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WO2002100378A2 - Procede - Google Patents

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Publication number
WO2002100378A2
WO2002100378A2 PCT/GB2002/002423 GB0202423W WO02100378A2 WO 2002100378 A2 WO2002100378 A2 WO 2002100378A2 GB 0202423 W GB0202423 W GB 0202423W WO 02100378 A2 WO02100378 A2 WO 02100378A2
Authority
WO
WIPO (PCT)
Prior art keywords
particulate material
pharmaceutically active
active agent
process according
laser
Prior art date
Application number
PCT/GB2002/002423
Other languages
English (en)
Other versions
WO2002100378A3 (fr
Inventor
Philip Braithwaite
Original Assignee
Ml Lab Plc
Philip Braithwaite
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
Application filed by Ml Lab Plc, Philip Braithwaite filed Critical Ml Lab Plc
Priority to AU2002302767A priority Critical patent/AU2002302767A1/en
Publication of WO2002100378A2 publication Critical patent/WO2002100378A2/fr
Publication of WO2002100378A3 publication Critical patent/WO2002100378A3/fr

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D1/00—Evaporating
    • B01D1/0011—Heating features
    • B01D1/0029—Use of radiation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D1/00—Evaporating
    • B01D1/16—Evaporating by spraying
    • B01D1/18—Evaporating by spraying to obtain dry solids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient

