CA2190134C - Continuous method of grinding pharmaceutical substances - Google Patents
Continuous method of grinding pharmaceutical substances Download PDFInfo
- Publication number
- CA2190134C CA2190134C CA002190134A CA2190134A CA2190134C CA 2190134 C CA2190134 C CA 2190134C CA 002190134 A CA002190134 A CA 002190134A CA 2190134 A CA2190134 A CA 2190134A CA 2190134 C CA2190134 C CA 2190134C
- Authority
- CA
- Canada
- Prior art keywords
- grinding media
- therapeutic
- agent
- diagnostic agent
- particle size
- 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.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/70—Nanostructure
- Y10S977/773—Nanoparticle, i.e. structure having three dimensions of 100 nm or less
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/70—Nanostructure
- Y10S977/773—Nanoparticle, i.e. structure having three dimensions of 100 nm or less
- Y10S977/775—Nanosized powder or flake, e.g. nanosized catalyst
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/84—Manufacture, treatment, or detection of nanostructure
- Y10S977/888—Shaping or removal of materials, e.g. etching
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/84—Manufacture, treatment, or detection of nanostructure
- Y10S977/895—Manufacture, treatment, or detection of nanostructure having step or means utilizing chemical property
- Y10S977/896—Chemical synthesis, e.g. chemical bonding or breaking
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/84—Manufacture, treatment, or detection of nanostructure
- Y10S977/90—Manufacture, treatment, or detection of nanostructure having step or means utilizing mechanical or thermal property, e.g. pressure, heat
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
- Y10S977/915—Therapeutic or pharmaceutical composition
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
- Y10S977/927—Diagnostic contrast agent
Abstract
A continuous method of preparing submicron particles of a therapeutic or diagnostic agent comprises the steps of continuously introducing the agent and rigid grinding media into a milling chamber, contacting the agent with the grinding media while in the chamber to reduce the particle sire of the agent, continuously removing the agent and the grinding media from the milling chamber, and thereafter separating the agent from the grinding media. In a preferred embodiment, the grinding media is a polymeric resin having a mean particle size of less than 300 µm. In another preferred embodiment, the agent, grinding media and a liquid dispersion medium are continuously introduced into the milling chamber. In a further embodiment, the agent and grinding media are recirculated through the milling chamber.
The method enables the use of the grinding media, e.g., of a particle size of less than about 300 µm, in a continuous grinding process which provides extremely fine particles of the agent, e.g., particles less than 100 nm in size, while avoiding problems, e.g., separator screen plugging, associated with prior art processes requiring the separation of agent from the grinding media in the milling chamber.
The method enables the use of the grinding media, e.g., of a particle size of less than about 300 µm, in a continuous grinding process which provides extremely fine particles of the agent, e.g., particles less than 100 nm in size, while avoiding problems, e.g., separator screen plugging, associated with prior art processes requiring the separation of agent from the grinding media in the milling chamber.
Description
WO 95131973 ~ ~ 9 ~ 13 4 PCT/US95/05728 CONTINUOUS METHOD OF GRINDING PHARMACEUTICAL SUBSTANCES
BACKGROUND OF THE INVENTION
Various grinding media, such as stainless steel, zirconium silicate, zirconium oxide, glass, and the like, typically in the form of spherical beads, are commonly used in various mills, including media mills, for grinding materials. Heretofore, efforts have been made to control the size and size range of drug particles in pharmaceutical compositions by a variety of methods, including various milling techniques, such as airjet milling and wet milling.
Conventional mills used for size reduction in a continuous mode incorporate a means for retaining milling media in the milling zone of the mill, i.e., the milling chamber, while allowing the dispersion or slurry to recirculate through the mill to a stirred holding vessel.
Various techniques have been established for retaining media in these mills, including rotating gap separators, screens, sieves, centrifugally-assisted screens, and similar devices to physically restrict passage of media from the mill.
Recently, significant efforts have been made toward the use of smaller milling media in conventional media mill processes for the preparation of various paints, and pigment, photographic and pharmaceutical dispersions. This has been possible due to improvements in mill designs which allow the use of media as small as about 300 ~tm. The advantages of small media include more efficient comminution, e.g., faster rates of size reduction, and smaller ultimate particle sizes. However, even with the best machine designs available, it is generally not possible to use media smaller than about 300 Eun due to separator screen plugging and unacceptable WO 95/31973 219 ~ 1 ~ ~ PCT/US95/05728 pressure build-up due to hydraulic packing of the media.
In fact, for commercial applications, a grinding. media size of 350 Eun is considered the practical lower limit due to media separator screen limitations.
SUMMARY OF THE INVENTION
We have discovered a continuous grinding process for preparing extremely fine particles which avoids various problems, e.g., separator screen plugging and unacceptable pressure build up due to hydraulic packing of the media, associated with prior art processes requiring the separation of the dispersion agent from the grinding media in the milling chamber.
More specifically, in accordance with this invention, there is provided a method of preparing submicron-sued particles of a therapeutic or diagnostic agent which comprises continuously introducing the agent and rigid grinding media into a milling chamber, contacting the agent with the grinding media while in the chamber to reduce the particle size of the agent, continuously removing the agent and the grinding media from the milling chamber, and thereafter separating the agent from the grinding media.
In another embodiment of the invention, the therapeutic or diagnostic agent, grinding media and a liquid dispersion medium are continuously introduced and removed from the milling chamber.
It is a particularly advantageous feature of this invention that there is provided a continuous method of preparing extremely fine particles of therapeutic and diagnostic agents.
It is another advantageous feature of this invention that there is provided a grinding method which , enables the use of ultra-fine grinding media, e.g., of a particle size less than 300 um, in a continuous grinding process.
According to one aspect of the present invention, there is provided a continuous method of preparing submicron particles of a therapeutic or diagnostic agent, said method comprising the steps of: (a) continuously introducing the therapeutic or diagnostic agent and rigid grinding media into a milling chamber, wherein said rigid grinding media have a particle size of 1000 microns or less; (b) contacting the therapeutic or diagnostic agent with the grinding media while in the milling chamber to reduce the particle size of the therapeutic or diagnostic agent to a submicron size;
(c) continuously removing the therapeutic or diagnostic agent and the grinding media from the milling chamber; and (d) separating the submicron-sized therapeutic or diagnostic agent from the grinding media to obtain a composition comprising submicron-sized particles of the therapeutic or diagnostic agent.
According to another aspect of the present invention, there is provided a continuous method of preparing submicron particles of a poorly soluble therapeutic or diagnostic agent, wherein said therapeutic or diagnostic agent has a surface modifier adsorbed on to the surface of said agent, said method comprising the steps of:
(a) continuously introducing the poorly soluble therapeutic or diagnostic agent, the surface modifier, a liquid dispersion medium, and rigid grinding media into a milling chamber, wherein the rigid grinding media have a particle size of 1000 microns or less; (b) contacting the poorly soluble therapeutic or diagnostic agent and the surface 3a modifier with the grinding media while in the milling chamber to reduce the particle size of the therapeutic or diagnostic agent to a submicron size and to adsorb the surface modifier to the surface of the therapeutic or diagnostic agent; (c) continuously removing the therapeutic or diagnostic agent, having the surface modifier adsorbed to the surface thereof, and the grinding media from the milling chamber; and (d) separating the therapeutic or diagnostic agent, having the surface modifier adsorbed to the surface thereof, from the grinding media to obtain a composition comprising surface modified submicron-sized particles of the therapeutic or diagnostic agent.
Still another advantageous feature of this invention is that there is provided a continuous grinding process which avoids problems, e.g., separator screen plugging, associated with prior art processes requiring the separation of the dispersion agent from the grinding media in the milling chamber.
Yet another advantageous feature of this invention is that there is provided a method of fine grinding therapeutic and diagnostic agents, which method generates less heat and reduces potential heat-related problems such as chemical instability and contamination.
Other advantageous features will become readily apparent upon reference to the following description of preferred embodiments when read in light of the accompanying drawing.
BRIEF DESCRIPTION OF THE DRAWING
Fig. 1 is a schematic view of a preferred embodiment of a continuous grinding process in accordance with this invention.
3b DESCRIPTION OF PREFERRED EMBODIMENTS
In accordance with this invention, there is provided a continuous method of preparing submicron particles of a therapeutic or diagnostic agent. By "continuous method" it is meant that both the dispersion agent and the'grinding media are continuously introduced and removed from the milling chamber. This can be contrasted to a conventional roller mill process wherein the agent and grinding media are introduced and removed from the grinding vessel in a batch process.
Liversidge et al, U.S. Patent No. 5,145,684, and European Patent Application 498;492, describe dispersible particles consisting of a drug substance or an x-ray. contrast agent having a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than about 400 nm. The particles are prepared by dispersing a drug substance or imaging agent in a liquid dispersion medium and wet grinding in the presence of rigid grinding media. Liversidge et al do not suggest a continuous milling process wherein the grinding media is separated from the pharmaceutical agent outside the milling chamber.
Bruno et al, only-owned U.S. Patent No. 5,518,187 1 5 (continuation of Application Serial No. 07/981,639 filed November 25,.1992) entitled Method for Grinding Pharmaceutica3 Substances discloses polymeric grinding media for fine grinding pharmaceutical compositions. However, Bruno et al do not suggest a continuous process wherein the grinding media is separated from the pharmaceutical agent outside the milling chamber.
In a preferred embodiment, the grinding media can comprise particles, preferably substantially spherical in shape, e.g., beads, of a polymeric resin.
However, grinding media in the form of other non-spherical shapes are expected to be useful in the practice of this invention.
In general, polymeric resins suitable for use herein are chemically and physically inert, substadtially free of metals, solvent'and monomers, and of sufficient hardness and friability to enable them to avoid being chipped or crushed during grinding. Suitable polymeric resins include crosslinked polystyrenes, such as polystyrene crosslinked with divinylbenzene, styrene copolymers, polyacrylates such as polymethyl methylczylate, polycarbonates, polyacetals, such as , , CA 02190134 2004-05-07 TM
Delrin_, vinyl chloride polymers and copolymers, polyurethanes, polyamides, poly(tetr-afluoroethylenes), ,M
e.g., Teflon_, and other fluoropolymers, high density polyethylenes, polypropylenes, cellulose ethers and 5 esters such as cellulose acetate, polyhydroxymethacxylate, polyhydroxyethyl acrylate, silicone containing polymers such as polysiloxanes and the like. The polymer can be biodegradable. Exemplary biodegradable polymers include poly(lactides), poly(glycolide) copolymers of lactides and glycolide, polyanhydrides, poly(hydroxyethyl methacrylate), poly(imino carbonates), poly(N-acylhydroxyproline)esters.
poly(N-palmitoyl hydroxyproline) esters, ethylene-vinyl acetate copolymers, poly(orthoesters), poly(caprolactones), and poly(phosphazenes). In the case of biodegradable polymers, contamination from the media itself advantageously can metabolize in vivo into biologically acceptable products which can be eliminated from the body.
