WO2004060547A1 - Methods and apparatus for making particles using spray dryer and in-line jet mill - Google Patents
Methods and apparatus for making particles using spray dryer and in-line jet mill Download PDFInfo
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- WO2004060547A1 WO2004060547A1 PCT/US2003/037108 US0337108W WO2004060547A1 WO 2004060547 A1 WO2004060547 A1 WO 2004060547A1 US 0337108 W US0337108 W US 0337108W WO 2004060547 A1 WO2004060547 A1 WO 2004060547A1
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- drying chamber
- feedstream
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- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F26—DRYING
- F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
- F26B17/00—Machines or apparatus for drying materials in loose, plastic, or fluidised form, e.g. granules, staple fibres, with progressive movement
- F26B17/10—Machines or apparatus for drying materials in loose, plastic, or fluidised form, e.g. granules, staple fibres, with progressive movement with movement performed by fluid currents, e.g. issuing from a nozzle, e.g. pneumatic, flash, vortex or entrainment dryers
- F26B17/101—Machines or apparatus for drying materials in loose, plastic, or fluidised form, e.g. granules, staple fibres, with progressive movement with movement performed by fluid currents, e.g. issuing from a nozzle, e.g. pneumatic, flash, vortex or entrainment dryers the drying enclosure having the shape of one or a plurality of shafts or ducts, e.g. with substantially straight and vertical axis
- F26B17/102—Machines or apparatus for drying materials in loose, plastic, or fluidised form, e.g. granules, staple fibres, with progressive movement with movement performed by fluid currents, e.g. issuing from a nozzle, e.g. pneumatic, flash, vortex or entrainment dryers the drying enclosure having the shape of one or a plurality of shafts or ducts, e.g. with substantially straight and vertical axis with material recirculation, classifying or disintegrating means
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D1/00—Evaporating
- B01D1/16—Evaporating by spraying
- B01D1/18—Evaporating by spraying to obtain dry solids
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
- B01J2/02—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by dividing the liquid material into drops, e.g. by spraying, and solidifying the drops
- B01J2/04—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by dividing the liquid material into drops, e.g. by spraying, and solidifying the drops in a gaseous medium
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- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F26—DRYING
- F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
- F26B3/00—Drying solid materials or objects by processes involving the application of heat
- F26B3/02—Drying solid materials or objects by processes involving the application of heat by convection, i.e. heat being conveyed from a heat source to the materials or objects to be dried by a gas or vapour, e.g. air
- F26B3/10—Drying solid materials or objects by processes involving the application of heat by convection, i.e. heat being conveyed from a heat source to the materials or objects to be dried by a gas or vapour, e.g. air the gas or vapour carrying the materials or objects to be dried with it
- F26B3/12—Drying solid materials or objects by processes involving the application of heat by convection, i.e. heat being conveyed from a heat source to the materials or objects to be dried by a gas or vapour, e.g. air the gas or vapour carrying the materials or objects to be dried with it in the form of a spray, i.e. sprayed or dispersed emulsions or suspensions
Definitions
- This invention is generally in the field of process equipment and methods for making particles, and more particularly to methods of deagglomerating or grinding spray dried particles.
- Spray drying is commonly used in the production of particles for many applications, including pharmaceuticals, food, cosmetics, fertilizers, dyes, and abrasives. Spray drying can be tailored to create a wide spectrum of particle sizes, including microparticles. Spray dried particles are useful in a variety of biomedical and pharmaceutical applications, such as the delivery of therapeutic and diagnostic agents, as described for example in U.S. Patent No. 5,853,698 to Straub et al.; U.S. Patent No. 5,855,913 to Hanes et al.; and U.S. Patent No. 5,622,657 to Takada et al. For these applications, microparticles having very specific sizes and size ranges often are needed in order to effectively deliver the active agents.
- Particles may tend to agglomerate during their production and processing, thereby undesirably altering the effective size of the particles, to the detriment of the particle formulation's performance and/or reproducibility. hi other circumstances, the particles made may simply be larger than desired for a particular application.
