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WO2004045585A9 - Broyage au moyen de corps broyants non spheriques - Google Patents

Broyage au moyen de corps broyants non spheriques

Info

Publication number
WO2004045585A9
WO2004045585A9 PCT/US2003/036910 US0336910W WO2004045585A9 WO 2004045585 A9 WO2004045585 A9 WO 2004045585A9 US 0336910 W US0336910 W US 0336910W WO 2004045585 A9 WO2004045585 A9 WO 2004045585A9
Authority
WO
WIPO (PCT)
Prior art keywords
media
grinding
pharmaceutical
grinding media
substance
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US2003/036910
Other languages
English (en)
Other versions
WO2004045585A1 (fr
Inventor
Sean Mark Dalziel
William Norman Ford
Henricus Jacobus Corn Gommeren
Douglas Eric Spahr
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
EIDP Inc
Original Assignee
EI Du Pont de Nemours and Co
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 EI Du Pont de Nemours and Co filed Critical EI Du Pont de Nemours and Co
Priority to EP03786831A priority Critical patent/EP1562551A1/fr
Priority to JP2004553913A priority patent/JP2006515766A/ja
Priority to AU2003295631A priority patent/AU2003295631A1/en
Publication of WO2004045585A1 publication Critical patent/WO2004045585A1/fr
Anticipated expiration legal-status Critical
Publication of WO2004045585A9 publication Critical patent/WO2004045585A9/fr
Ceased legal-status Critical Current

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B02—CRUSHING, PULVERISING, OR DISINTEGRATING; PREPARATORY TREATMENT OF GRAIN FOR MILLING
    • B02C—CRUSHING, PULVERISING, OR DISINTEGRATING IN GENERAL; MILLING GRAIN
    • B02C17/00—Disintegrating by tumbling mills, i.e. mills having a container charged with the material to be disintegrated with or without special disintegrating members such as pebbles or balls
    • B02C17/18—Details
    • B02C17/20—Disintegrating members
    • 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
    • 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
    • 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
    • A61K9/146—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 organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect

Definitions

  • This invention relates to a media milling method in which nonspherical grinding media are used to produce small particles that are particularly useful in the pharmaceutical, nutraceutical, and diagnostic fields.
  • BACKGROUND OF THE INVENTION Methods for producing fine particles have many commercial applications, such as in the production of oral, transdermal, injected or inhaled pharmaceuticals and biopharmaceuticals, nutraceuticals, diagnostic test components and diagnostic agents.
  • rate of dissolution of a solid compound will increase with increasing surface area of the solid.
  • particle dissolution rates can be increased by increasing the surface area to weight ratios of the particles that make up the solid through particle size reduction techniques.
  • bioavailability is related to dissolution kinetics and membrane permeability
  • bioavailability of poorly water soluble pharmaceutical or diagnostic compounds in many instances can also be increased via a reduction in the particle size.
  • it is particularly desirable to have methods of reducing the size of pharmaceutical particles since a large portion of small molecule drugs (Class 2 and Class 4 pharmaceuticals) are poorly soluble in water or gastric fluids.
  • successful production of small particles can result in end products having shorter dissolution times, increased bioavailability and potentially faster therapeutic onset.
  • media milling is a frequently used method for producing fine and ultra fine (nano) particles. The media milling process typically involves charging grinding media to the milling chamber together with the material to be ground.
  • the material to be ground is added to the mill as a slurry comprised of a solid suspended in a liquid. Often, a surfactant is added to stabilize the slurry.
  • a stirring device of some form can then be used to agitate the grinding media, thereby causing the solid particles to be ground.
  • the grinding media can be set in motion by either applying planetary, tumbling or vibratory motion to the milling chamber, or subjecting magnetic grinding media that has been charged to the milling chamber to an alternating/fluctuating magnetic field.
  • Typical wet mills include colloid mills, pressure homogenizers, rotor stators, and media mills. See, for example, "Technical Aspects of Dispersion" by D.
  • the type of grinding media charged to the media mill is generally selected from any variety of dense, tough, hard materials, such as, for example, sand, stainless steal, zirconium silicate, zirconium oxide, yttrium oxide, glass, alumina, titanium, and the like. In situations involving either metal (oxide) contamination, or shifts in pH, a polymeric grinding media is utilized.
  • the grinding media charged to the milling chamber has consisted of spherically shaped media milling beads.
  • Spherically shaped grinding media had been thought to be the most mechanically stable form of hard grinding media, as theoretically there are no edges to be attrited or chipped off.
  • spherically shaped hard, rigid grinding media has been utilized in the milling process when chipping and attrition of the hard grinding media is sought to be avoided or reduced.
  • Liversidge et al, U.S. Patent No. 5,145,684, and EPO 498,492 describe dispersible particles consisting of a drug substance or an x-ray contrast agent having a surface modifier absorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than about 400nm.
  • the particles are prepared by dispersing a drug substance or contrast agent in a liquid dispersion medium and wet grinding in the presence of rigid spherically shaped or particulate grinding media.
  • Bruno, et al, U.S. Patent No. 5,518,187 describes a method for preparing particles of a drug substance or a diagnostic imaging agent that comprises grinding the drug substance or imaging agent in the presence of grinding media that consists essentially of a polymeric resin.
  • the grinding media is characterized in the disclosure as being substantially spherical in shape.
  • 5,862,999 describes a method for preparing particles of therapeutic and diagnostic imaging agents that have an average particle size of less than about 500nm by grinding the therapeutic or diagnostic imaging agent in the presence of rigid grinding media having a mean particle size less than about 100 microns.
  • the grinding media is characterized by the disclosure as being substantially spherical in shape.
  • Verhoff, et al, U.S. Patent Application No 2002/0003179 A1 describes a process for preparing a dispersion of solid particles of a milled substrate comprising using together a plurality of large size media and small size media in the same milling chamber.
  • U.S. Patent No. 3,210,016 discloses an apparatus and method for a process similar to ball milling which utilizes milling agents having planar rather than rounded surfaces.
  • U.S. Patent No 6,634,572 B2 discloses a process for milling a solid substrate in the presence of two or more different milling media bodies.
  • PCT Application International NO PCT/US02/16159 is a co-owned, co-pending application disclosing an apparatus and method for high pressure media milling.
  • U.S. Patent No. 5,891 ,231 relates to a grinding method for making colorants for inks wherein the grinding medium may be spherical, cylindrical or cubical.
  • Co-owned, co-pending patent application WO 03/040245 discloses the use of cubic grinding media to produce colorant particles for the ink industry.
  • a method of preparing fine particles of a pharmaceutical, nutraceutical, or diagnostic agent that comprises grinding the pharmaceutical, nutraceutical, or diagnostic agent using nonspherical grinding media.
  • the grinding media can be made essentially of any tough resilient material.
  • the grinding media can comprise particles comprising a core that has the tough resilient material adhered thereon.