The polymeric resin can have a density from 0.8 to 3.0 g/cm3. Higher density resins are preferred inasmuch as it is believed that these provide more efficient particle size reduction. The use of polymeric resins enable improved pH control.
Furthermore, Applicants believe that the invention can be practiced in conjunction with various inorganic grinding media prepared in the appropriate particle size. Such media include zirconium oxide, such as 95% Zr0 stabilized with magnesia, zirconium silicate.
glass, stainless steel, titanic, alumina, and 95% Zr0 stabilized with yttrium.
The media can range in size up to about 100D
microns. However, it is particularly advantageous that the invention enables the use of grinding media having a particle size of less than about 300 microns. More preferably, the media is less than about 75 microns, and.
WO95131973 ~ ~ g 01 ~ ~ PCfIUS95105728 most preferably, less than about 50 microns, in size.
Excellent particle size-reduction has been achieved with polymeric media having a particle size of about 50 microns.
The milling process can be a dzy process, e.g., a dry milling process, or a wet process, i.e., wet-grinding. In preferred embodiments, this invention is practiced in accordance with the teaching of U.S. Patent No. 5,145,684 and European Patent Application 498,482.
Thus, the wet grinding process can be practiced in conjunction with a liquid dispersion medium and surface modifier such as described in these publications. Useful liquid dispersion media include water, aqueous salt solutions, ethanol, butanol, hexane, glycol and the like.
The surface modifier can be selected from known organic and inorganic pharmaceutical excipients such as described in U.S. Patent No. 5,145,684 and can be present in an amount of 0.1-90%, preferably 1-80% by weight based on the total weight of the dzy particle. A preferred surface modifier is polyvinyl pyrrolidone.
In preferred embodiments, the therapeutic or diagnostic agent can be prepared in submicron or nanoparticulate particle size, e.g., less than about 500 nm. Applicants have demonstrated that particles can be prepared having an average particle size of less than about 300 nm. In certain embodiments, particles having an average particle size of less than 100 nm have been prepared in accordance with the present invention. It was particularly surprising and unexpected that such fine particles could be prepared free of unacceptable contamination.
Grinding can take place in any suitable grinding mill. Suitable mills include an sirjet mill, an attritor mill, a vibratory mill, a sand mill and a bead mill. A high energy media mill is preferred especially when the grinding media is a polymeric resin. The mill can contain a rotating shaft. This invention can also be practiced in conjunction with high speed dispersers such as a Cowles disperser, rotor-stator mixers, or other conventional mixers which can deliver high fluid velocity and high shear.
The preferred proportions of the grinding media, the therapeutic and/or diagnostic agent, the optional liquid dispersion medium, and surface modifier present in the grinding vessel can vary within wide limits and depends, for example, upon the particular therapeutic or diagnostic agent selected, the size and density of the grinding media, the type of mill selected, etc. Grinding media concentrations can range from about 10-958, preferably 20-908 by volume depending on the application and can be optimized based on the above factors; milling performance requirements, and the flow characteristics of the combined grinding media and agent dispersion.
The attrition time can vary widely and depends primarily upon the particular therapeutic or diagnostic agent, mechanical means and residence conditions selected, the initial and desired final particle size and so forth. Residence times of less than about 8 hours are generally required using high energy dispersers and/or media mills.
The process can be carried out within a wide range of temperatures and pressures. The process preferably is carried out at a temperature below that which can cause the agent to degrade. For many agents, ambient temperatures are appropriate. Temperatures of less than about 30C-40C are typically preferred.
, Control of the temperature, e.g., by jacketing or immersion of the milling chamber in ice water are contemplated. Processing pressures from about 1 psi (0.07 lcg/cm2) up to about 50 psi (3.5 kg/cm2) are contemplated. Processing pressures from about 10 psi (0.7 kg/cm2) to about 20 psi (1:9 kg/cm2) are typical.
The therapeutic or diagnostic agent and the grinding media are continuously removed from the milling chamber: Thereafter, the grinding media is separated from the milled particulate agent (in either a dxy or liquid dispersion form) using conventional separation techniques, in a secondazy process such as by simple filtration, sieving through a mesh filter or screen, and the like. Other separation techniques such as centrifugation may also be employed.
The invention~can be practiced with a wide variety of therapeutic and diagnostic agents. In the case of dry milling, the drug substances and imaging agents must be capable of being formed into solid particles. In the case of wet milling; the drug substances and imaging agents must be poorly soluble and dispersible in at least one liquid medium. By "poorly soluble", it is meant that the therapeutic or diagnostic agent has a solubility in the liquid dispersion medium, e.g., water, of less than about 10 mg/ml, and preferably of less than about 1 mg/ml. The preferred liquid dispersion medium is water. Additionally, the invention can be practiced with other liquid media. The therapeutic and diagnostic agents preferably are organic, crystalline materials.
Suitable therapeutic agents and classes of therapeutic agents are described in U.S. Patent No.
5,145,684 and include Danazol, 5a; l7oc,-1'-(methylsulfonyl)-1'H-gregn-20-yno[3,2-cl-pyrazol-17-0l, camptothecin, piposulfam, piposulfan, naproxen and phenytoin.
R'O 95131973 PCTIUS95/05728 Suitable diagnostic agents include derivatives of iodinated aromatic acids such as ethyl-3,5-bisacetoamido-2,4,6-triiodobenzoate (WIN 8883), ethyl(3,5-bis(acetylamino)-2,4,6-triodobenzoyloxy) 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). Other suitable imaging agents are described in U.S. Patent No. 5,260,478, U.S. Patent No. 5,264,610 and European Patent Application 498,482.
In a preferred embodiment, the agent and grinding media are recirculated through the milling chamber. Examples of suitable means to effect such recirculation include conventional pumps such as peristaltic pumps, diaphragm pumps, piston pumps, centrifugal pumps and other positive displacement pumps which do not use sufficiently close tolerances to damage the grinding media. Peristaltic pumps are generally preferred.
Another variation of this process includes the use of mixed media sizes. For example, larger media may be employed in a conventional manner where such media is restricted to the milling chamber. Smaller grinding media may be continuously recirculated through the system and permitted to pass through the agitated bed of larger grinding media. In this embodiment, the smaller media is preferably between about 1 and 300 N.m in mean particle size and the larger grinding media is between about 300 and 1000 Etm in mean particle size.
With reference to Figure 1, the process of this invention can be carried out as follows. The therapeutic or diagnostic agent 10 and rigid grinding media 12 are continuously introduced into milling chamber 14 which, as . illustrated, contains rotating shaft 16. Peristaltic pump 18 provides the energy to recirculate the dispersion containing both the agent and grinding media through the milling chamber to holding tank 20. As opposed to conventional prior art process, there is no means for retaining the grinding media within the milling chamber, such as a screen or rotating gap separator.
The following examples further illustrate the invention.
Example 1 Continuous Millina Process Us,'_na Fine PO~vmeric Media in a 0.3 Liter DvnoM~ »
A premix dispersion was formed by combining micronized Danazol powder (2-10)lm mean size) with an aqueous PVP (average molecular weight = 15,000) solution at a ratio of 5.0% Danazol, 1.5% PVP and 93.5% water.
292 grams of thispremix dispersion was combined with 379.6 grams of polystyrene crosslinked with divinyl benzene (20% styrene; 80% divinylbenzene), milling media, nominal 50 micron size. This combined mixture was recirculated through a 0.3 liter DynoMill at 3200 rpm (100cm3/min) for -60 minutes (residence time). There was no means for retaining the grinding media within the milling chamber.--After removal of the slurry from the milling chamber, the media was separated from the particulate Danaaol using a 10 ~1m filter. Thereafter, the particle size was measured by CHDF. The particle size distribution showed a weight average particle size of 35 nm.
Example 2 Continuous Millina Process Usina Fine Polymeric Media in a 0.6 Liter DvnoMill A premix dispersion was formed by combining micronized Danazol powder (2-10 Eun mean size) with an aqueous PVP
(average MW = 15,000) solution at a ratio of 5.0%
Danazol, 1.5% PVP and 93.5% water. 2768 grams of this , premix dispersion was combined with 3324 grams of polystyrene crosslinked with divinyl benzene (20%
R'O 95/31973 PCTIUS95/05728 styrene; 80~ divinyl benzene) recirculated through a 0.6 liter DynoMill at 3200 rpm (100 cm3/min) for 60 minutes residence time. There was no means for retaining the grinding media within the milling chamber. After removal of the slurry from the milling chamber, the media was separated from the particle Danazol using a 10 Nm filter.
The particle size of this batch was not measured but microscopic examination indicated that the mean size was likely below 100 nm.
The invention has been described in detail with particular reference to certain preferred embodiments thereof, but it will be understood that variations and modifications can be effected within the spirit and scope of the invention.
BACKGROUND OF THE INVENTION
Various grinding media, such as stainless steel, zirconium silicate, zirconium oxide, glass, and the like, typically in the form of spherical beads, are commonly used in various mills, including media mills, for grinding materials. Heretofore, efforts have been made to control the size and size range of drug particles in pharmaceutical compositions by a variety of methods, including various milling techniques, such as airjet milling and wet milling.
Conventional mills used for size reduction in a continuous mode incorporate a means for retaining milling media in the milling zone of the mill, i.e., the milling chamber, while allowing the dispersion or slurry to recirculate through the mill to a stirred holding vessel.
Various techniques have been established for retaining media in these mills, including rotating gap separators, screens, sieves, centrifugally-assisted screens, and similar devices to physically restrict passage of media from the mill.
Recently, significant efforts have been made toward the use of smaller milling media in conventional media mill processes for the preparation of various paints, and pigment, photographic and pharmaceutical dispersions. This has been possible due to improvements in mill designs which allow the use of media as small as about 300 ~tm. The advantages of small media include more efficient comminution, e.g., faster rates of size reduction, and smaller ultimate particle sizes. However, even with the best machine designs available, it is generally not possible to use media smaller than about 300 Eun due to separator screen plugging and unacceptable WO 95/31973 219 ~ 1 ~ ~ PCT/US95/05728 pressure build-up due to hydraulic packing of the media.
