to the target site or lung.
  • compositions of the invention have unexpectedly good flow properties, this minimizes the need for disaggregation of the particles by increased IAF and turbulence produced by the inhalation device. This in turn improves the balance between the two forces discussed hereinbefore, and thus improves delivery of active ingredients to the lower lung without loss of drug in the upper lung. This further reduces the dependence on the inhalation device that is employed.
  • a drug delivery device adapted for delivery of active ingredients to the lung, which delivery device comprises a composition of the invention.
  • the delivery device may be a MDI, a DPI or a SMI.
  • the composition of the invention is optionally mixed with a propellant, which propellant has a sufficient vapour pressure to form aerosols upon activation of the delivery device.
  • the propellant may be selected from the group a hydrocarbon, a fluorocarbon, a hydrogen-containing fluorocarbon and a mixture thereof.
  • excipients may be commercially-available or otherwise are described in the literature, for example, Remington The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995) and the documents referred to therein, the relevant disclosures in all of which documents are hereby incorporated by reference. Otherwise, the preparation of suitable pulmonary formulations may be achieved non-inventively by the skilled person using routine techniques.
  • the amount of active ingredient in the formulation will depend on the severity of the condition, and on the patient, to be treated, but may be determined by the skilled person.
  • compositions of the invention include those that are known in the art and described for the drugs in question to in the medical literature, such as Martindale - The Complete Drug Reference (35 th Edition) and the documents referred to therein, the relevant disclosures in all of which documents are hereby incorporated by reference.
  • Doses may be split into multiple individual doses per day. Inhaled doses may be given between once and six, such as four times daily, preferably three times daily and more preferably twice daily. Alternatively, inhaled doses may be given between once and four times weekly, for example every other day.
  • the medical practitioner or other skilled person, will be able to determine routinely the actual dosage, which will be most suitable for an individual patient, depending on the severity of the condition and route of administration.
  • the above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to affect an appropriate response (e.g. a reduction in symptoms) in the mammal (e.g. human) over a reasonable timeframe (as described hereinbefore).
  • an appropriate response e.g. a reduction in symptoms
  • the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature, stage and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the age, condition, body weight, sex and response of the patient to be treated, and the stage/severity of the disease, as well as genetic differences between patients.
  • compositions of the invention may provide for an improved drug loading for the reasons described hereinbefore.
  • This enables high quantities/doses of bioactive compound to be presented in dosage forms comprising compositions of the invention, and also efficient delivery of such higher doses to the desired site in the lung in a consistent/uniform manner.
  • This in turn means that the frequency of dosing may be reduced, so increasing the effectiveness and efficiency of treatment as well as reducing costs of healthcare.
  • compositions of the invention may also be improved by compositions of the invention.
  • compositions of the invention that comprise mesoporous silica particles may include additional bioactive compounds, which may also be loaded into those particles without substantial loss of material. This may be useful in e.g. co-therapy as described hereinbefore, and moreover may further reduce cost of manufacture.
  • compositions of the invention comprising mesoporous silica particles
  • such compositions also have the advantage that the dissolution kinetics of the active is largely independent of particle size, morphology of the compound and site of delivery in the lung. Adjusting pore size may thus be employed to tailor drug dissolution kinetics, but the dissolution kinetics of the drug will be independent of the will be independent of the position of the particles in the lung.
  • compositions of the invention may be more convenient for the physician and/or patient than, be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, or that it may have other useful pharmacological properties over, similar methods (treatments) known in the prior art.
  • Figures 1 and 2 are light microscope images showing silica particles produced according to a prior art method ( Figure 1) and according to the method of the invention ( Figure 2); and Figures 3 and 4 are MMAD distributions of silica particles loaded with remdesivir and clofazimine, respectively.
  • Pluronic 123 triblock co-polymer, E020P070E020, Sigma-Aldrich; 4 g; templating agent
  • TMB 1,3,5-trimethylbenzene
  • H2O distilled H2O
  • hydrochloric acid HAI, 37%, Sigma-Aldrich
  • TEOS tetraethyl orthosilicate
  • the product was calcined to remove the surfactant template and swelling agent.
  • the calcination was conducted by heating to 600°C with a heating rate of 1.5°C/min and kept at 600°C for 6 hours, followed by cooling to ambient conditions.
  • the resultant product was a white powder comprising porous silica particles. Comparative Example 2 Silica Particle Manufacture II
  • a drop of acetic acid was added and vacuum (200 bar) was applied during heating at 80°C to remove the aqueous phase.
  • the resulting particles were collected by filtration and washing with acetone.
  • the product was calcined by heating to 600°C with a heating rate of 1.5°C/min and kept at 600°C for 6 hours, followed by cooling to ambient conditions.
  • the resultant product was a white powder comprising porous silica particles in the size range 2 to 4 microns measured by scanning electron microscope (JEOL, Japan) and by electrical sensing zone method (Elzone, Micromeretics USA).
  • the particles were further treated by refluxing in ammonium hydroxide overnight followed by filtering and refluxing in nitric acid overnight and finally filtered and washed in water and oven dried at 80°C.
  • silica particles were made by essentially the same process as described in Comparative Example 3 above and were characterised to determine their GSD and GPS using an 8-Stage Cascade Impactor (Marple), as shown in Table 2 below.
  • Marple 8-Stage Cascade Impactor
  • Silica compositions prepared essentially as described in Comparative Example 1, Comparative Example 2, Comparative Example 3 and/or Comparative Example 4 above were fractionated into tight particle sizes in which fine particles were removed through elutriation.
  • a conical stainless steel funnel 17 L was used. 200 g of silica particles were added as a slurry in methanol to the elutriation funnel. Methanol was pumped into the funnel through the bottom inlet tube using an HPLC pump (Aglient) at a flow rate of 1 mL/min until the funnel was full and the methanol drained out of the top outlet tube. The flow rate was increased to 1.2 mL/min and maintained at fixed flow until particles emerged through the outlet.
  • HPLC pump Aglient
  • the particle size was measured using Elzone/Electric Sensing Zone (Micromeritics, USA). The flow was maintained at a fixed flow until no further particle sizes were detected coming from the outlet (typically from one day to several days).
  • the flow rate was increased systematically in increments of 0.2 mL/min and the particles emerging from the outlet tube were measured for particle size. The elutriation continued until a particle sizes of 2 pm was reached. The residue particles were collected by filtration and dried overnight in an oven at 40°C. The collected particles were measured for particle size The particles that were collected had a mean particle size of 3.7 pm measured by optical microscopy (Nikon) and Electric Sensing Zone (Micromeritics, USA) and GSD of 1.25.
  • shaking powders in a vial gave rise to particles that were more discrete and did not aggregate to the same degree as corresponding particles in which fines had not been removed, not only by visual observation of the vials, but also by optical microscopy, after sprinkling particles onto a microscope slide.
  • silica particles were characterised to determine their GSD and GPS using an 8-Stage Cascade Impactor (Marple), as shown in Table 3 below.
  • An active ingredient such as any of those mentioned hereinbefore, e.g. clofazimine, is encapsulated into the porous silica particles described above in the same manner as described in Example 1 above.
  • Remdesivir 150 mg; Adooq Biosciences, USA
  • ethanol 50 mL
  • Porous silica particles 750 mg; made by essentially the same process as described in Example 1 above
  • the flask was connected to a rotary evaporator and mixed at 40°C at 100 rpm for 10 minutes. After this, a vacuum was applied at a pressure of 120 mbar and evaporation conducted for about an hour until the solvent was fully removed.
  • the loaded particles were transferred to a crucible and dried in oven at 40°C under vacuum overnight.
  • the remdesivir loading was calculated as 16% by weight.
  • MMAD measurements were carried out in a Next Generation Impactor (Copley Scientific, UK) with a flow rate of 60 L/minute and pressure drop of approximately 4 kPa using standard Pharmacopoeia conditions, fitted with USP throat and pre-separator.
  • Loaded silica particles were filled into single use capsules by hand to a fill weight of approximately 10 mg and fitted into a Breezehaler. Particle size distribution calculations were obtained from API concentration measured by HPLC analysis using acetone as solvent.
  • Example 5 MMAD measurements were carried out as described in Example 3 above and the distribution is shown in Figure 4.
  • Example 5 MMAD measurements were carried out as described in Example 3 above and the distribution is shown in Figure 4.
  • MMAD measurements were carried out as described in Example 3 above using ethanol/water (50:50) as eluent in the HPLC analysis.