  • the type of material selected to comprise the media will be determined, in part, by the toughness and hardness required to effectively mill the particular particles to be ground.
  • FIGURES Figure 1 is a light micrograph at 80X magnification showing a 500 micron cubic nylon grinding particle purchased from Norstone Inc., Wyncote, PA, USA.
  • Figure 2 is a light micrograph at 80X magnification showing a 500 micron spherical polystyrene grinding particle purchased from Norstone Inc., Wyncote, PA, USA.
  • Figure 3 is an electron micrograph showing the starting ibuprofen used in Example 2.
  • Figure 4 is an electron micrograph showing the ibuprofen after grinding according to the method of Example 2.
  • DETAILED DESCRIPTION OF THE INVENTION All references cited in this disclosure are specifically incorporated by reference in their entirety.
  • the present invention is a media milling method that utilizes nonspherical shaped grinding media to produce small particles useful in many commercial applications including particularly pharmaceuticals, nutraceuticals, and diagnostic agents.
  • nonspherical means any three- dimensional shape that is not substantially spherical.
  • the term “spherical” 1 is given its traditional meaning, and is defined as any three-dimensionally shaped object wherein all points as measured in straight lines from the center of the object to the surface of the object are equidistant.
  • nonspherically shaped media can include media shapes that are substantially cubic, rectangular, hexagonal, rod-like, needle-like, or ellipsoidal.
  • the grinding media is not necessarily comprised of "perfectly shaped” cubes, rectangles, hexagons, rods, needles, etc., as such terms are classically used in the field of geometry.
  • media comprised of combinations of the aforementioned nonspherical shapes are contemplated for use in the method according to the invention.
  • a media mill, or media milling, as those terms are used by Applicants, describes generally any device or method that achieves reduction in the size of solid particulate materials through a grinding process utilizing grinding media.
  • the media milling process practiced in the invention can be any wet or dry grinding process that uses an attritor, a tumbling ball mill, a vibratory ball mill, a planetary ball mill, a horizontal media mill, a vertical media mill, or an annular media mill.
  • the carrier fluid can either be a gas, such as air or nitrogen, or an inert or reactive gas.
  • a typical wet milling process is called slurry milling, wherein a liquid is used as the carrier fluid. Possible liquids include water, salt solutions, buffered solutions, solvents (ethanol, hexane, glycol etc.), solvent/water mixtures, solvent/solvent mixtures, and the like.
  • the carrier fluid can be either a pressurized gas, e.g., pressurized nitrogen, or a gas under supercritical pressure or temperature conditions, e.g., CO 2 pressurized past its critical point.
  • a pressurized gas e.g., pressurized nitrogen
  • a gas under supercritical pressure or temperature conditions e.g., CO 2 pressurized past its critical point.
  • the invention can be practiced in accordance with the high pressure media milling process described in commonly owned, copending patent application PCT/US02/16159 entitled High Pressure Media Milling, the disclosure of which is hereby incorporated by reference.
  • the nonspherical shaped media milling beads of the invention can be comprised of any material of greater hardness and rigidity than the material to be ground into particles.
  • the grinding material can be comprised of almost any hard, tough material including, for example, nylon and polymeric resins, metals, and a range of naturally occurring substances, such as sand, silica, or chitin obtained from crab shells.
  • the nonspherical shaped grinding media of the present invention is comprised of a tough resilient material having a low rate of attrition, and therefore a low incidence of contamination of the ground material with attrited media pieces.
  • the nonspherical shaped grinding media can either consist entirely of a single material that is tough and resilient, or in the alternative, be comprised of more than one material, i.e., comprise a core portion having a coating of tough resilient material adhered thereon.
  • nonspherical shaped grinding media can be comprised of mixtures of any materials that are suitable for grinding.
  • the polymeric resins suitable for use herein as grinding media are chemically and physically inert, preferably substantially free of metals, solvents and monomers, and of sufficient hardness and friability to avoid being chipped and crushed during grinding.
  • Suitable polymeric resins include, but are not limited to, crosslinked polystyrenes, such as polystyrene crosslinked with divinylbenzene, styrene copolymers, polycarbonates, polyacetals, such as DelrinTM, vinyl chloride polymers and copolymers, polyurethanes, polyamides, poly(tetrafluoroethylenes), e.g., TeflonTM, and other fluoropolymers, high density polyethylenes, polypropylenes, cellulose ethers and esters such as cellulose acetate, polyhydroxymethacrylate, polyhydroxyethyl acrylate, silicone containing polymers such as polysiloxanes and the like.
  • crosslinked polystyrenes such as polystyrene crosslinked with divinylbenzene, styrene copolymers, polycarbonates, polyacetals, such as DelrinTM, vinyl chloride polymers and copolymers, polyurethanes
  • Biodegradable polymeric resins are also suitable for use herein.
  • Exemplary biodegradable polymers include poly(lactides), poly(glycolide) copolymers of lactides and glycolide, polyanhydrides, poly(hydroxyethyl methacylate), poly(imino carbonates), poly(N-acylhydroxyproline)esters, poly(N-palmitoyl hydroxyproline) esters, ethylene-vinyl acetate copolymers, poly(orthoesters), poly(caprolactones), and poly(phosphazenes).
  • media contaminants can be advantageously metabolized in vivo to biologically acceptable products that can be eliminate from the body.