In fact, for commercial applications, a grinding. media size of 350 Eun is considered the practical lower limit due to media separator screen limitations.
SUMMARY OF THE INVENTION
We have discovered a continuous grinding process for preparing extremely fine particles which avoids various problems, e.g., separator screen plugging and unacceptable pressure build up due to hydraulic packing of the media, associated with prior art processes requiring the separation of the dispersion agent from the grinding media in the milling chamber.
More specifically, in accordance with this invention, there is provided a method of preparing submicron-sued particles of a therapeutic or diagnostic agent which comprises continuously introducing the agent and rigid grinding media into a milling chamber, contacting the agent with the grinding media while in the chamber to reduce the particle size of the agent, continuously removing the agent and the grinding media from the milling chamber, and thereafter separating the agent from the grinding media.
In another embodiment of the invention, the therapeutic or diagnostic agent, grinding media and a liquid dispersion medium are continuously introduced and removed from the milling chamber.
It is a particularly advantageous feature of this invention that there is provided a continuous method of preparing extremely fine particles of therapeutic and diagnostic agents.
It is another advantageous feature of this invention that there is provided a grinding method which , enables the use of ultra-fine grinding media, e.g., of a particle size less than 300 um, in a continuous grinding process.
According to one aspect of the present invention, there is provided a continuous method of preparing submicron particles of a therapeutic or diagnostic agent, said method comprising the steps of: (a) continuously introducing the therapeutic or diagnostic agent and rigid grinding media into a milling chamber, wherein said rigid grinding media have a particle size of 1000 microns or less; (b) contacting the therapeutic or diagnostic agent with the grinding media while in the milling chamber to reduce the particle size of the therapeutic or diagnostic agent to a submicron size;
(c) continuously removing the therapeutic or diagnostic agent and the grinding media from the milling chamber; and (d) separating the submicron-sized therapeutic or diagnostic agent from the grinding media to obtain a composition comprising submicron-sized particles of the therapeutic or diagnostic agent.
According to another aspect of the present invention, there is provided a continuous method of preparing submicron particles of a poorly soluble therapeutic or diagnostic agent, wherein said therapeutic or diagnostic agent has a surface modifier adsorbed on to the surface of said agent, said method comprising the steps of:
(a) continuously introducing the poorly soluble therapeutic or diagnostic agent, the surface modifier, a liquid dispersion medium, and rigid grinding media into a milling chamber, wherein the rigid grinding media have a particle size of 1000 microns or less; (b) contacting the poorly soluble therapeutic or diagnostic agent and the surface 3a modifier with the grinding media while in the milling chamber to reduce the particle size of the therapeutic or diagnostic agent to a submicron size and to adsorb the surface modifier to the surface of the therapeutic or diagnostic agent; (c) continuously removing the therapeutic or diagnostic agent, having the surface modifier adsorbed to the surface thereof, and the grinding media from the milling chamber; and (d) separating the therapeutic or diagnostic agent, having the surface modifier adsorbed to the surface thereof, from the grinding media to obtain a composition comprising surface modified submicron-sized particles of the therapeutic or diagnostic agent.
Still another advantageous feature of this invention is that there is provided a continuous grinding process which avoids problems, e.g., separator screen plugging, associated with prior art processes requiring the separation of the dispersion agent from the grinding media in the milling chamber.
Yet another advantageous feature of this invention is that there is provided a method of fine grinding therapeutic and diagnostic agents, which method generates less heat and reduces potential heat-related problems such as chemical instability and contamination.
Other advantageous features will become readily apparent upon reference to the following description of preferred embodiments when read in light of the accompanying drawing.
BRIEF DESCRIPTION OF THE DRAWING
Fig. 1 is a schematic view of a preferred embodiment of a continuous grinding process in accordance with this invention.
3b DESCRIPTION OF PREFERRED EMBODIMENTS
In accordance with this invention, there is provided a continuous method of preparing submicron particles of a therapeutic or diagnostic agent. By "continuous method" it is meant that both the dispersion agent and the'grinding media are continuously introduced and removed from the milling chamber. This can be contrasted to a conventional roller mill process wherein the agent and grinding media are introduced and removed from the grinding vessel in a batch process.
Liversidge et al, U.S. Patent No. 5,145,684, and European Patent Application 498;492, describe dispersible particles consisting of a drug substance or an x-ray. contrast agent having a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than about 400 nm. The particles are prepared by dispersing a drug substance or imaging agent in a liquid dispersion medium and wet grinding in the presence of rigid grinding media. Liversidge et al do not suggest a continuous milling process wherein the grinding media is separated from the pharmaceutical agent outside the milling chamber.
Bruno et al, only-owned U.S. Patent No. 5,518,187 1 5 (continuation of Application Serial No. 07/981,639 filed November 25,.1992) entitled Method for Grinding Pharmaceutica3 Substances discloses polymeric grinding media for fine grinding pharmaceutical compositions. However, Bruno et al do not suggest a continuous process wherein the grinding media is separated from the pharmaceutical agent outside the milling chamber.
In a preferred embodiment, the grinding media can comprise particles, preferably substantially spherical in shape, e.g., beads, of a polymeric resin.
However, grinding media in the form of other non-spherical shapes are expected to be useful in the practice of this invention.
In general, polymeric resins suitable for use herein are chemically and physically inert, substadtially free of metals, solvent'and monomers, and of sufficient hardness and friability to enable them to avoid being chipped or crushed during grinding. Suitable polymeric resins include crosslinked polystyrenes, such as polystyrene crosslinked with divinylbenzene, styrene copolymers, polyacrylates such as polymethyl methylczylate, polycarbonates, polyacetals, such as , , CA 02190134 2004-05-07 TM
Delrin_, vinyl chloride polymers and copolymers, polyurethanes, polyamides, poly(tetr-afluoroethylenes), ,M
e.g., Teflon_, and other fluoropolymers, high density polyethylenes, polypropylenes, cellulose ethers and 5 esters such as cellulose acetate, polyhydroxymethacxylate, polyhydroxyethyl acrylate, silicone containing polymers such as polysiloxanes and the like. The polymer can be biodegradable. Exemplary biodegradable polymers include poly(lactides), poly(glycolide) copolymers of lactides and glycolide, polyanhydrides, poly(hydroxyethyl methacrylate), poly(imino carbonates), poly(N-acylhydroxyproline)esters.
poly(N-palmitoyl hydroxyproline) esters, ethylene-vinyl acetate copolymers, poly(orthoesters), poly(caprolactones), and poly(phosphazenes). In the case of biodegradable polymers, contamination from the media itself advantageously can metabolize in vivo into biologically acceptable products which can be eliminated from the body.
The polymeric resin can have a density from 0.8 to 3.0 g/cm3. Higher density resins are preferred inasmuch as it is believed that these provide more efficient particle size reduction. The use of polymeric resins enable improved pH control.
Furthermore, Applicants believe that the invention can be practiced in conjunction with various inorganic grinding media prepared in the appropriate particle size. Such media include zirconium oxide, such as 95% Zr0 stabilized with magnesia, zirconium silicate.
glass, stainless steel, titanic, alumina, and 95% Zr0 stabilized with yttrium.
The media can range in size up to about 100D
microns. However, it is particularly advantageous that the invention enables the use of grinding media having a particle size of less than about 300 microns. More preferably, the media is less than about 75 microns, and.
WO95131973 ~ ~ g 01 ~ ~ PCfIUS95105728 most preferably, less than about 50 microns, in size.
Excellent particle size-reduction has been achieved with polymeric media having a particle size of about 50 microns.
The milling process can be a dzy process, e.g., a dry milling process, or a wet process, i.e., wet-grinding. In preferred embodiments, this invention is practiced in accordance with the teaching of U.S. Patent No. 5,145,684 and European Patent Application 498,482.
Thus, the wet grinding process can be practiced in conjunction with a liquid dispersion medium and surface modifier such as described in these publications. Useful liquid dispersion media include water, aqueous salt solutions, ethanol, butanol, hexane, glycol and the like.
The surface modifier can be selected from known organic and inorganic pharmaceutical excipients such as described in U.S. Patent No. 5,145,684 and can be present in an amount of 0.1-90%, preferably 1-80% by weight based on the total weight of the dzy particle. A preferred surface modifier is polyvinyl pyrrolidone.
In preferred embodiments, the therapeutic or diagnostic agent can be prepared in submicron or nanoparticulate particle size, e.g., less than about 500 nm. Applicants have demonstrated that particles can be prepared having an average particle size of less than about 300 nm. In certain embodiments, particles having an average particle size of less than 100 nm have been prepared in accordance with the present invention. It was particularly surprising and unexpected that such fine particles could be prepared free of unacceptable contamination.
Grinding can take place in any suitable grinding mill. Suitable mills include an sirjet mill, an attritor mill, a vibratory mill, a sand mill and a bead mill. A high energy media mill is preferred especially when the grinding media is a polymeric resin. The mill can contain a rotating shaft. This invention can also be practiced in conjunction with high speed dispersers such as a Cowles disperser, rotor-stator mixers, or other conventional mixers which can deliver high fluid velocity and high shear.
The preferred proportions of the grinding media, the therapeutic and/or diagnostic agent, the optional liquid dispersion medium, and surface modifier present in the grinding vessel can vary within wide limits and depends, for example, upon the particular therapeutic or diagnostic agent selected, the size and density of the grinding media, the type of mill selected, etc. Grinding media concentrations can range from about 10-958, preferably 20-908 by volume depending on the application and can be optimized based on the above factors; milling performance requirements, and the flow characteristics of the combined grinding media and agent dispersion.
The attrition time can vary widely and depends primarily upon the particular therapeutic or diagnostic agent, mechanical means and residence conditions selected, the initial and desired final particle size and so forth. Residence times of less than about 8 hours are generally required using high energy dispersers and/or media mills.
The process can be carried out within a wide range of temperatures and pressures. The process preferably is carried out at a temperature below that which can cause the agent to degrade. For many agents, ambient temperatures are appropriate. Temperatures of less than about 30C-40C are typically preferred.
, Control of the temperature, e.g., by jacketing or immersion of the milling chamber in ice water are contemplated. Processing pressures from about 1 psi (0.07 lcg/cm2) up to about 50 psi (3.5 kg/cm2) are contemplated. Processing pressures from about 10 psi (0.7 kg/cm2) to about 20 psi (1:9 kg/cm2) are typical.