- particles may require additional processing for size reduction and/or deagglomeration.
- step (c) is conducted to deagglomerate at least a portion of agglomerated particles, if any, while substantially maintaining the size and morphology of the individual particles.
- step (c) can be conducted to grind the particles.
- the feedstream of step (b) is directed through a particle concentration means to separate and remove at least a portion of the drying gas from the feedstream.
- the particle concentration means comprises a cyclone separator.
- the cyclone separates between about 50 and 100 vol.% of the drying gas from the particles.
- the feedstream of step (b) is directed, before step (c), through at least one secondary drying chamber in fluid communication with the discharge outlet of the primary drying chamber to ev porate a second portion of the solvent into the drying gas.
- the secondary drying chamber comprises tubing having an inlet in fluid communication with the discharge outlet of the primary drying chamber, wherein the ratio of the cross-sectional area of the primary drying chamber to the cross-sectional area of the tubing is at least 4:3, and wherein the ratio of the length of the tubing to the length of the primary drying chamber is at least 2:1.
- multiple nozzles are used in step (a) to introduce multiple emulsions, solutions, suspensions, or combinations thereof.
- the bulk material comprises a pharmaceutical agent.
- the pharmaceutical agent may be a therapeutic, a prophylactic, or a diagnostic agent.
- the therapeutic or prophylactic agent comprises a hydrophobic drug and the particles are microspheres having voids or pores therein
- the bulk material comprises a diagnostic agent, such as an ultrasound contrast agent or another agent for diagnostic imaging.
- the bulk material further comprises a shell forming material, such as a polymer (e.g., a biocompatible synthetic polymer), a lipid, a sugar, a protein, an amino acid, or a combination thereof.
- the particles are microparticles.
- the microparticles comprise microspheres having voids or pores therein.
- the bulk material comprises a therapeutic or prophylactic agent, i one embodiment, the therapeutic or prophylactic agent comprises a hydrophobic drug and the particles are microspheres having voids or pores therein.
- the bulk material comprises a diagnostic agent, such as an ultrasound contrast agent or other agent for diagnostic imaging.
- the method further comprises adding an excipient material or pharmaceutical agent to the feedstream of step (b).
- an excipient material or pharmaceutical agent for example, this could be done after the feedstream has flowed through a particle concentration means to separate and remove at least a portion of the drying gas from the feedstream. In another example, this could be done before the feedstream has flowed through a particle concentration means to separate and remove at least a portion of the drying gas from the feedstream.
- the excipient or pharmaceutical agent is in the form of a dry powder. Examples of the excipient material include amino acids, proteins, polymers, carbohydrates, starches, surfactants, and combinations thereof.
- a method for making a dry powder blend.
- the method includes the steps of (a) spraying an emulsion, solution, or suspension, which comprises a solvent and a bulk material, through an atomizer and into a primary drying chamber having a drying gas inlet, a discharge outlet, and a drying gas flowing therethrough, to form droplets comprising the solvent and the bulk material, wherein the droplets are dispersed in the drying gas; (b) evaporating, in the primary drying chamber, at least a portion of the solvent into the drying gas to solidify the droplets and form particles dispersed in the drying gas, the particles dispersed in the drying gas being a feedstream; (c) adding a dry powder excipient material to the feedstream to form a blended feedstream; and (d) flowing the particles and excipient material through a jet mill to deagglomerate or grind the particles and excipient material.
- the method includes directing the feedstream of step (b) through a particle concentration means to separate and remove at least a portion of the drying gas from the feedstream.
- the particles are microparticles comprising a pharmaceutical agent and the excipient material is in the form of microparticles having a size that is larger than the size of the microparticles comprising a pharmaceutical agent.
- step (d) is conducted to deagglomerate at least a portion of agglomerated particles, if any, while substantially maintaining the size and morphology of the individual particles.
- a second pharmaceutical agent can be added in step (c), in place of or in addition to the excipient.
- an apparatus for making particles and deagglomerating or grinding them.