Definitions

  • This invention relates to a novel method of preparation of particulate material, novel particles produced by such a method and, when the particulate material comprises a pharmaceutically active ingredient, a method of treatment comprising administration of the finely divided particulate material of the invention.
  • US Patent No 5,876,195 describes the use of a laser in a method for enhancing fuel ignition performance by preheating the fuel with laser light at a wavelength that is absorbable by the fuel prior to ignition of the fuel with a second laser.
  • European Patent Application No. 1 006 327 describes a method of drying a fibre web which comprises the use of a laser light wherein the frequency of the laser is set to maximise the absorption by water.
  • European Patent Application No. 0 072 046 describes a method for the preparation of a finely divided inhalation drug which comprises atomising a solution of the drug by spray drying.
  • Spray drying has become an acceptable technique in the manufacture of foodstuffs, for example, instant coffee granules, powdered milk, etc and in the manufacture of certain pharmaceutically active agents, for example, dextran or dextrin.
  • the technique is not suitable for the manufacture of finely divided powders of, for example, some thermally unstable materials and/or materials/solvents that may be difficult to dry, for example, macromolecules.
  • the desired material may be in the form of an aqueous solution and conventionally known spray drying techniques may be unsuitable because the macromolecule can become unstable if maintained at a high temperature for a prolonged duration.
  • spray dryers it is possible for the dry particle to heat up from hot air.
  • An example of such a thermally unstable material is a pharmaceutically active macromolecule, such as insulin.
  • conventionally known spray drying techniques have limitations with regard to, inter alia, efficiency, yield, control of particle properties, e.g. size.
  • the process of the invention comprises the use of a laser tuned to one or more wavelengths to permit maximum absorbency of the solvent.
  • the material may be any material which is conventionally produced by spray drying. Such materials include, but are not limited to, foodstuffs, such as coffee, dried milk, etc, and pharmaceutically active agents.
  • the process is especially suitable for the manufacture of pharmaceutically active agents.
  • Such agents may comprise any agents administered or dispensed in particulate form and especially those dispensed in powder form, e.g. a finely divided powder.
  • such agents may, for example, comprise active ingredients used in conventional inhalation therapies.
  • the pharmaceutically active agent may be a systemically active agent, which may optionally be administered by inhalation, such as insulin.
  • the pharmaceutically active agent may be a polysaccharide, such as dextrin.
  • the process of the invention is most suited for the production of finely divided particles, e.g. powders.
  • particles may be advantageous in that, inter alia, they can penetrate deep into the lung or be of a specific size to be potentially targeted to a specific lung region and yet which are sufficiently free flowing to be filled into capsules, cartridges, spools or other dry powder delivery devices, optionally without mixing with a coarse diluent or formation into soft pellets or granules.
  • Such particles can disperse well from an inhaler at both low and high air flow rates, thus, in certain circumstances, improving consistency of emptying of the metering member.
  • the particles produced by the process of the invention are preferentially mechanically strong so that they do not break during encapsulation and/or delivery.
  • the shape of the particles may vary depending upon the nature of, inter alia, the material, the solvent, etc. Furthermore, the shape of the particles may be unrelated to particle size.
  • the particles are preferably as uniform as possible in all respects.
  • the surface texture of the particles will vary according to the particular material concerned and the techniques used to produce the particles.
  • the roughness of the surface of the particles can be determined by measuring the total surface area of the particle by the Brunauer, Emmett and Teller (BET) method (British Standard 4359 (1969) Part 1) and comparing this with the envelope surface area of the particles as measured by permeametry (Papadakis M. (1963), Rev. Mater. Construct. Trave. 570, 79-81).
  • particles may be produced by the process of the invention, but one example of particles are those of which are substantially strong and dense.
  • the particle density of the particles may be measured by conventional methods known per se. Such methods are described in the prior art of, inter alia, EP 0 072 046.
  • Spray drying of materials is well established as a drying technique in the food and other industries, including in the pharmaceutical industry.
  • spray drying is routinely used in the production of coarse particle products such as dried milk, instant coffee and certain medicaments.
  • spray drying techniques are used to produce very fine powders.
  • the use of a spray drying technique is advantageous in that it is adapted to suit large batch productions, thus decreasing the amount of quality control required and also in that it may remove the need of recrystallisations and micronisation to get the drug into the desired form.
  • a variety of conventionally known lasers may be used in the process of the invention. It is preferred that the laser operates at a wavelength at which the appropriate solvent has maximum absorbency. Thus preferably the laser is one which operates in the UV or near IR spectrum. When the solvent is water then the laser preferably operates at a wavelength of between 900 and 1000 nm, most preferably about 950nm, e.g. 949 nm.
  • the wavelength selected must be one at which the solvent absorbs but the solid particles have negligible or at least much reduced absorption.
  • the laser light can be focused on aerosolised droplets.
  • solvent such as water