The therapeutic or diagnostic agent and the grinding media are continuously removed from the milling chamber: Thereafter, the grinding media is separated from the milled particulate agent (in either a dxy or liquid dispersion form) using conventional separation techniques, in a secondazy process such as by simple filtration, sieving through a mesh filter or screen, and the like. Other separation techniques such as centrifugation may also be employed.
The invention~can be practiced with a wide variety of therapeutic and diagnostic agents. In the case of dry milling, the drug substances and imaging agents must be capable of being formed into solid particles. In the case of wet milling; the drug substances and imaging agents must be poorly soluble and dispersible in at least one liquid medium. By "poorly soluble", it is meant that the therapeutic or diagnostic agent has a solubility in the liquid dispersion medium, e.g., water, of less than about 10 mg/ml, and preferably of less than about 1 mg/ml. The preferred liquid dispersion medium is water. Additionally, the invention can be practiced with other liquid media. The therapeutic and diagnostic agents preferably are organic, crystalline materials.
Suitable therapeutic agents and classes of therapeutic agents are described in U.S. Patent No.
5,145,684 and include Danazol, 5a; l7oc,-1'-(methylsulfonyl)-1'H-gregn-20-yno[3,2-cl-pyrazol-17-0l, camptothecin, piposulfam, piposulfan, naproxen and phenytoin.
R'O 95131973 PCTIUS95/05728 Suitable diagnostic agents include derivatives of iodinated aromatic acids such as ethyl-3,5-bisacetoamido-2,4,6-triiodobenzoate (WIN 8883), ethyl(3,5-bis(acetylamino)-2,4,6-triodobenzoyloxy) 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). Other suitable imaging agents are described in U.S. Patent No. 5,260,478, U.S. Patent No. 5,264,610 and European Patent Application 498,482.
In a preferred embodiment, the agent and grinding media are recirculated through the milling chamber. Examples of suitable means to effect such recirculation include conventional pumps such as peristaltic pumps, diaphragm pumps, piston pumps, centrifugal pumps and other positive displacement pumps which do not use sufficiently close tolerances to damage the grinding media. Peristaltic pumps are generally preferred.
Another variation of this process includes the use of mixed media sizes. For example, larger media may be employed in a conventional manner where such media is restricted to the milling chamber. Smaller grinding media may be continuously recirculated through the system and permitted to pass through the agitated bed of larger grinding media. In this embodiment, the smaller media is preferably between about 1 and 300 N.m in mean particle size and the larger grinding media is between about 300 and 1000 Etm in mean particle size.
With reference to Figure 1, the process of this invention can be carried out as follows. The therapeutic or diagnostic agent 10 and rigid grinding media 12 are continuously introduced into milling chamber 14 which, as . illustrated, contains rotating shaft 16. Peristaltic pump 18 provides the energy to recirculate the dispersion containing both the agent and grinding media through the milling chamber to holding tank 20. As opposed to conventional prior art process, there is no means for retaining the grinding media within the milling chamber, such as a screen or rotating gap separator.
The following examples further illustrate the invention.
Example 1 Continuous Millina Process Us,'_na Fine PO~vmeric Media in a 0.3 Liter DvnoM~ »
A premix dispersion was formed by combining micronized Danazol powder (2-10)lm mean size) with an aqueous PVP (average molecular weight = 15,000) solution at a ratio of 5.0% Danazol, 1.5% PVP and 93.5% water.
292 grams of thispremix dispersion was combined with 379.6 grams of polystyrene crosslinked with divinyl benzene (20% styrene; 80% divinylbenzene), milling media, nominal 50 micron size. This combined mixture was recirculated through a 0.3 liter DynoMill at 3200 rpm (100cm3/min) for -60 minutes (residence time). There was no means for retaining the grinding media within the milling chamber.--After removal of the slurry from the milling chamber, the media was separated from the particulate Danaaol using a 10 ~1m filter. Thereafter, the particle size was measured by CHDF. The particle size distribution showed a weight average particle size of 35 nm.
Example 2 Continuous Millina Process Usina Fine Polymeric Media in a 0.6 Liter DvnoMill A premix dispersion was formed by combining micronized Danazol powder (2-10 Eun mean size) with an aqueous PVP
(average MW = 15,000) solution at a ratio of 5.0%
Danazol, 1.5% PVP and 93.5% water. 2768 grams of this , premix dispersion was combined with 3324 grams of polystyrene crosslinked with divinyl benzene (20%
R'O 95/31973 PCTIUS95/05728 styrene; 80~ divinyl benzene) recirculated through a 0.6 liter DynoMill at 3200 rpm (100 cm3/min) for 60 minutes residence time. There was no means for retaining the grinding media within the milling chamber. After removal of the slurry from the milling chamber, the media was separated from the particle Danazol using a 10 Nm filter.
The particle size of this batch was not measured but microscopic examination indicated that the mean size was likely below 100 nm.
The invention has been described in detail with particular reference to certain preferred embodiments thereof, but it will be understood that variations and modifications can be effected within the spirit and scope of the invention.
Claims (27)
1. A continuous method of preparing submicron particles of a therapeutic or diagnostic agent, said method comprising the steps of:
(a) continuously introducing the therapeutic or diagnostic agent and rigid grinding media into a milling chamber, wherein said rigid grinding media have a particle size of 1000 microns or less;
(b) contacting the therapeutic or diagnostic agent with the grinding media while in the milling chamber to reduce the particle size of the therapeutic or diagnostic agent to a submicron size;
(c) continuously removing the therapeutic or diagnostic agent and the grinding media from the milling chamber; and (d) separating the submicron-sized therapeutic or diagnostic agent from the grinding media to obtain a composition comprising submicron-sized particles of the therapeutic or diagnostic agent.
(a) continuously introducing the therapeutic or diagnostic agent and rigid grinding media into a milling chamber, wherein said rigid grinding media have a particle size of 1000 microns or less;
(b) contacting the therapeutic or diagnostic agent with the grinding media while in the milling chamber to reduce the particle size of the therapeutic or diagnostic agent to a submicron size;
(c) continuously removing the therapeutic or diagnostic agent and the grinding media from the milling chamber; and (d) separating the submicron-sized therapeutic or diagnostic agent from the grinding media to obtain a composition comprising submicron-sized particles of the therapeutic or diagnostic agent.
2. A continuous method of preparing submicron particles of a poorly soluble therapeutic or diagnostic agent, wherein said therapeutic or diagnostic agent has a surface modifier adsorbed on to the surface of said agent, said method comprising the steps of:
(a) continuously introducing the poorly soluble therapeutic or diagnostic agent, the surface modifier, a liquid dispersion medium, and rigid grinding media into a milling chamber, wherein the rigid grinding media have a particle size of 1000 microns or less;
(b) contacting the poorly soluble therapeutic or diagnostic agent and the surface modifier with the grinding media while in the milling chamber to reduce the particle size of the therapeutic or diagnostic agent to a submicron size and to adsorb the surface modifier to the surface of the therapeutic or diagnostic agent;
(c) continuously removing the therapeutic or diagnostic agent, having the surface modifier adsorbed to the surface thereof, and the grinding media from the milling chamber; and (d) separating the therapeutic or diagnostic agent, having the surface modifier adsorbed to the surface thereof, from the grinding media to obtain a composition comprising surface modified submicron-sized particles of the therapeutic or diagnostic agent.
(a) continuously introducing the poorly soluble therapeutic or diagnostic agent, the surface modifier, a liquid dispersion medium, and rigid grinding media into a milling chamber, wherein the rigid grinding media have a particle size of 1000 microns or less;
(b) contacting the poorly soluble therapeutic or diagnostic agent and the surface modifier with the grinding media while in the milling chamber to reduce the particle size of the therapeutic or diagnostic agent to a submicron size and to adsorb the surface modifier to the surface of the therapeutic or diagnostic agent;
(c) continuously removing the therapeutic or diagnostic agent, having the surface modifier adsorbed to the surface thereof, and the grinding media from the milling chamber; and (d) separating the therapeutic or diagnostic agent, having the surface modifier adsorbed to the surface thereof, from the grinding media to obtain a composition comprising surface modified submicron-sized particles of the therapeutic or diagnostic agent.
3. The method of claim 1 or 2, wherein the grinding media comprises a polymeric resin.
4. The method of claim 3, wherein said polymeric resin is selected from the group consisting of crosslinked polystyrenes, styrene copolymers, polyacrylates, polycarbonates, polyacetals, vinyl chloride polymers and copolymers, polyurethanes, polyamides, fluoropolymers, high density polyethylenes, polypropylenes, cellulose ethers and esters, polyhydroxymethacrylate, polyhydroxyethyl acrylate, and silicone containing polymers.
5. The method of claim 4, wherein the polymeric resin is selected from the group consisting of polystyrene crosslinked with divinylbenzene, poly(tetrafluoroethylenes), polymethyl methacrylate, cellulose acetate, and polysiloxanes.
6. The method of claim 5, wherein said polymeric resin is polystyrene crosslinked with divinylbenzene.
7. The method of claim 5, wherein said polymeric resin is polymethylmethacrylate.
8. The method of claim 3, wherein the polymeric resin is biodegradable.
9. The method of claim 8, wherein the biodegradable polymeric resin is selected from the group consisting of poly(lactides), poly(glycolide) copolymers of lactides and glycolide, polyanhydrides, poly(hydroxyethyl methacrylate), poly(imino carbonates), poly(N-acylhydroxyproline) esters, poly(N-palmitoyl hydroxyproline) esters, ethylene-vinyl acetate copolymers, poly(orthoesters), poly(caprolactones), and poly(phosphazenes).
10. The method of any one of claims 1 and 2, wherein the grinding media is selected from the group consisting of zirconium oxide, 95% ZrO stabilized with magnesia, zirconium silicate, glass, stainless steel, titania, alumina, and 95%
ZrO stabilized with yttrium.
ZrO stabilized with yttrium.
11. The method of any one of claims 2 to 10, wherein the dispersion medium is selected from the group consisting of water, an aqueous salt solution, ethanol, butanol, hexane, and glycol.
12. The method of any one of claims 1 to 11, wherein step (b) additionally comprises contacting or wet grinding said agent in the presence of at least one surface modifier for the therapeutic or diagnostic agent.
13. The method of claim 12, wherein the surface modifier is polyvinyl pyrrolidone.
14. The method of claim 12, wherein said surface modifier is present in an amount of 0.1 to 90% (w/w).
15. The method of any one of claims 1 to 14, wherein the therapeutic or diagnostic agent of step (d) has an average particle size of less than about 500 nm.