- the apparatus comprises: (a) an atomizer disposed for spraying an emulsion, solution, or suspension which comprises a solvent and a bulk material to form droplets of the solvent and the bulk material; (b) a primary drying chamber having a drying gas inlet and a discharge outlet, the atomizer being located in the primary drying chamber which provides for evaporation of at least a portion of the solvent into the drying gas to solidify the droplets and form particles dispersed in the drying gas; and (c) a jet mill having an inlet in fluid communication with the discharge outlet primary drying chamber, the jet mill being operable to receive the particles dispersed in at least a portion of the drying gas and grind or deagglomerate the particles.
- the apparatus further includes at least one secondary drying chamber interposed between, and in fluid communication with, the discharge outlet of the primary drying chamber and the inlet of the jet mill, which provides additional drying of the particles, i.e., provides for evaporation of a second portion of the solvent into the drying gas.
- the secondary drying chamber comprises tubing having an inlet in fluid communication with the discharge outlet of the primary drying chamber, wherein the ratio of the cross-sectional area of the primary drying chamber to the cross-sectional area of the tubing is at least 4:3, and wherein the ratio of the length of the tubing to the length of the primary drying chamber is at least 2:1.
- the apparatus also includes a particle concentration means, such as a cyclone separator, to separate and remove at least a portion of the drying gas from the particles, wherein the particle concentration means has a particle discharge outlet in fluid communication with the inlet of the jet mill.
- a particle concentration means such as a cyclone separator
- the apparatus further comprises a collection cyclone to separate the drying gas from the deagglomerated or ground particles that are discharged from the jet mill.
- the apparatus includes a control valve to control the flow rate of the drying gas discharged from the collection cyclone, a control valve to control the flow rate of the drying gas discharged from the particle concentration means, or both of these control valves.
- the apparatus further comprises a means for introducing an excipient material into the particles and drying gas flowing between the discharge outlet of the primary drying chamber and the inlet of the jet mill. This apparatus can be used, for example, to make a dry powder blend in a single step, i.e., without intermediate collection and blending steps between spray drying and jet milling.
- the apparatus further comprises multiple nozzles to introduce separate emulsions, solutions, suspensions, or combinations thereof into the primary drying chamber.
- the multiple nozzles of this apparatus can be used, for example, to introduce materials that comprise a pharmaceutical agent, an excipient, or combinations thereof.
- the multiple nozzles can be used, for example, to spray the same material in order to increase the throughput or can be used to spray different materials in order to create dry powders that are mixtures of different particles.
- compositions comprise particles or dry powder blends made by the spray drying and inline jet milling methods described herein.
- FIG. 1 is a process flow diagram of one embodiment of a process for making microparticles by spraying drying with in-line jet milling to deagglomerate or grind the microparticles.
- FIG. 2 is a process flow diagram of one embodiment of a process for making blends of microparticles by spray drying with in-line excipient feeding and in-line jet milling.
- FIG. 3 is a cross-sectional view of a typical jet mill that can be incorporated into the in-line process for spray drying and jet milling.
- Process systems and methods have been developed for making particles, such as microparticles, by spray drying and then deagglomerating or grinding the particles using an in-line jet mill.
- By coupling spray drying with "in-line" jet milling a single step process is created from two separate unit operations, and an additional collection step is eliminated, which otherwise would be associated with a yield loss and possible aseptic transfer which would be undesirable for pharmaceutical production.
- the one-step, in- line process has further advantages in time and cost of processing.
- the systems also provide in-line blending of an excipient material with the particles.
- the jet milling step beneficially lowers residual moisture and solvent levels in the particles, leading to better stability and handling properties for dry powder pharmaceutical formulations or other dry powder forms comprising the particles.
- in-line refers to process equipment in fluid communication arranged and adapted to process the materials in a continuous, sequential manner. That is, the particles being processed flow between and through the individual pieces of equipment, without an intervening collection step.
- the particles are microparticles.