  • the laser can be used to preheat and eventually vaporise the solvent within an aerosol solvent spray.
  • any suitable form of atomiser can be used.
  • Atomisation results from an energy source acting on liquid bulk. Resultant forces build up to a point where liquid break up and disintegration occurs and individual spray droplets are created.
  • the different atomisation techniques available concern the different energy forms applied to the liquid bulk. Common to all atomisers is the use of energy to break up liquid bulk. Centrifugal, pressure and kinetic energy are used in common forms of atomiser. Sonic and vibratory atomisers are also used. Specific atomisers which may be mentioned include rotary atomisers, e.g. those involving vaned wheels, vaneless discs, cups, bowls and plates; pressure atomisers, e.g.
  • kinetic energy or pneumatic atomisers e.g. those involving two or three fluids, or internal or external mixing
  • sonic energy nozzles e.g. involving sirens or whistles.
  • kinetic or pneumatic energy atomisers particularly two fluid pressure or syphon or sonic nozzle atomisers. In general two fluid pressure nozzles tend to produce powders having more reproducible results and use less energy.
  • the atomiser can be used in a spray or flash drying apparatus.
  • the conditions of operation of the apparatus and storage of the solution should clearly not be such as to degrade the material, or introduce impurities, or biological contamination, into the final particulate product.
  • the spray drying apparatus preferably comprises an atomiser, a main chamber, one or more (e.g. two) cyclones, a bag filter and, if desired or necessary to maximise recovery, a terminal wet scrubber or electrostatic precipitator.
  • the particle collection system is designed to capture the desired size range of particles and also to maximise the yield. All over and under size material may be recovered and recycled or put to other uses.
  • the solution of the material may be in any suitable solvent, e.g. water for a water soluble material.
  • concentration of the material in the solvent may vary over a wide range depending, inter alia, on the nature of the material and the solvent. To avoid possible blockage of the atomisation device and to avoid the incorporation of unwanted impurities it may be desirable to filter the solution immediately before it is passed to the atomiser.
  • the particle size of the material particles produced may tend to increase with concentration.
  • the temperature of the solution to be fed to the spray drier will vary with the material and the solvent to be used. In general we prefer to use a temperature at which the solution can be stored for a long period in large batches without degradation. As high a temperature as possible commensurate with stability is desirable to reduce solution viscosity and provide energy to the drying process.
  • the air flow rate, direction into the spray drier, the temperature of the air and the rate of feed of solution to the spray drier can be optimised by simple experiment. All of the parameters in the spray drying process interrelate and can be adjusted to produce the desired product.
  • Gases other than air can be used if desired.
  • the use of an inert gas will be advantageous when an inflammable solvent or a readily oxidisable drug is used.
  • the gas used e.g. air or nitrogen, may, if desired, be recycled to avoid loss of entrained drug and/or to conserve energy and the inert gas.
  • the particle size of the material produced may be dependent upon the concentration of the feed solution, the rate of feed to the spray drier, the means of atomising the solution, e.g. the type of atomiser and the pressure of the air, and solution to be dried, the temperature and temperature gradient within the drier and, to a small extent, the air flow in the drier.
  • the process of the invention is that the use of a laser provides a degree of control on, inter alia, particle size.
  • the range of air pressures suitable will naturally depend on the atomisation device used.
  • the cyclone or cyclones used to collect the dried particles are of conventional design.
  • the pressure differential across the cyclones, the combination of two or more cyclones and the design of the particular cyclones used may be adjusted to enable capture of appropriate particles.
  • the final product may be put in any suitable form of container or delivery device for delivery of a pharmaceutically active agent.
  • the delivery device may comprise a conventionally known inhaler with a system of the invention attached thereto.
  • a conventional inhaler is a CLICKHALER (available from rnnovata Biomed in the UK and described in European Patent application No. 0 539 469) which is provided with an inhalation passage.
  • an example of such an inhaler system is a TECHNOHALER (available from hmovata Biomed in the UK and described in European Patent Application No. 0 626 689).
  • Each spool has a flange at each end which form a tight slidable fit within the body of the spool carrier. The space left between the body of the spool and the spool carrier is filled with an appropriate powder.
  • particulate materials may be spray dried by using the apparatus and method of the invention.
  • Such particulate materials are generally drugs for the treatment of asthma, chronic obstructive pulmonary disease and respiratory infections.
  • Such powders include, but are not limited to ⁇ 2 -agonists, e.g. fenoterol, formoterol, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol and terbutaline; non-selective beta-stimulants such as isoprenaline; xanthine bronchodilators, e.g. theophylline, aminophylline and choline theophyllinate; anticholinergics, e.g.
  • mast cell stabilisers e.g. sodium cromoglycate and ketotifen
  • bronchial anti-inflammatory agents e.g. nedocromil sodium
  • steroids e.g. beclomethasone dipropionate, fluticasone, budesonide and flunisolide
  • antibiotics such as Gentamicin and Tobramycin; and combinations thereof.
  • two or more particulate materials e.g. powders
  • spray dried together it is within the scope of this invention for two or more particulate materials, e.g. powders, to be spray dried together.