16. The method of any one of claims 1 to 14, wherein the therapeutic or diagnostic agent of step (d) has an average particle size of less than about 300 nm.
17. The method of any one of claims 1 to 14, wherein the therapeutic or diagnostic agent of step (d) has an average particle size of less than about 100 nm.
18. The method of any one of claims 1 to 17, wherein the grinding media have a mean particle size of less than about 300 microns.
19. The method of any one of claims 1 to 17, wherein the grinding media have a mean particle size of less than about 75 microns.
20. The method of any one of claims 1 to 17, wherein the grinding media have a mean particle size of less than about 50 microns.
21. The method of any one of claims 1 to 17, wherein the grinding media have a mean particle size of less than about 25 microns.
22. The method of any one of claims 1 to 17, wherein the grinding media have a mixed particle size in which smaller grinding media have a mean particle size of from about 1 to about 300 microns in diameter and larger grinding media have a mean particle size of from about 300 to about 1000 microns in diameter.
23. The method of any one of claims 1 to 22, wherein the therapeutic agent is selected from the group consisting of Danazol; 5.alpha., 17.alpha.,-1'-(methylsulfonyl)-1'H-pregn-20-yno[3,2-c]-pyrazol-17-ol; camptothecin; piposulfam;
piposulfan; naproxen; and phenytoin.
piposulfan; naproxen; and phenytoin.
24. The method of any one of claims 1 to 22, wherein the therapeutic agent is an NSAID or an anticancer agent.
25. The method of any one of claims 1 to 22, wherein the diagnostic agent is selected from the group consisting of ethyl-3,5-bisacetoamido-2,4,6-triiodobenzoate;
ethyl(3,5-bis(acetylamino)-2,4,6-triiodobenzoyloxy) acetate;
ethyl-2-(his(acetylamino)-2,4,6-triiodobenzoyloxy) butyrate;
and 6-ethoxy-6-oxohexyl-3,5-bis(acetylamino)-2,4,6-triiodobenzoate.
ethyl(3,5-bis(acetylamino)-2,4,6-triiodobenzoyloxy) acetate;
ethyl-2-(his(acetylamino)-2,4,6-triiodobenzoyloxy) butyrate;
and 6-ethoxy-6-oxohexyl-3,5-bis(acetylamino)-2,4,6-triiodobenzoate.
26. The method of any one of claims 1 to 25, further including the step of recirculating said agent and said grinding media through said milling chamber.
27. The method of any one of claims 1 to 26, wherein said milling chamber comprises a rotating shaft.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/249,787 US5718388A (en) | 1994-05-25 | 1994-05-25 | Continuous method of grinding pharmaceutical substances |
| US08/249,787 | 1994-05-25 | ||
| PCT/US1995/005728 WO1995031973A1 (en) | 1994-05-25 | 1995-05-08 | Continuous method of grinding pharmaceutical substances |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2190134A1 CA2190134A1 (en) | 1995-11-30 |
| CA2190134C true CA2190134C (en) | 2005-03-08 |
Family
ID=22944996
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002190134A Expired - Lifetime CA2190134C (en) | 1994-05-25 | 1995-05-08 | Continuous method of grinding pharmaceutical substances |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US5718388A (en) |
| EP (1) | EP0804161B1 (en) |
| JP (1) | JP3607294B2 (en) |
| AT (1) | ATE208191T1 (en) |
| AU (1) | AU2476195A (en) |
| CA (1) | CA2190134C (en) |
| DE (1) | DE69523781T2 (en) |
| DK (1) | DK0804161T3 (en) |
| ES (1) | ES2165913T3 (en) |
| IL (1) | IL113851A (en) |
| MY (1) | MY113569A (en) |
| PT (1) | PT804161E (en) |
| TW (1) | TW460297B (en) |
| WO (1) | WO1995031973A1 (en) |
Families Citing this family (192)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU4990696A (en) * | 1995-02-24 | 1996-09-11 | Nanosystems L.L.C. | Aerosols containing nanoparticle dispersions |
| US6832735B2 (en) * | 2002-01-03 | 2004-12-21 | Nanoproducts Corporation | Post-processed nanoscale powders and method for such post-processing |
| US5993856A (en) * | 1997-01-24 | 1999-11-30 | Femmepharma | Pharmaceutical preparations and methods for their administration |
| UA72189C2 (en) | 1997-11-17 | 2005-02-15 | Янссен Фармацевтика Н.В. | Aqueous suspensions of 9-hydroxy-risperidone fatty acid esters provided in submicron form |
| US6000646A (en) * | 1998-03-16 | 1999-12-14 | Ranne; Bethyl H. | Double barrel media mill for grinding and dispersing particulate matter and pigment for paint, coatings, ink and other fluid pigment vehicles |
| US20080213378A1 (en) * | 1998-10-01 | 2008-09-04 | Elan Pharma International, Ltd. | Nanoparticulate statin formulations and novel statin combinations |
| US8236352B2 (en) * | 1998-10-01 | 2012-08-07 | Alkermes Pharma Ireland Limited | Glipizide compositions |
| US20040013613A1 (en) * | 2001-05-18 | 2004-01-22 | Jain Rajeev A | Rapidly disintegrating solid oral dosage form |
| US8293277B2 (en) * | 1998-10-01 | 2012-10-23 | Alkermes Pharma Ireland Limited | Controlled-release nanoparticulate compositions |
| NZ511442A (en) * | 1998-11-02 | 2003-02-28 | Elan Corp Plc | Multiparticulate modified release composition for multiple dosing of ADD patients with methylphenidate HCl |
| US20090297602A1 (en) * | 1998-11-02 | 2009-12-03 | Devane John G | Modified Release Loxoprofen Compositions |
| US6428814B1 (en) * | 1999-10-08 | 2002-08-06 | Elan Pharma International Ltd. | Bioadhesive nanoparticulate compositions having cationic surface stabilizers |
| US20040141925A1 (en) * | 1998-11-12 | 2004-07-22 | Elan Pharma International Ltd. | Novel triamcinolone compositions |
| US6969529B2 (en) | 2000-09-21 | 2005-11-29 | Elan Pharma International Ltd. | Nanoparticulate compositions comprising copolymers of vinyl pyrrolidone and vinyl acetate as surface stabilizers |
| US6444223B1 (en) | 1999-05-28 | 2002-09-03 | Alkermes Controlled Therapeutics, Inc. | Method of producing submicron particles of a labile agent and use thereof |
| ATE271922T1 (en) | 1999-06-01 | 2004-08-15 | Elan Pharma Int Ltd | SMALL MILL AND METHOD THEREOF |
| US20040115134A1 (en) * | 1999-06-22 | 2004-06-17 | Elan Pharma International Ltd. | Novel nifedipine compositions |
| US6656504B1 (en) | 1999-09-09 | 2003-12-02 | Elan Pharma International Ltd. | Nanoparticulate compositions comprising amorphous cyclosporine and methods of making and using such compositions |
| EP1313564B1 (en) | 2000-04-26 | 2009-12-30 | Elan Pharma International Limited | Apparatus for sanitary wet milling |
| ATE389455T1 (en) | 2000-05-10 | 2008-04-15 | Jagotec Ag | GRINDING BY MEANS OF GRINDING MEDIUM |
| US6316029B1 (en) | 2000-05-18 | 2001-11-13 | Flak Pharma International, Ltd. | Rapidly disintegrating solid oral dosage form |
| ATE424811T1 (en) | 2000-08-31 | 2009-03-15 | Jagotec Ag | GROUND PARTICLES |
| US20030224058A1 (en) * | 2002-05-24 | 2003-12-04 | Elan Pharma International, Ltd. | Nanoparticulate fibrate formulations |
| US7276249B2 (en) * | 2002-05-24 | 2007-10-02 | Elan Pharma International, Ltd. | Nanoparticulate fibrate formulations |
| US20080241070A1 (en) * | 2000-09-21 | 2008-10-02 | Elan Pharma International Ltd. | Fenofibrate dosage forms |
| US7998507B2 (en) * | 2000-09-21 | 2011-08-16 | Elan Pharma International Ltd. | Nanoparticulate compositions of mitogen-activated protein (MAP) kinase inhibitors |
| US7198795B2 (en) | 2000-09-21 | 2007-04-03 | Elan Pharma International Ltd. | In vitro methods for evaluating the in vivo effectiveness of dosage forms of microparticulate of nanoparticulate active agent compositions |
| US20060287254A1 (en) * | 2001-01-26 | 2006-12-21 | Schering Corporation | Use of substituted azetidinone compounds for the treatment of sitosterolemia |
| NZ525921A (en) * | 2001-01-26 | 2005-06-24 | Schering Corp | Combinations of peroxisome proliferator-activated receptor (PPAR) activator(s) and sterol absorption inhibitor(s) and treatments for vascular indications |
| EP1381448B1 (en) * | 2001-04-27 | 2006-10-11 | Kansai Paint Co., Ltd | Method and apparatus for dispersing pigment in liquid medium |
| US6976647B2 (en) * | 2001-06-05 | 2005-12-20 | Elan Pharma International, Limited | System and method for milling materials |
| US20030087308A1 (en) * | 2001-06-22 | 2003-05-08 | Elan Pharma International Limited | Method for high through put screening using a small scale mill or microfluidics |
| US7758890B2 (en) | 2001-06-23 | 2010-07-20 | Lyotropic Therapeutics, Inc. | Treatment using dantrolene |
| US6722699B2 (en) | 2001-08-02 | 2004-04-20 | Eastman Kodak Company | Authentication using near-field optical imaging |
| US8403367B2 (en) | 2001-08-02 | 2013-03-26 | Eastman Kodak Company | Authentication using near-field optical imaging |
| US20030054042A1 (en) * | 2001-09-14 | 2003-03-20 | Elaine Liversidge | Stabilization of chemical compounds using nanoparticulate formulations |
| PT1429731E (en) * | 2001-09-19 | 2007-04-30 | Elan Pharma Int Ltd | Nanoparticulate insulin formulations |