- the microparticles comprise one or more pharmaceutical agents, hi one embodiment, the microparticle is formed entirely of a pharmaceutical agent. In another embodiment, the microparticle has a core of pharmaceutical agent encapsulated in a shell. In yet another embodiment, the pharmaceutical agent is interspersed within the shell or matrix. In another embodiment, the pharmaceutical agent is uniformly mixed within the material comprising the shell or matrix.
- the microparticles of any of these embodiments can be blended with one or more excipients.
- the terms “comprise,” “comprising,” “include,” and “including” are intended to be open, non-limiting terms, unless the contrary is expressly indicated. I. In-Line Methods and Apparatus for Making Particles
- the methods include (a) spraying an emulsion, solution, or suspension, which comprises a solvent and a bulk material, through one or more atomizers and into a primary drying chamber having a drying gas inlet, a discharge outlet, and a drying gas flowing therethrough, to form droplets comprising the solvent and the bulk material, wherein the droplets are dispersed in the drying gas; (b) evaporating, in the primary drying chamber, at least a portion of the solvent into the drying gas to solidify the droplets and form particles dispersed in the drying gas, the particles dispersed in the drying gas being a feedstream; and (c) flowing the particles and at least a portion of the drying gas of the feedstream through a jet mill to deagglomerate or grind the particles, hi a preferred embodiment, step (c) is conducted to deagglomerate at least a portion of agglomerated particles, if any, while substantially maintaining the size and morphology of the individual particles.
- step (c) is conducted to grind the particles.
- the feedstream of step (b) is directed through a particle concentration means to separate and remove at least a portion of the drying gas from the feedstream. This provides a concentration of solids in the dispersion entering the jet mill that is high enough to permit the jet mill to operate effectively as intended, i.e., to deagglomerate or grind the particles.
- the apparatus in another preferred embodiment, which can be used with or without the particle concentration means, includes one or more secondary drying chambers interposed between, and in fluid communication with, the discharge outlet of the primary drying chamber and the inlet of the jet mill. These secondary drying chambers provide additional drying of the particles, that is, they provide time and volume for evaporation of a second portion of the solvent into the drying gas.
- the apparatus includes a means for introducing another material into the particles and drying gas flowing between the discharge outlet of the primary drying chamber and the inlet of the jet mill.
- this other material could be an excipient, a second pharmaceutical agent, or a combination thereof.
- a dry powder beta agonist could be introduced into a feed stream from a spray dryer that is producing microparticles containing a corticosteroid.
- This apparatus can be used, for example, to make a dry powder blend in a single step, i.e., without an intermediate collection step between spray drying and jet milling.
- FIG. 1 illustrates one example of an in-line system, or apparatus, 10 for making and jet-milling particles.
- a liquid feed i.e., an emulsion, solution, or suspension, which comprises a solvent and a bulk material
- an atomization gas e.g., air, nitrogen, etc.
- the atomized droplets of solvent and bulk material are formed in the primary drying chamber 12.
- a drying gas is fed through an optional heater 18 and into a primary drying chamber 12. In the primary drying chamber, the droplets are dispersed in the drying gas, and at least a portion of the solvent is evaporated into the drying gas to solidify the droplets and form a feed a feedstream of particles dispersed in the drying gas.
- This feedstream then exits the primary drying chamber 12 through outlet 16 and enters (optional) secondary drying apparatus 20, which includes a coiled tube through which the feedstream flows.
- secondary drying apparatus 20 Upon exiting the secondary drying apparatus 20, the dispersion enters the cyclone separator 22, which serves to concentrate the particles. A portion of the drying gas is separated from the feedstream and exits the top vent 23 of the cyclone separator 22. The concentrated particles/drying gas then exits the cyclone separator 22 and flows into a jet mill 24.
- a grinding gas e.g., dry nitrogen
- the jet mill 24 deagglomerates or grinds the particles, depending, in part, on the operating parameters selected for the jet mill.
- the jet-milled particles dispersed in drying gas (and grinding gas) then flow from the jet mill 24 to a collection cyclone 26.
- the jet- milled particles are collected in collection jar 28 or other suitable apparatus, and the drying and grinding gases are exhausted from the system 10.