  • kits which may be mentioned include combinations of steroids, such as, beclomethasone dipropionate, fluticasone, budesonide, ciclesonide and flunisolide; and combinations of ⁇ 2 -agonists, such as, formoterol and salmeterol. It is also within the scope of this invention to include combinations of one or more of the aforementioned steroids with one or more of the aforementioned ⁇ 2 -agonists.
  • steroids such as, beclomethasone dipropionate, fluticasone, budesonide, ciclesonide and flunisolide
  • ⁇ 2 -agonists such as, formoterol and salmeterol
  • Further powders which may be mentioned include systemically active materials, such as, proteinaceous compounds and/or macromolecules, for example, hormones and mediators, such as insulin, human growth hormone, leuprolide and alpha interferon; • growth factors, anticoagulants, antibodies, enzymes, immunomodulators, cytokines and nucleic acids.
  • hormones and mediators such as insulin, human growth hormone, leuprolide and alpha interferon
  • growth factors, anticoagulants, antibodies, enzymes, immunomodulators, cytokines and nucleic acids include systemically active materials, such as, proteinaceous compounds and/or macromolecules, for example, hormones and mediators, such as insulin, human growth hormone, leuprolide and alpha interferon; • growth factors, anticoagulants, antibodies, enzymes, immunomodulators, cytokines and nucleic acids.
  • the particulate material or powder is a pharmaceutically active agent manufactured according to a process as hereinbefore described.
  • the pharmaceutically active agent as hereinbefore described may, for example, be in the form of a pharmaceutical composition.
  • Such macromolecules include, but shall not be limited to, a group selected from a macromolecule, such as insulin, or dextrin, e.g. icodextrin.
  • Such pharmaceuticals compositions are preferentially suitable for administration by inhalation.
  • a respiratory disorder which comprises the adrriinistration of a pharmaceutical composition as hereinbefore described.
  • the method comprises administration of the pharmaceutical composition by inhalation.
  • a preferred embodiment we provide a method of treatment of a patient with a systemic disorder which comprises the administration of a medicament using an inhaler as hereinbefore described.
  • the device of the invention is especially suited for the efficient delivery of macromolecules, such as insulin.
  • macromolecules such as insulin.
  • the method of the invention may be used in the production of powders of pharmaceutically active agents and/or formulations, especially those which would be delivered by use of an inhalers, e.g. in the treatment of lung disease etc.
  • the pharmaceutically active agent and/or the formulation may be made up into a solution, either aqueous or solvent based, and passed through conventionally known spray drying equipment, wherein the liquid is broken into discrete droplets by passing it (under pressure) through a spray nozzle (this method is known as continuous droplet production).
  • this method is known as continuous droplet production.
  • the droplets are produced by passing the liquid through equipment designed to produce discrete droplets one at a time (this method is known as drop on demand).
  • apparatus that operates by the drop on demand method is an ink jet printer of which there are numerous examples and would be well understood by one skilled in the art. Indeed, the use of a drop on demand technique in a method of spray drying is novel per se.
  • a particulate material which comprises atomising and drying a solution of the material characterised in that the volatilising is achieved by use of a drop on demand technique and the drying is achieved by use of a laser.
  • One advantage of the method of the invention is that the energy may only be absorbed by the solvent and not by the dried particle.
  • Figure 1 is a schematic representation of the method of the invention being used to prepare a particulate material
  • Figure 2 is a schematic representation of the method of the invention being used to prepare agglomerated particles.
  • a formulated liquid solution (1) is fed from a reservoir (2) through drop on demand apparatus (3).
  • a drop of solution (4) is ejected at a known velocity and trajectory from the nozzle (5).
  • a laser beam is directed to intercept the droplet (6); the width of beam (7) of the laser (frequency etc) is such that the droplet is evaporated leaving a solid particulate (8), which falls under gravity into a collection vessel (9) for subsequent removal.
  • a first solution (1) is contained in reservoir (2) and the second solution (3) is contained in reservoir (4).
  • Solution (1) is fed through a nozzle (5) and solution (3) is fed through an annulated nozzle (6), creating continuous flow of solution (1) sheathed by solution (3).
  • the combined solutions (7) are then directed through a droplet generator (8), which perturbs the stream into droplets (9).
  • the droplet generator is able to produce multiple streams, e.g. dual stream droplets at a known frequency, which in effect delivers drops on demand at a known size and trajectory.
  • a single laser beam or if the combined solution is made up of solutions that have evaporation points at different frequencies, two laser beams are directed to intercept the droplet (description as above).
  • the method may also include the preparation of composite particles.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Toxicology (AREA)
  • Medicinal Preparation (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un procédé de préparation d'une matière particulaire qui consiste à atomiser et faire sécher une solution de ladite matière caractérisée en ce que le séchage est obtenu par volatilisation du solvant à l'aide d'un laser. L'invention concerne également une matière particulaire produite par un procédé selon l'invention et un procédé de traitement associé.
PCT/GB2002/002423 2001-06-09 2002-06-10 Procede WO2002100378A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002302767A AU2002302767A1 (en) 2001-06-09 2002-06-10 Process for the preparation of a particulate material