| CA2460340C (en) * | 2001-09-21 | 2011-02-15 | Schering Corporation | Methods and therapeutic combinations for the treatment of xanthoma using sterol absorption inhibitors |
| US7053080B2 (en) * | 2001-09-21 | 2006-05-30 | Schering Corporation | Methods and therapeutic combinations for the treatment of obesity using sterol absorption inhibitors |
| DK1443912T3 (en) * | 2001-10-12 | 2008-01-21 | Elan Pharma Int Ltd | Compositions with a combination of immediate and controlled release properties |
| WO2003039601A1 (en) * | 2001-11-07 | 2003-05-15 | Imcor Pharmaceutical Company | Methods for vascular imaging using nanoparticulate contrast agents |
| MXPA04006017A (en) | 2001-12-20 | 2005-06-08 | Femmepharma Inc | Vaginal delivery of drugs. |
| US20030129242A1 (en) * | 2002-01-04 | 2003-07-10 | Bosch H. William | Sterile filtered nanoparticulate formulations of budesonide and beclomethasone having tyloxapol as a surface stabilizer |
| EP1471887B1 (en) * | 2002-02-04 | 2010-04-21 | Elan Pharma International Ltd. | Nanoparticulate compositions having lysozyme as a surface stabilizer |
| US20040101566A1 (en) * | 2002-02-04 | 2004-05-27 | Elan Pharma International Limited | Novel benzoyl peroxide compositions |
| US6699963B2 (en) | 2002-03-18 | 2004-03-02 | The Procter & Gamble Company | Grinding process for plastic material and compositions therefrom |
| US20080220075A1 (en) * | 2002-03-20 | 2008-09-11 | Elan Pharma International Ltd. | Nanoparticulate compositions of angiogenesis inhibitors |
| WO2003080023A2 (en) * | 2002-03-20 | 2003-10-02 | Elan Pharma International Limited | Fast dissolving dosage forms having reduced friability |
| DE60309300T3 (en) * | 2002-03-20 | 2011-02-24 | Elan Pharma International Ltd. | NANOPARTICLE COMPOSITIONS OF ANGIOGENIC INHIBITORS |
| AU2003224808A1 (en) * | 2002-03-28 | 2003-10-13 | Imcor Pharmaceutical Company | Compositions and methods for delivering pharmaceutically active agents using nanoparticulates |
| CA2481390C (en) | 2002-04-12 | 2012-11-27 | Elan Pharma International Ltd. | Nanoparticulate megestrol formulations |
| US20040105889A1 (en) * | 2002-12-03 | 2004-06-03 | Elan Pharma International Limited | Low viscosity liquid dosage forms |
| US20100226989A1 (en) * | 2002-04-12 | 2010-09-09 | Elan Pharma International, Limited | Nanoparticulate megestrol formulations |
| US7101576B2 (en) | 2002-04-12 | 2006-09-05 | Elan Pharma International Limited | Nanoparticulate megestrol formulations |
| US9101540B2 (en) | 2002-04-12 | 2015-08-11 | Alkermes Pharma Ireland Limited | Nanoparticulate megestrol formulations |
| DE10218109A1 (en) * | 2002-04-23 | 2003-11-20 | Jenapharm Gmbh | Process for the production of crystals, then available crystals and their use in pharmaceutical formulations |
| DE10218107A1 (en) * | 2002-04-23 | 2003-11-20 | Jenapharm Gmbh | Process for the production of crystals of steroids, crystals available thereafter and their use in pharmaceutical formulations |
| US20070264348A1 (en) * | 2002-05-24 | 2007-11-15 | Elan Pharma International, Ltd. | Nanoparticulate fibrate formulations |
| JP4533134B2 (en) * | 2002-06-10 | 2010-09-01 | エラン ファーマ インターナショナル，リミティド | Nanoparticulate policosanol formulations and novel policosanol combinations |
| JP4776229B2 (en) * | 2002-07-16 | 2011-09-21 | エラン ファーマ インターナショナル，リミティド | Stable nanoparticulate active substance liquid dosage composition |
| ATE487470T1 (en) * | 2002-09-11 | 2010-11-15 | Elan Pharma Int Ltd | GEL-STABILIZED ACTIVE COMPOSITIONS IN NANOPARTICLE SIZE |
| CN101119795B (en) * | 2002-10-09 | 2011-02-23 | 诺维信公司 | A method for improving particle compositions |
| JP4776233B2 (en) * | 2002-11-12 | 2011-09-21 | エラン ファーマ インターナショナル，リミティド | Fast disintegrating solid formulation that is resistant to abrasion and contains pullulan |
| US20050095267A1 (en) * | 2002-12-04 | 2005-05-05 | Todd Campbell | Nanoparticle-based controlled release polymer coatings for medical implants |
| US20040173696A1 (en) * | 2002-12-17 | 2004-09-09 | Elan Pharma International Ltd. | Milling microgram quantities of nanoparticulate candidate compounds |
| US9173836B2 (en) | 2003-01-02 | 2015-11-03 | FemmeParma Holding Company, Inc. | Pharmaceutical preparations for treatments of diseases and disorders of the breast |
| EP1578421A4 (en) | 2003-01-02 | 2009-04-22 | Femmepharma Holding Co Inc | Pharmaceutical preparations for treatments of diseases and disorders of the breast |
| CA2513064C (en) * | 2003-01-31 | 2009-11-10 | Elan Pharma International, Ltd. | Nanoparticulate topiramate formulations |
| US20040208833A1 (en) * | 2003-02-04 | 2004-10-21 | Elan Pharma International Ltd. | Novel fluticasone formulations |
| US20100297252A1 (en) | 2003-03-03 | 2010-11-25 | Elan Pharma International Ltd. | Nanoparticulate meloxicam formulations |
| US8512727B2 (en) | 2003-03-03 | 2013-08-20 | Alkermes Pharma Ireland Limited | Nanoparticulate meloxicam formulations |
| EP1606103A4 (en) * | 2003-03-06 | 2007-01-10 | Rensselaer Polytech Inst | Rapid generation of nanoparticles from bulk solids at room temperature |
| DE602004018617D1 (en) * | 2003-03-07 | 2009-02-05 | Schering Corp | SUBSTITUTED AZETIDINONE DERIVATIVES, THEIR PHARMACEUTICAL FORMULATIONS AND THEIR USE FOR THE TREATMENT OF HYPERCHOLESTEROLMIA |
| ATE406364T1 (en) * | 2003-03-07 | 2008-09-15 | Schering Corp | SUBSTITUTED AZETIDINONE DERIVATIVES, THEIR PHARMACEUTICAL FORMULATIONS AND THEIR USE IN THE TREATMENT OF HYPERCHOLESTEROLEMIA |
| US7459442B2 (en) * | 2003-03-07 | 2008-12-02 | Schering Corporation | Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof |
| US7842232B2 (en) * | 2003-05-22 | 2010-11-30 | Elan Pharma International, Ltd. | Sterilization of dispersions of nanoparticulate active agents with gamma radiation |
| DE602004018150D1 (en) * | 2003-08-08 | 2009-01-15 | Elan Pharma Int Ltd | NEW METAXALON COMPOSITIONS |
| US7618181B2 (en) * | 2003-10-23 | 2009-11-17 | Kansai Paint Co., Ltd. | Method for dispersing pigment in liquid medium |
| ATE509618T1 (en) * | 2003-11-05 | 2011-06-15 | Elan Pharma Int Ltd | NANOPARTICLE-SHAPED COMPOSITIONS HAVING A PEPTIDE AS A SURFACE STABILIZER |
| EP1559419A1 (en) * | 2004-01-23 | 2005-08-03 | Fournier Laboratories Ireland Limited | Pharmaceutical formulations comprising metformin and a fibrate, and processes for their obtention |
| EP1621200A1 (en) * | 2004-07-26 | 2006-02-01 | Fournier Laboratories Ireland Limited | Pharmaceutical combinations containing an inhibitor of platelet aggregation and a fibrate |
| AU2005307797B2 (en) | 2004-11-16 | 2011-06-02 | Alkermes Pharma Ireland Limited | Injectable nanoparticulate olanzapine formulations |
| UA89513C2 (en) * | 2004-12-03 | 2010-02-10 | Элан Фарма Интернешнл Лтд. | Nanoparticulate raloxifene hydrochloride composition |
| BRPI0519088A2 (en) * | 2004-12-15 | 2008-12-23 | Elan Pharma Int Ltd | nanoparticulate tacrolimus formulations |
| WO2006069098A1 (en) * | 2004-12-22 | 2006-06-29 | Elan Pharma International Ltd. | Nanoparticulate bicalutamide formulations |
| KR20070104574A (en) * | 2004-12-30 | 2007-10-26 | 신벤션 아게 | Combination comprising an agent providing a signal, an implant material and a drug |
| JP6091041B2 (en) * | 2004-12-31 | 2017-03-08 | イシューティカ ピーティーワイ リミテッド | Nanoparticle composition and synthesis method thereof |
| KR20070118224A (en) * | 2005-01-06 | 2007-12-14 | 엘란 파마 인터내셔널 리미티드 | Nanoparticulate candesartan formulations |
| EP2014708A1 (en) * | 2005-01-13 | 2009-01-14 | Cinvention Ag | Shaped body made of a composite material |
| KR20070102717A (en) * | 2005-01-24 | 2007-10-19 | 신벤션 아게 | Metal containing composite materials |
| MX2007009915A (en) | 2005-02-15 | 2007-11-06 | Elan Pharma Int Ltd | Aerosol and injectable formulations of nanoparticulate benzodiazepine. |
| CA2598288A1 (en) * | 2005-03-03 | 2006-09-14 | Elan Pharma International Limited | Nanoparticulate compositions of heterocyclic amide derivatives |
| US20060204588A1 (en) * | 2005-03-10 | 2006-09-14 | Elan Pharma International Limited | Formulations of a nanoparticulate finasteride, dutasteride or tamsulosin hydrochloride, and mixtures thereof |
| KR20070121759A (en) * | 2005-03-17 | 2007-12-27 | 엘란 파마 인터내셔널 리미티드 | Nanoparticulate bisphosphonate compositions |
| JP2008532913A (en) * | 2005-03-18 | 2008-08-21 | シンベンション アーゲー | Process for the preparation of porous sintered metal materials |
| WO2006102494A2 (en) * | 2005-03-23 | 2006-09-28 | Elan Pharma International Limited | Nanoparticulate corticosteroid and antihistamine formulations |
| CN101171000A (en) * | 2005-04-12 | 2008-04-30 | 依兰药物国际有限公司 | Nanoparticulate and controlled release compositions comprising cyclosporine |