- the exhaust gas from the cyclones 22 and 26 typically is filtered (filters not shown) before release from the system and/or into the atmosphere.
- FIG. 2 illustrates one example of an in-line system, or apparatus, 40 for making particle blends.
- particles are made by spray drying, directly blended with an excipient using an in-line excipient feed device, and then the resulting blend is jet-milled using an in-line jet mill, to yield a highly uniform particle blend.
- the process is like that shown in FIG. 1, except an excipient material (or pharmaceutical material or combination thereof) is added to the particles/drying gas, after, or more preferably before, the particles/drying gas flows through cyclone separator 22.
- the resulting mixture of particles, excipient material, and drying gas then flows into jet mill 24, where the mixture is deagglomerated or ground.
- the jet-milled particle/excipient blend dispersed in drying gas then flows from the jet mill 24 to a collection cyclone 26 and collected in collection jar 28.
- the drying gas and grinding gas are exhausted from system 40, as described above.
- the methods and systems are adapted for making pharmaceutical formulations comprising microparticles.
- the microparticles are made by spray drying, and the jet milling is effective to deagglomerate or grind the microparticles.
- the jet- milling step can advantageously reduce moisture content and residual solvent levels in the formulation through the addition of dry and solvent free gas directly to the jet mill (e.g., as grinding gas).
- the jet-milling step also can improve the suspendability and wettability of the dry powder formulation (e.g., for better injectability) and give the dry powder formulation improved aerodynamic properties (e.g., for better pulmonary delivery).
- Spray Drying The particles are formed by a spray drying technique known in the art.
- the particles can be produced using the spray drying methods and devices described, for example, in U.S. Patent No. 5,853,698 to Straub et al., U.S. Patent No. 5,611,344 to Bernstein et al., U.S. Patent No. 6,395,300 to Straub et al., and U.S. Patent No. 6,223,455 to Chickering m, et al.
- the symbol "0" is used to indicate the term
- solvent refers to the liquid in which the material forming the bulk of the spray dried particle is dissolved, suspended, or emulsified for delivery to the atomizer of a spray dryer and which is evaporated into the drying gas, whether or not the liquid is a solvent or nonsolvent for the material.
- Other volatilizable components such as a volatile salt, may be included in the bulk material/liquid, and volatilized into the drying gas.
- microparticles are produced by dissolving a pharmaceutical agent and/or shell material in an appropriate solvent, (and optionally dispersing a solid or liquid active agent, pore forming agent (e.g., a volatile salt), or other additive into the solution containing the pharmaceutical agent and/or shell material) and then spray drying the solution, to form microparticles.
- a solid or liquid active agent e.g., a volatile salt
- pore forming agent e.g., a volatile salt
- the solution containing the pharmaceutical agent and/or shell material may be atomized into a drying chamber, dried within the chamber, and then collected via a cyclone at the outlet of the chamber.
- suitable atomization devices include ultrasonic, pressure feed, air atomizing, and rotating disk.
- the temperature may be varied depending on the solvent or materials used.
- the temperature of the inlet and outlet ports can be controlled to produce the desired products.
- Multiple nozzles (or other atomization devices) can be used to allow for introduction of multiple emulsions, solutions, suspensions, or combinations thereof into the primary drying chamber.
- the multiple nozzles can be used, for example, to introduce materials that comprise a pharmaceutical agent, an excipient, or combinations thereof.
- the multiple nozzles are used to spray the same material (from each nozzle) in order increase process throughput of the material, h another embodiment, the multiple nozzles are used to spray different materials (e.g., different materials from each nozzle), for example, in order to create dry powders that are mixtures of different particles, e.g., composed of different materials.
- the size of the particulates of pharmaceutical agent and/or shell material is a function of the nozzle used to spray the solution of the pharmaceutical agent and/or shell material, nozzle pressure, the solution and atomization flow rates, the pharmaceutical agent and/or shell material used, the concentration of the pharmaceutical agent and/or shell material, the type of solvent, the temperature of spraying (both inlet and outlet temperature), and the molecular weight of a shell material such as a polymer or other matrix material.