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0114033.4 2001-06-09
GB0114033A GB0114033D0 (en) 2001-06-09 2001-06-09 Process

Publications (2)

Publication Number Publication Date
WO2002100378A2 true WO2002100378A2 (fr) 2002-12-19
WO2002100378A3 WO2002100378A3 (fr) 2003-04-10

Family

ID=9916229

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2002/002423 WO2002100378A2 (fr) 2001-06-09 2002-06-10 Procede

Country Status (3)

Country Link
AU (1) AU2002302767A1 (fr)
GB (1) GB0114033D0 (fr)
WO (1) WO2002100378A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007018885A3 (fr) * 2005-07-29 2007-08-09 Hewlett Packard Development Co Procede de traitement de medicaments
US20090317336A1 (en) * 2006-03-03 2009-12-24 Amit Gupta Method and apparatus for high mass concentration nano particle generation
WO2012047620A1 (fr) * 2010-09-28 2012-04-12 Goji Ltd. Systèmes et procédés de concentration d'une solution à l'aide d'énergie électromagnétique
US9505845B2 (en) 2005-12-08 2016-11-29 E. R. Squibb & Sons, L.L.C. Treating lung cancer using human monoclonal antibodies to protein tyrosine kinase 7 (PTK7)

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0360340A1 (fr) * 1988-09-19 1990-03-28 Akzo N.V. Composition pour administration par voie nasale contenant un peptide
FR2677558B1 (fr) * 1991-06-14 1995-01-06 Commissariat Energie Atomique Procede et dispositif de fabrication de poudres ultrafines inorganiques par couplage aerosols-laser.
ATE189124T1 (de) * 1991-07-02 2000-02-15 Inhale Inc Verfahren und vorrichtung zum abgeben von medikamenten in aerosolform
TW402506B (en) * 1993-06-24 2000-08-21 Astra Ab Therapeutic preparation for inhalation
US6524557B1 (en) * 1994-12-22 2003-02-25 Astrazeneca Ab Aerosol formulations of peptides and proteins
GB9513218D0 (en) * 1995-06-29 1995-09-06 Fisons Plc Inhalation device and method
US5738087A (en) * 1995-09-21 1998-04-14 King; Russell W. Aerosol medication delivery system
WO2000061178A1 (fr) * 1999-04-13 2000-10-19 Inhale Therapeutics Systems, Inc. Administration pulmonaire de formulations de poudre seche pour le traitement de l'infecondite
WO2000062819A1 (fr) * 1999-04-21 2000-10-26 1355540 Ontario Inc. Formulations pour detecter l'asthme
US6540982B1 (en) * 2000-01-25 2003-04-01 Aeropharm Technology Incorporated Medical aerosol formulation

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007018885A3 (fr) * 2005-07-29 2007-08-09 Hewlett Packard Development Co Procede de traitement de medicaments
US9505845B2 (en) 2005-12-08 2016-11-29 E. R. Squibb & Sons, L.L.C. Treating lung cancer using human monoclonal antibodies to protein tyrosine kinase 7 (PTK7)
US20090317336A1 (en) * 2006-03-03 2009-12-24 Amit Gupta Method and apparatus for high mass concentration nano particle generation
US9845242B2 (en) * 2006-03-03 2017-12-19 Battelle Memorial Institute Method and apparatus for high mass concentration nano particle generation
US10392252B2 (en) 2006-03-03 2019-08-27 Battelle Memorial Institute Method and apparatus for high mass concentration nano particle generation
WO2012047620A1 (fr) * 2010-09-28 2012-04-12 Goji Ltd. Systèmes et procédés de concentration d'une solution à l'aide d'énergie électromagnétique

Also Published As

Publication number Publication date
GB0114033D0 (en) 2001-08-01
AU2002302767A1 (en) 2002-12-23
WO2002100378A3 (fr) 2003-04-10

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