| US8309133B2 (en) * | 2005-04-12 | 2012-11-13 | Alkermes Pharma Ireland Limited | Nanoparticulate quinazoline derivative formulations |
| WO2006110809A2 (en) * | 2005-04-12 | 2006-10-19 | Elan Pharma International, Limited | Nanoparticulate lipase inhibitor formulations |
| US20070003628A1 (en) * | 2005-05-10 | 2007-01-04 | Elan Pharma International Limited | Nanoparticulate clopidogrel formulations |
| US20110064803A1 (en) * | 2005-05-10 | 2011-03-17 | Elan Pharma International Limited. | Nanoparticulate and controlled release compositions comprising vitamin k2 |
| AU2006344711A1 (en) * | 2005-05-16 | 2008-01-24 | Alkermes Pharma Ireland Limited | Nanoparticulate and controlled release compositions comprising a cephalosporin |
| US20100028439A1 (en) * | 2005-05-23 | 2010-02-04 | Elan Pharma International Limited | Nanoparticulate stabilized anti-hypertensive compositions |
| CA2610448A1 (en) | 2005-06-03 | 2006-12-14 | Elan Pharma International, Limited | Nanoparticulate imatinib mesylate formulations |
| KR20080017065A (en) * | 2005-06-03 | 2008-02-25 | 엘란 파마 인터내셔널 리미티드 | Nanoparticulate acetaminophen formulations |
| US20070042049A1 (en) * | 2005-06-03 | 2007-02-22 | Elan Pharma International, Limited | Nanoparticulate benidipine compositions |
| JP2009517485A (en) | 2005-06-08 | 2009-04-30 | エラン・ファルマ・インターナショナル・リミテッド | Nanoparticulate and controlled release compositions containing cefditoren |
| US20070059371A1 (en) * | 2005-06-09 | 2007-03-15 | Elan Pharma International, Limited | Nanoparticulate ebastine formulations |
| AU2006259606A1 (en) * | 2005-06-13 | 2006-12-28 | Elan Pharma International, Limited | Nanoparticulate clopidogrel and aspirin combination formulations |
| JP2008543862A (en) * | 2005-06-15 | 2008-12-04 | エラン ファーマ インターナショナル リミテッド | Nanoparticulate azelnidipine formulation |
| EP1902087A1 (en) * | 2005-07-01 | 2008-03-26 | Cinvention Ag | Process for the production of porous reticulated composite materials |
| MX2008000131A (en) * | 2005-07-01 | 2008-04-04 | Cinv Ag | Medical devices comprising a reticulated composite material. |
| US20070015719A1 (en) * | 2005-07-07 | 2007-01-18 | Elan Pharma International Limited | Nanoparticulate clarithromycin formulations |
| GB0516549D0 (en) * | 2005-08-12 | 2005-09-21 | Sulaiman Brian | Milling system |
| EP1937217A2 (en) * | 2005-09-13 | 2008-07-02 | Elan Pharma International Limited | Nanoparticulate tadalafil formulations |
| EP1933814A2 (en) * | 2005-09-15 | 2008-06-25 | Elan Pharma International Limited | Nanoparticulate aripiprazole formulations |
| JP2009511727A (en) * | 2005-10-18 | 2009-03-19 | シンベンション アーゲー | Thermosetting particles and manufacturing method thereof |
| US7858609B2 (en) * | 2005-11-28 | 2010-12-28 | Marinus Pharmaceuticals | Solid ganaxolone formulations and methods for the making and use thereof |
| ES2684821T3 (en) | 2005-12-29 | 2018-10-04 | Lexicon Pharmaceuticals, Inc. | Multicyclic amino acid derivatives and methods of their use |
| US7649098B2 (en) | 2006-02-24 | 2010-01-19 | Lexicon Pharmaceuticals, Inc. | Imidazole-based compounds, compositions comprising them and methods of their use |
| US8367112B2 (en) * | 2006-02-28 | 2013-02-05 | Alkermes Pharma Ireland Limited | Nanoparticulate carverdilol formulations |
| US11311477B2 (en) | 2006-03-07 | 2022-04-26 | Sgn Nanopharma Inc. | Ophthalmic preparations |
| US10137083B2 (en) | 2006-03-07 | 2018-11-27 | SGN Nanopharma Inc | Ophthalmic preparations |
| WO2007103294A2 (en) * | 2006-03-07 | 2007-09-13 | Novavax, Inc. | Nanoemulsions of poorly soluble pharmaceutical active ingredients and methods of making the same |
| BRPI0712130A2 (en) * | 2006-05-30 | 2012-01-17 | Elan Pharma Int Ltd | nanoparticulate posaconazole formulations |
| EP2054042B8 (en) | 2006-06-30 | 2020-06-10 | iCeutica Pty Ltd | Methods for the preparation of biologically active compounds in nanoparticulate form |
| EP2049084A2 (en) * | 2006-07-10 | 2009-04-22 | Elan Pharma International Limited | Nanoparticulate sorafenib formulations |
| EP2043623A4 (en) * | 2006-07-12 | 2013-03-20 | Elan Pharma Int Ltd | Nanoparticulate formulations of modafinil |
| BRPI0717721A2 (en) * | 2006-11-28 | 2013-10-29 | Marinus Pharmaceuticals | "COMPLEX DRUG PARTICLES, PHARMACEUTICAL COMPOSITION, USE OF A PHARMACEUTICAL COMPOSITION, COMPLEX DRUG PARTICLES STABILIZED IN THE SIZE, METHOD FOR THE PREPARATION OF STABILIZED DRUG PARTICLES, EMOTIONAL COMPOSITION IN PHARMACEUTICAL, PHARMACEUTICAL UNDERSTANDING |
| UA99270C2 (en) | 2006-12-12 | 2012-08-10 | Лексикон Фармасьютикалз, Инк. | 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds and methods of their use |
| BRPI0806916A2 (en) * | 2007-01-19 | 2014-04-29 | Cinv Ag | NON-DEGRADABLE POROUS IMPLANT MADE BY DUST |
| US20080206862A1 (en) * | 2007-02-28 | 2008-08-28 | Cinvention Ag | High surface cultivation system bag |
| EP2129766A2 (en) * | 2007-02-28 | 2009-12-09 | Cinvention Ag | High surface cultivation system with filler |
| EP2126040A1 (en) * | 2007-02-28 | 2009-12-02 | Cinvention Ag | High surface cultivation system |
| EP2129768A2 (en) * | 2007-02-28 | 2009-12-09 | Cinvention Ag | High surface cultivation system with surface increasing substrate |
| WO2009117401A2 (en) * | 2008-03-21 | 2009-09-24 | Elan Pharama International Limited | Compositions for site-specific delivery of imatinib and methods of use |
| EP2398499B1 (en) | 2009-02-18 | 2017-09-06 | Eyeon Particle Sciences LLC | Bi-functional co-polymer use for ophthalmic and other topical and local applications |
| US20120065221A1 (en) | 2009-02-26 | 2012-03-15 | Theraquest Biosciences, Inc. | Extended Release Oral Pharmaceutical Compositions of 3-Hydroxy-N-Methylmorphinan and Method of Use |
| FR2945950A1 (en) | 2009-05-27 | 2010-12-03 | Elan Pharma Int Ltd | ANTICANCER NANOPARTICLE COMPOSITIONS AND METHODS FOR PREPARING THE SAME |
| EP2435027B1 (en) | 2009-05-27 | 2016-10-05 | Alkermes Pharma Ireland Limited | Reduction of flake-like aggregation in nanoparticulate meloxicam compositions |
| AU2010259971C1 (en) | 2009-06-12 | 2017-02-16 | Sunovion Pharmaceuticals Inc. | Sublingual apomorphine |
| HUP0900384A2 (en) | 2009-06-19 | 2011-01-28 | Nangenex Nanotechnologiai Zartkoerueen Muekoedoe Reszvenytarsasag | Nanoparticulate olmesartan medoxomil compositions |
| HUP0900376A2 (en) | 2009-06-19 | 2011-01-28 | Nangenex Nanotechnologiai Zartkoerueen Muekoedoe Reszvenytarsasag | Nanoparticulate candesartan cilexetil composition |
| AU2010261509A1 (en) | 2009-06-19 | 2012-02-09 | Nanoform Hungary Ltd. | Nanoparticulate telmisartan compositions and process for the preparation thereof |
| JP5947717B2 (en) | 2009-06-19 | 2016-07-06 | ナノフォーム ハンガリー リミテッド | Nanostructured sildenafil base, pharmaceutically acceptable salts and co-crystals thereof, compositions thereof, methods of preparation thereof, and pharmaceutical compositions containing them |
| CA2779681A1 (en) | 2009-11-05 | 2011-05-12 | Lexicon Pharmaceuticals, Inc. | Tryptophan hydroxylase inhibitors for the treatment of cancer |
| JP2013519673A (en) | 2010-02-10 | 2013-05-30 | レクシコン ファーマシューティカルズ インコーポレイテッド | Tryptophan hydroxylase inhibitors for the treatment of metastatic bone disease |
| PL2560624T3 (en) | 2010-04-23 | 2019-01-31 | Kempharm, Inc. | Therapeutic formulation for reduced drug side effects |
| US9012511B2 (en) | 2010-05-19 | 2015-04-21 | Alkermes Pharma Ireland Limited | Nanoparticulate cinacalcet compositions |
| HUP1000299A2 (en) | 2010-06-08 | 2012-02-28 | Nanoform Cardiovascular Therapeutics Ltd | Nanostructured atorvastatin, its pharmaceutically acceptable salts and pharmaceutical compositions containing them and process for their preparation |
| HUP1000327A2 (en) | 2010-06-18 | 2012-01-30 | Druggability Technologies Ip Holdco Jersey Ltd | Composition containing nanostructured ezetibime and process for it's preparation |
| HUP1000325A2 (en) | 2010-06-18 | 2012-01-30 | Druggability Technologies Ip Holdco Jersey Ltd | Nanostructured aprepitant compositions and process for their preparation |
| EP2618816A4 (en) | 2010-09-22 | 2014-10-29 | Map Pharmaceuticals Ltd | Aerosol composition for administering drugs |
| DE102010052656A1 (en) * | 2010-11-26 | 2012-05-31 | Netzsch-Feinmahltechnik Gmbh | Hydraulic grinding ball supply and removal for agitator ball mills |
| BR112013015204A2 (en) | 2010-12-16 | 2019-10-01 | Arx Llc | pharmaceutical composition in unit dosage form formulated for sublingual administration and use of said composition |
| EP2768481A4 (en) | 2011-10-21 | 2015-07-08 | Subhash Desai | Compositions for reduction of side effects |
| EP2780009A4 (en) | 2011-11-17 | 2015-05-06 | Univ Colorado Regents | Methods and compositions for enhanced drug delivery to the eye and extended delivery formulations |