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Abstract

La présente invention concerne une composition pharmaceutique appropriée pour une administration aux poumons, ladite composition comprenant une pluralité de particules, lesdites particules comprenant ou étant constituées d'un ou plusieurs principes actifs appropriés pour l'administration aux poumons, et lesdites particules ayant : • (a) un diamètre aérodynamique médian en masse qui est compris entre environ 0,95 µm et environ 6,05 µm ; et • (b) un écart-type géométrique qui est inférieur ou égal à 1,33. Lorsque les compositions comprennent un principe actif, les principes actifs peuvent être chargés dans des particules nanoporeuses (mésoporeuses) de silice amorphe. Les compositions sont utiles dans le traitement des troubles respiratoires par une administration pulmonaire. Les compositions comprennent ou sont constituées de particules qui sont très petites, mais qui présentent une répartition granulométrique bien définie, avec une faible quantité de fines. De manière surprenante, il a été constaté que cela donnait lieu à un manque inattendu d'agrégation et à des propriétés d'écoulement étonnamment bonnes.
PCT/GB2020/052810 2019-11-06 2020-11-06 Nouvelle composition comprenant des particules nanoporeuses de silice amorphe Ceased WO2021090013A1 (fr)

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CN117860742A (zh) * 2023-11-16 2024-04-12 上海交通大学医学院 氨来占诺在耐药性肺癌治疗中的新应用

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Publication number Priority date Publication date Assignee Title
CN117860742A (zh) * 2023-11-16 2024-04-12 上海交通大学医学院 氨来占诺在耐药性肺癌治疗中的新应用

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