- a polymer the higher the molecular weight, the larger the particle size, assuming the concentration is the same (because an increase in molecular weight generally increases the solution viscosity).
- Particles having a target diameter between 0.5 ⁇ m and 500 ⁇ m can be obtained.
- the morphology of these microparticles depends, for example, on the selection of shell material, concentration, molecular weight of a shell material such as a polymer or other matrix material, spray flow, and drying conditions.
- the apparatus further includes one or more secondary drying chambers downstream from the primary drying chamber to provide additional solvent removal.
- the secondary drying chamber comprises the drying apparatus described in U.S. Patent No. 6,308,434 and U.S. Patent No. 6,223,455.
- the secondary drying chamber preferably comprises tubing having an inlet in fluid communication with the discharge outlet of the primary drying chamber, to evaporate a second portion of the solvent into the drying gas, wherein the ratio of the cross-sectional area of the primary drying chamber to the cross-sectional area of the tubing is at least 4:3, and wherein the ratio of the length of the tubing to the length of the primary drying chamber is at least 2:1.
- the particle concentration means can be essentially any device suitable for concentrating the particles in the drying gas such that the particles can be effectively jet milled, whether for grinding or deagglomeration.
- Representative devices for concentrating the particles in the drying gas include cyclone separators, gravity settling chambers (knock-out pots), electrostatic charge precipitators, impingement separators, mechanical centrifugal separators and uniflow cyclones.
- the particle concentration means includes at least one cyclone separator as known in the art, to separate and remove at least a portion of the drying gas from said particles.
- the cyclone separator consists of a vertical cylinder with a conical bottom. The particle/drying gas dispersion enters the cyclone through a tangential inlet near the top, entering in a vortical motion. The centrifugal force created causes the particles to be thrown toward the wall, and the (hying gas falls downward along the wall and then spirals upward through the center when it reaches the bottom, producing a double vortex. The particles fall by gravity to the bottom of the device.
- One skilled in the art can select the appropriate dimensions of the separator based, for example, on the flow rates of gas and particles, percentage of gas to be separated, system pressures, particle mass and size, etc.
- control of the flow through the system 10 or system 40 can be performed with the use of a control valve 30 downstream from the collection cyclone 26 and/or a control valve 32 downstream from the separator cyclone 22, either or both of which can be used to control the pressure on the systems.
- a control valve 30 downstream from the collection cyclone 26 and/or a control valve 32 downstream from the separator cyclone 22 either or both of which can be used to control the pressure on the systems.
- more drying gas can be separated and expelled through the top vent of the cyclone separator.
- less drying gas can be directed through the top vent of the cyclone separator by lowering the backpressure on the system.
- the drying gas exhausted through the cyclone separator can be in part or entirely redirected into the system downstream of the jet mill outlet.
- fresh gas can be added into the system downstream of the jet mill outlet. Such redirected or added gases can be used to balance pressures in the process.
- control valve While a control valve is shown in FIGS. 1 and 2, other flow controlling devices known in the art can be used to control the system pressure and/or flow rate of drying gas discharged from the particle concentration means or the collection cyclone.
- the flow controlling devices could comprise a device selected from control valves, filters, regulators, orifices, and combinations thereof.
- the solids content of the feedstream (particles/drying gas) from the primary and secondary drying chambers is increased by separating out between about 50 and 100 vol.%, more preferably about 90 and 100 vol.%, of the drying gas, which is expelled through top vent 23.
- the flow rate of the particles/drying gas from the spray dryer is 52 CFM (1500 L/min.) and the flow rate of the particles/drying gas to the jet mill is 0.52 CFM (15 L/min.).
- the system components would be sized to maintain the appropriate gas velocity throughout the process.
- jet mill and “jet milling” include and refer to the use of any type of fluid energy impact mills, including spiral jet mills, loop jet mills, hammer mills, grinders, crushers, and fluidized bed jet mills, with or without internal air classifiers. These mills are known in the art.
- the jet mill is used to deagglomerate or to grind the particles.