| NZ629438A (en) * | 2012-02-28 | 2016-10-28 | Iceutica Holdings Inc | Inhalable pharmaceutical compositions |
| WO2013148978A1 (en) | 2012-03-30 | 2013-10-03 | Lexicon Pharmaceuticals, Inc. | Methods and compositions for the treatment of necrotizing enterocolitis |
| US9827191B2 (en) | 2012-05-03 | 2017-11-28 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
| US11596599B2 (en) | 2012-05-03 | 2023-03-07 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
| EP4008355A1 (en) | 2012-05-03 | 2022-06-08 | Kala Pharmaceuticals, Inc. | Pharmaceutical nanoparticles showing improved mucosal transport |
| EP3808339A1 (en) | 2012-05-03 | 2021-04-21 | Kala Pharmaceuticals, Inc. | Pharmaceutical nanoparticles showing improved mucosal transport |
| US9353122B2 (en) | 2013-02-15 | 2016-05-31 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
| MX368903B (en) | 2013-02-20 | 2019-10-21 | Kala Pharmaceuticals Inc | THERAPEUTIC COMPOUNDS and USES THEREOF. |
| US9688688B2 (en) | 2013-02-20 | 2017-06-27 | Kala Pharmaceuticals, Inc. | Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof |
| BR112015020572B1 (en) * | 2013-02-28 | 2022-02-22 | Sun Chemical Corporation | Continuous process to transform ground solid into liquid dispersion and apparatus |
| KR101741344B1 (en) | 2013-06-28 | 2017-05-29 | 렉산 파마슈티컬스, 인코포레이티드 | Nanoparticulate compositions and formulations of piperazine compounds |
| EP3062618B1 (en) | 2013-11-01 | 2020-02-05 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| US9890173B2 (en) | 2013-11-01 | 2018-02-13 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| WO2015071841A1 (en) | 2013-11-12 | 2015-05-21 | Druggability Technologies Holdings Limited | Complexes of dabigatran and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
| HU231309B1 (en) | 2014-02-25 | 2022-11-28 | Darholding Kft. | Compositions comprising indometacine, its pharmaceutically acceptable salts and cocrystals; and process for the preparation |
| US20150343453A1 (en) * | 2014-05-28 | 2015-12-03 | NanoCentrix L.L.C. | Fluid energy media mill system and method |
| WO2016026822A1 (en) | 2014-08-18 | 2016-02-25 | Alkermes Pharma Ireland Limited | Aripiprazole prodrug compositions |
| US10016415B2 (en) | 2014-08-18 | 2018-07-10 | Alkermes Pharma Ireland Limited | Aripiprazole prodrug compositions |
| US10166197B2 (en) | 2015-02-13 | 2019-01-01 | St. John's University | Sugar ester nanoparticle stabilizers |
| CA3127926A1 (en) | 2015-04-21 | 2016-10-27 | Sunovion Pharmaceuticals Inc. | Methods of treating parkinson's disease by administration of apomorphine to an oral mucosa |
| MX2017013956A (en) | 2015-05-01 | 2018-09-05 | Cocrystal Pharma Inc | Nucleoside analogs for treatment of the flaviviridae family of viruses and cancer. |
| EP3310786B1 (en) | 2015-06-16 | 2021-03-03 | Nanophagix LLC | Drug delivery and imaging chemical conjugate, formulations and methods of use thereof |
| CA3001722A1 (en) | 2015-10-16 | 2017-04-20 | Marinus Pharmaceuticals, Inc. | Injectable neurosteroid formulations containing nanoparticles |
| EP3416616B1 (en) | 2016-02-17 | 2021-08-04 | Alkermes Pharma Ireland Limited | Compositions of multiple aripiprazole prodrugs |
| CN109715151A (en) | 2016-08-11 | 2019-05-03 | 奥维德医疗公司 | For treating the method and composition of epilepsy sexual disorder |
| AU2017324716B2 (en) | 2016-09-08 | 2020-08-13 | KALA BIO, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| AU2017324713B2 (en) | 2016-09-08 | 2020-08-13 | KALA BIO, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| US10336767B2 (en) | 2016-09-08 | 2019-07-02 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| US10391105B2 (en) | 2016-09-09 | 2019-08-27 | Marinus Pharmaceuticals Inc. | Methods of treating certain depressive disorders and delirium tremens |
| CN109641056A (en) | 2016-09-13 | 2019-04-16 | 协和发酵麒麟株式会社 | Pharmaceutical composition |
| WO2020118142A1 (en) | 2018-12-07 | 2020-06-11 | Marinus Pharmaceuticals, Inc. | Ganaxolone for use in prophylaxis and treatment of pospartum depression |
| EP4009982A4 (en) | 2019-08-05 | 2023-08-09 | Marinus Pharmaceuticals, Inc. | Ganaxolone for use in treatment of status epilepticus |
| MX2022006014A (en) | 2019-12-06 | 2022-06-22 | Marinus Pharmaceuticals Inc | Ganaxolone for use in treating tuberous sclerosis complex. |
| EP3928772A1 (en) | 2020-06-26 | 2021-12-29 | Algiax Pharmaceuticals GmbH | Nanoparticulate composition |
| CN112427096B (en) * | 2020-10-19 | 2022-01-28 | 上海旭军机械有限公司 | Grinding equipment for nano materials |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2595117A (en) * | 1950-03-08 | 1952-04-29 | Smidth & Co As F L | Method and apparatus for grinding |
| ES293103A1 (en) * | 1962-11-12 | 1964-03-16 | Aziende Colori Naz Affini Acna S P A | Procedure for the preparation of quinacridone in the form of pigment (Machine-translation by Google Translate, not legally binding) |
| US3713593A (en) * | 1970-08-11 | 1973-01-30 | Freeport Sulphur Co | Fine media milling process |
| SU514627A1 (en) * | 1972-07-19 | 1976-05-25 | Институт Биохимии И Физиологии Микроорганизмов Ан Ссср | Disintegrator for microorganisms |
| US4860957A (en) * | 1988-03-29 | 1989-08-29 | Lidstroem Lars | Treatment of middlings |
| JPH02132162A (en) * | 1988-11-11 | 1990-05-21 | Showa Shell Sekiyu Kk | Dispersion of pigment by very small ball of calcined zirconia |
| US5174512A (en) * | 1988-12-16 | 1992-12-29 | Snamprogetti S.P.A. | Grinding process and a continuous high-capacity micronizing mill for its implementation |
| JPH02196719A (en) * | 1989-01-24 | 1990-08-03 | Green Cross Corp:The | Powdery drug composition |
| DK546289D0 (en) * | 1989-11-02 | 1989-11-02 | Danochemo As | carotenoid |
| JPH04166246A (en) * | 1990-10-31 | 1992-06-12 | Matsushita Electric Ind Co Ltd | Medium agitating mill and grinding method |
| AU642066B2 (en) * | 1991-01-25 | 1993-10-07 | Nanosystems L.L.C. | X-ray contrast compositions useful in medical imaging |
| JPH05253509A (en) * | 1991-05-08 | 1993-10-05 | Fuaimatetsuku:Kk | Flowing type medium agitating ultra-fine crusher |
| JPH05253512A (en) * | 1992-03-11 | 1993-10-05 | Chuo Kakoki Kk | Treatment medium for powder or slurry |
| NZ248813A (en) * | 1992-11-25 | 1995-06-27 | Eastman Kodak Co | Polymeric grinding media used in grinding pharmaceutical substances |
-
1994
- 1994-05-25 US US08/249,787 patent/US5718388A/en not_active Expired - Lifetime
-
1995
- 1995-04-13 TW TW084103642A patent/TW460297B/en not_active IP Right Cessation
- 1995-05-08 ES ES95919062T patent/ES2165913T3/en not_active Expired - Lifetime
- 1995-05-08 WO PCT/US1995/005728 patent/WO1995031973A1/en active IP Right Grant
- 1995-05-08 DE DE69523781T patent/DE69523781T2/en not_active Expired - Lifetime
- 1995-05-08 EP EP95919062A patent/EP0804161B1/en not_active Expired - Lifetime
- 1995-05-08 CA CA002190134A patent/CA2190134C/en not_active Expired - Lifetime
- 1995-05-08 PT PT95919062T patent/PT804161E/en unknown
- 1995-05-08 DK DK95919062T patent/DK0804161T3/en active
- 1995-05-08 AU AU24761/95A patent/AU2476195A/en not_active Abandoned
- 1995-05-08 JP JP53031795A patent/JP3607294B2/en not_active Expired - Lifetime
- 1995-05-08 AT AT95919062T patent/ATE208191T1/en active
- 1995-05-25 IL IL11385195A patent/IL113851A/en not_active IP Right Cessation
- 1995-05-25 MY MYPI95001375A patent/MY113569A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JP3607294B2 (en) | 2005-01-05 |
| TW460297B (en) | 2001-10-21 |
| DE69523781D1 (en) | 2001-12-13 |
| DK0804161T3 (en) | 2002-03-04 |
| ATE208191T1 (en) | 2001-11-15 |
| WO1995031973A1 (en) | 1995-11-30 |
| EP0804161A1 (en) | 1997-11-05 |
| MY113569A (en) | 2002-04-30 |
| DE69523781T2 (en) | 2002-06-13 |
| EP0804161B1 (en) | 2001-11-07 |
| IL113851A (en) | 1999-12-22 |
| US5718388A (en) | 1998-02-17 |
| CA2190134A1 (en) | 1995-11-30 |
| ES2165913T3 (en) | 2002-04-01 |
| JPH10500593A (en) | 1998-01-20 |
| IL113851A0 (en) | 1995-08-31 |
| PT804161E (en) | 2002-04-29 |
| AU2476195A (en) | 1995-12-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2190134C (en) | Continuous method of grinding pharmaceutical substances | |
| EP0760653B1 (en) | Method of grinding pharmaceutical substances | |
| US5518187A (en) | Method of grinding pharmaceutical substances | |
| DE60133270T2 (en) | CRUSHING BY MEANS OF GRINDING BODY | |
| KR100200061B1 (en) | Surface modified drug nanoparticles | |
| US5662279A (en) | Process for milling and media separation | |
| IE83410B1 (en) | Surface modified drug nanoparticles | |
| AU2001259671A1 (en) | Media milling | |
| WO1996025152A1 (en) | Process of preparing therapeutic compositions containing nanoparticles | |
| EP1398083B1 (en) | A method of producing fine solid particles and dispersions thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20150508 |