  • Additional grinding media materials include digestible ingredients having "GRAS" (generally recognized as safe) status.
  • GRAS generally recognized as safe
  • starch based materials or other carbohydrates for instance, starch based materials or other carbohydrates, protein based materials, and salt based materials, e.g., cubic sodium chloride crystals.
  • the core material(s) preferably can be selected from materials known to be useful as grinding media when fabricated as spheres or particles. Suitable core materials include, but are not limited to, zirconium oxides (such as 95% zirconium oxide stabilized with magnesia or yttrium), zirconium silicate, glass, stainless steel, titania, alumina, ferrite, and the like.
  • the core material(s) can also be magnetic.
  • Particle sizes produced according to the method of the invention can vary widely, depending upon the desired application. However, with regard to many pharmaceutical, nutraceutical and diagnostic applications, the desired size will range from 100 ⁇ m down to the nanometer range. Often, a useful size range in the pharmaceutical field, especially, will be approximately 500 nm or less.
  • nonspherically shaped grinding media may enable small particles of pharmaceuticals, nutraceuticals, and diagnostic agents to be produced on a large-scale.
  • the nonspherically shaped grinding media may reduce mill processing times, particularly when there is a need to produce ultra fine particles. Applicants have noted, as demonstrated in Example 1 , that when grinding conditions and grinding materials are the same, grinding can progress faster with nonspherical shaped grinding media than with spherical shaped grinding media.
  • nonspherical grinding media used according to the method of the present invention.
  • the media material can be cryogenically ground and then subjected to screening or air classification techniques to obtain the size class/fraction desired.
  • nonspherical grinding media can be formed by being 1) extruded through different die designs, 2) subjected to various cutting techniques, or 3) cast via available casting processes.
  • nonspherical grinding media having the desired size and material characteristics can be purchased commercially.
  • the present invention can be practiced to produce a wide variety of particle sizes, particularly in the pharmaceutical, nutraceutical, and diagnostic fields. In the case of dry milling, the pharmaceuticals, nutraceuticals, and diagnostic agents must be capable of being formed into solid particles.
  • the pharmaceuticals, nutraceuticals, and diagnostic agents are preferably dispersible and poorly soluble in at least one fluid medium.
  • “poorly soluble” is meant that the pharmaceutical, nutraceutical, or diagnostic agent has a solubility in the liquid dispersion medium, e.g., water, of less than about 10mg/ml, and in most instances less than about 1 mg/ml, at room temperature.
  • solubility in the liquid dispersion medium e.g., water
  • compounds that are not poorly soluble can still be milled by utilizing a fluid that is saturated with the compound.
  • fluid as used by Applicants in the context of wet milling means that the continuous phase may be a liquid, a gas, a pressurized gas, a liquefied gas, a supercritical fluid, a subcritical fluid, or any combination thereof.
  • Suitable water soluble and water insoluble pharmaceuticals for use in the invention include, but are not limited to, anabolic steroids, analeptics, analgesics, anesthetics, antacids, anti-arrthymics, anti- asthmatics, antibiotics, anti-cariogenics, anticoagulants, anticolonergics, anticonvulsants, antidepressants, antidiabetics, antidiarrheals, anti- emetics, anti-epileptics, antifungals, antihelmintics, antihemorrhoidals, antihistamines, antihormones, antihypertensives, anti-hypotensives, anti- inflammatories, antimuscarinics, antimycotics, antineoplastics, anti-obesity drugs, antiplaque agents, antiprotozoals, antipsychotics, antiseptics, anti- spasmotics, anti-thrombics, antitussives, antivirals, anxiolytics
  • Suitable biopharmaceutical substances include, but are not limited to, any therapeutic compound being derived from a biological source or chemically synthesized to be equivalent to a product from a biological source, for example, a protein, a peptide, a vaccine, a nucleic acid, an immunoglobulin, a polysaccharide, cell product, a plant extract, a phytochemical, an animal extract, a recombinant protein, an enzyme or combinations thereof.
  • Suitable pharmaceutical and biopharmaceutical substances are intended to include those delivered via a pulmonary delivery mechanism, a parenteral delivery mechanism, a transdermal delivery mechanism, an oral delivery mechanism, an ocular delivery mechanism, a suppository or vaginal delivery mechanism, an aural delivery mechanism, a nasal delivery mechanism and an implanted delivery mechanism.
  • Suitable diagnostic agents include, but are not limited to, ethyl-3,5- bisacetoamido-2,4,6-triiodobenzoate (WIN 8883), ethyl(3,5- bis(acetylamino)-2,4,6-triiodobenzoyloxy)acetate(WIN 12901 ), ethyl-2- (bis(acetylamino)-2,4,6- triiodobenzoyloxy)butyrate (WIN 16318), 6- ethoxy-6-oxohexyl-3,5-bis(acetylamino)-2,4,6- triiodobenzoate (WIN 67722).
  • Suitable imaging agents are described in EPO 498, 482, the disclosure of which is hereby incorporated by reference. Diagnostic agents also include any other particulate material that is useful in vivo or in vitro in the detection or quantification of health or disease.
  • Suitable nutraceuticals may include, but are not limited to, dietary supplements, such as vitamins and minerals, herbal remedies, such as Asian ginseng, bilberry, black cohash, cascara, cat's claw, cayenne, cranberry, devil's claw, dong quai, echinacea, evening primrose oil, feverfew, garlic, ginger, ginkgo biloba, ginseng, golden seal, gotu kola, grape seed, green tea, hawthorn, kava, licorice, milk thistle, saw palmetto, Siberian ginseng, St.