- the term "deagglomerate” refers to the technique for substantially deagglomerating microparticle agglomerates that have been produced during or subsequent to formation of the microparticles, by bombarding the feed particles with high velocity air or other gas, typically in a spiral or circular flow.
- the jet milling process conditions can be selected so that the microparticles are substantially deagglomerated while substantially maintaining the size and morphology of the individual microparticles, which can be quantified as providing a volume average size reduction of at least 15% and a number average size reduction of no more than 75%.
- grind refers to particle size reduction by fracture, e.g., conventional milling. That is, the particles and/or agglomerates are reduced in size without substantially maintaining the size and morphology of the individual microparticles.
- the process is characterized by the acceleration of particles in a gas stream to high velocities for impingement on other particles, similarly accelerated, or impingement on the walls of the mill.
- a typical spiral jet mill 50 is illustrated in FIG. 3.
- Particles, with or without drying gas, are fed into feed chute 52.
- Optional injection gas is fed through one or more ports 56.
- the particles are forced through injector 54 into chamber 58.
- the particles enter an extremely rapid vortex in the chamber 58, where they collide with one another until small enough to become sufficiently entrained in the gas stream to exit a central discharge port 62 in the jet mill by the gas stream (against centrifugal forces experienced in the vortex).
- Grinding gas (so-named whether the jet mill is used for grinding or deagglomeration) is fed from port 60 into gas supply ring 61.
- the grinding gas then is fed into the chamber 58 via a plurality of apertures; only two 63a and 63b are shown.
- Ground or deagglomerated particles are discharged from the jet mill 50.
- the selection of the material forming the bulk of the particles and the temperature of the particles in the jet mill are among the factors that affect deagglomeration and grinding. Therefore, the jet mill optionally can be provided with a temperature control system.
- the control system may heat the particles, rendering the material less brittle and thus less easily fractured in the jet mill, thereby minimizing unwanted size reduction.
- the control system may need to cool the particles to below the glass transition or melting temperature of the material, so that deagglomeration is possible.
- the particles are aseptically fed to the jet mill, and a suitable gas, preferably dry nitrogen, is used to process the microparticles through the mill.
- a suitable gas preferably dry nitrogen
- Grinding and injection gas pressures can be adjusted as need, for example, based on the material characteristics.
- these gas pressures are between 0 and 10 bar, more preferably between 2 and 8 bar.
- Particle throughput depends on the size and capacity of the jet mill.
- the jet-milled particles can be collected by filtration or, more preferably, cyclone.
- Jet milling the particles in addition to providing the desired level of deagglomeration or grinding, can also lower the residual solvent and moisture levels in the particles or particle blend while in process (i.e., before collection), due to the addition of dry and solvent free gas (e.g., as grinding gas, injection gas, or both) provided to the jet mill.
- the injection/grinding gas preferably is a low humidity gas, such as dry nitrogen.
- the injection/grinding gas is at a temperature less than 100 °C (e.g., less than 75 °C, less than 50°C, less than 25 °C, etc.).
- the process further includes blending the particles with another material (e.g., an excipient material, a (second) pharmaceutical agent, or a combination thereof), which can be in a dry powder form.
- another material e.g., an excipient material, a (second) pharmaceutical agent, or a combination thereof
- the blending can be performed before jet milling as an in-line process, after jet milling, or both before and after jet milling.
- the blending is conducted in a single step process, such as an in-line process, as shown for example in FIG. 2. This process comprises spray drying with in-line blending and in-line jet milling.
- the excipient material preferably is added to the feedstream before it flows into the jet mill.
- the excipient material can be introduced into the feedstream using essentially any suitable introduction means known in the art.
- Non-limiting examples of such introduction means include screw or vibratory feed from a closed hopper, a venturi feed from a vented hopper, via a feedstream from one or more other spray drying units making the excipient particles, or via a feedstream from one or more jet milling devices.
- introduction means include screw or vibratory feed from a closed hopper, a venturi feed from a vented hopper, via a feedstream from one or more other spray drying units making the excipient particles, or via a feedstream from one or more jet milling devices.