  • any matter that is normally ingested by humans or animals for sustenance, growth and maintenance of optimal health is considered a food or food substance that can be used as a source of nutraceuticals.
  • a skilled practitioner will be capable of identifying other fields and applications in which many other types of articles can be milled according to the method of the invention.
  • the substance to be ground by means of the invention will often be milled at a temperature that does not cause the substance to significantly degrade or lose efficacy. Processing temperatures of less than about 30° to 40° C. are ordinarily preferred if the ground substance is a pharmaceutical.
  • the processing equipment can be cooled using conventional cooling equipment.
  • Super cooling conditions can also be employed if the fluid selected is a gas at ambient temperature.
  • Media milling methods can be carried out under a variety of pressure conditions. For example, typical media milling is traditionally carried out under conditions of ambient pressure. Ambient processing pressures are typical of ball, attritor and vibratory mills. Processing pressures of up to about 20 psi (1.4kg/cm 2 ) are typical of conventional media milling.
  • the method according to this invention can also be practiced at elevated pressures using pressurized gasses above their critical pressure, for example see commonly owned application PCT/US02/16159 entitled High Pressure Media milling.
  • the carrier fluid can be a pressurized gas, a pressurized liquid or a supercritical fluid.
  • the present invention may also be utilized for the production of any variety of small, high surface area particles that can be used as carrier particles for liquids or as seeds for crystallization or precipitation.
  • the particles formed by the method of the present invention can, in many cases, also be concurrently or subsequently coated with moisture barriers, taste-masking agents, or other additives or encapsulating agents that enhance the attributes of the pharmaceutical, nutraceutical or diagnostic agent.
  • Particles of pharmaceuticals, nutraceuticals and diagnostic agents can also be formulated with other materials during the milling process. Most often the other material will be an inactive agent, which may include, for example, surfactants, dispersants and the like.
  • a surface modifier such as a surfactant, emulsifier, or stabilizer, can be adsorbed on the surface of the pharmaceutical, nutraceutical or diagnostic agent particle during the milling process.
  • Useful surface modifiers are believed to include those that physically adhere, as well as, those that chemically bond, to the surface of the pharmaceutical, nutraceutical or diagnostic particle.
  • Surface modifiers can be present in an amount of 0.1-90%, preferably 1-10% by weight based on the total combined weight of the respective substance and the surface modifier.
  • the preferred proportions of grinding media, the pharmaceutical, nutraceutical and/or diagnostic agent, the optional liquid dispersion medium, and the inactive agent(s) present in the grinding vessel of the mill can vary within wide limits depending, for example, on the particular pharmaceutical, nutraceutical, or diagnostic agent selected, the size and density of the grinding media, the type of mill selected, etc.
  • the process can be carried out in a continuous, batch or semi- batch mode.
  • processing times of less than one day have provided the desired results using a high shear media mill.
  • the grinding media is separated from the milled particulate product (in either a dry or liquid dispersion form) using conventional separation techniques, such as by filtration, sieving through a mesh screen, and the like.
  • the grinding fluid advantageously is separated from the grinding media and the ground particles by vaporization after the high pressure media milling process is returned to ambient pressure.
  • Cubic nylon grinding media with a size of 500 microns (Norstone Inc., Wyncote, PA, USA) was added to a 2 oz glass jar, so that 50% of the jar was filled with the cubic nylon grinding media (bulk volume).
  • a Malvern Mastersizer 2000 (Malvern Instruments, Worcestershire, UK) was used to measure the size of the naproxen particles at 8hrs and 18hrs time intervals. The results are listed herein below in Table 1. After 8 hours of milling the cubic Nylon grinding media produced particles 2,986 nm in size. After 18 hours of milling that the cubic nylon, produced the fine naproxen particles with a median size of 363 nm. The end product produce was a milky white substance with no noticeable discoloration.
  • Table 1 Size of naproxen particles milled using Cubic nylon media (w/ Malvern MS2000)
  • the particle size of the feedstock and milled product were measured by forward light scattering (Mastersizer2000, Malvern Instruments, England). Particle size data is listed in Table 2. Particle Scanning micrographs (SEM, Hitachi S-4700, San Jose, CA) of the feedstock ( Figure 3) and milled product ( Figure 4) were taken. The particle size of the milled product had increased. However, the scanning electron micrographs show that the milled product was agglomerated and consisted of fine primary crystals.
  • a 1 -liter of naproxen dispersion was prepared by mixing the following ingredients as shown in Table 3.
  • Table 3 Formulation of naproxen dispersion
  • the dispersion was loaded into the feed tank of the Netzsch Labstar media mill (Netzsch Inc., Exton, PA). The mill chamber was charged with 80% Cubic nylon grinding media. The dispersion was circulated through the media mill that was operated at a speed of 3000 RPM. At fixed time points 1 g samples were taken from the mill return line for particle analyses by a Mastersizer 2000 (Malvern, England). The results are listed in table 4. The median size after 960 minutes is 230 nanometer.

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Rheumatology (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)
  • Crushing And Grinding (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de broyage dans lequel des corps broyants sont utilisés pour produire des particules de petite taille utiles dans des substances pharmaceutiques, des substances nutraceutiques et des agents diagnostiques.
PCT/US2003/036910 2002-11-18 2003-11-18 Broyage au moyen de corps broyants non spheriques Ceased WO2004045585A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP03786831A EP1562551A1 (fr) 2002-11-18 2003-11-18 Broyage au moyen de corps broyants non spheriques
JP2004553913A JP2006515766A (ja) 2002-11-18 2003-11-18 非球状の粉砕媒体を使用する媒体ミル粉砕
AU2003295631A AU2003295631A1 (en) 2002-11-18 2003-11-18 Media milling using nonspherical grinding media

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US42712202P 2002-11-18 2002-11-18
US60/427,122 2002-11-18

Publications (2)

Publication Number Publication Date
WO2004045585A1 WO2004045585A1 (fr) 2004-06-03
WO2004045585A9 true WO2004045585A9 (fr) 2005-12-01

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2003/036910 Ceased WO2004045585A1 (fr) 2002-11-18 2003-11-18 Broyage au moyen de corps broyants non spheriques

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EP (1) EP1562551A1 (fr)
JP (1) JP2006515766A (fr)
KR (1) KR20050085035A (fr)
CN (1) CN1713893A (fr)
AU (1) AU2003295631A1 (fr)
WO (1) WO2004045585A1 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005053851A1 (fr) * 2003-11-26 2005-06-16 E.I. Dupont De Nemours And Company Systeme de broyage par corps broyants a pression elevee et procede de broyage de particules
KR20060024927A (ko) 2004-09-15 2006-03-20 씨제이 주식회사 기계적 분쇄법에 의한 미크론 사이즈 인삼 분말의제조방법
JP4568878B2 (ja) * 2005-03-23 2010-10-27 独立行政法人産業技術総合研究所 バイオマス分解方法及び分解装置
BRPI0708470A2 (pt) * 2006-03-14 2011-05-31 Merck & Co Inc processo para a produção de partìculas cristalinas de um composto ativo orgánico, e, composição farmacêutica
EP2174717B1 (fr) 2008-10-09 2020-04-29 Imertech Sas Procédé de broyage
IT1404157B1 (it) * 2010-12-30 2013-11-15 Nano Active Film S R L Forma cristallina nanoporosa disordinata di polistirene sindiotattico, suo processo di preparazione e articoli comprendenti la stessa.
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JP2006515766A (ja) 2006-06-08
KR20050085035A (ko) 2005-08-29
WO2004045585A1 (fr) 2004-06-03
EP1562551A1 (fr) 2005-08-17
AU2003295631A1 (en) 2004-06-15

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