- One skilled in the art can readily connect a feed source line using standard techniques and provide the excipient feed material at a sufficient pressure to cause the material to flow into and combine with the drying gas and particles.
- the excipient material is blended with the particles post- jet milling, in a batch or continuous process, including an in-line process.
- the blending can be carried out using essentially any technique or device suitable for combining the microparticles with one or more other materials (e.g., excipients), preferably to achieve uniformity of blend.
- Jet milling can be conducted on the microparticles before blending or as part of a single process (spray drying with in-line blending and in-line jet milling) to enhance content uniformity. Jet-milling advantageously can provide improved wetting and dispersibility upon reconstitution of the blends, hi addition, the resulting microparticle formulation can provide improved injectability, passing through the needle of a syringe more easily. Jet milling can provide improved dispersibility of the dry powder, which provides for improved aerodynamic properties for nasal or pulmonary administration. Other Steps in the Process
- the particles may undergo additional processing steps. Representative examples of such processes include lyophilization or vacuum drying to further remove residual solvents, temperature conditioning to anneal materials, size classification to recover or remove certain fractions of the particles (i.e., to optimize the size distribution), compression molding to form a tablet or other geometry, and packaging.
- oversized e.g., 20 ⁇ m or larger, preferably 10 ⁇ m or larger
- microparticles are separated from the microparticles of interest.
- Some formulations also may undergo sterilization, such as by gamma irradiation. II.
- the particles made by the processes described herein comprise a bulk material.
- the term "bulk material” includes essentially any material that can be provided in a solution, suspension, or emulsion, and then fed through an atomizer and dried to form particles.
- the bulk material is a pharmaceutical agent, a shell material, or a combination of a pharmaceutical agent and a shell material, as described herein.
- the particles made by the in-line spray drying and jet mill process can be of any size.
- the term "particle” includes micro-, submicro-, and macro- particles. Generally, the particles are between about 100 nm and 5 mm in diameter or in the longest dimension. In a preferred embodiment, the particles are microparticles, which are between 1 and 999 microns in diameter or in the longest dimension.
- the term "microparticle” includes microspheres and microcapsules, as well as microparticles, unless otherwise specified. Microparticles may or may not be spherical in shape. Microcapsules are defined as microparticles having an outer shell surrounding a core of another material, such as a pharmaceutical agent. The core can be gas, liquid, gel, or solid. Microspheres can be solid spheres or can be porous and include a sponge-like or honeycomb structure formed by pores or voids in a matrix material or shell.
- size or “diameter” in reference to particles refers to the number average particle size, unless otherwise specified.
- An example of an equation that can be used to describe the number average particle size is shown below: p
- n number of particles of a given diameter (d).
- volume average diameter refers to the volume weighted diameter average.
- equations that can be used to describe the volume average diameter is shown below:
- n number of particles of a given diameter (d).
- Aerodynamic diameter refers to the equivalent diameter of a sphere with density of 1 g/mL were it to fall under gravity with the same velocity as the particle analyzed. Aerodynamic diameters can be determined on the dry powder using an Aerosizer (TSI), which is a time of flight technique, or by cascade impaction or liquid impinger techniques.
- TSI Aerosizer
- Particle size analysis can be performed on a Coulter counter, by light microscopy, scanning electron microscopy, transmittance electron microscopy, laser diffraction methods such as those using a Malvern Mastersizer, light scattering methods or time of flight methods.
- a Coulter method is described, the powder is dispersed in an electrolyte, and the resulting suspension analyzed using a Coulter Multisizer II fitted with a 50- ⁇ m aperture tube.
- the jet milling process described herein can deagglomerate agglomerated particles, such that the size and morphology of the individual particles is substantially maintained. That is, a comparison of the particle size before and after jet milling should show a volume average size reduction of at least 15% and a number average size reduction of no more than 75%. It is believed that the jet milling processes will be most useful in deagglomerating particles having a volume average diameter or aerodynamic average diameter greater than about 2 ⁇ m.
- the particles are microparticles comprising a pharmaceutical agent for use in a pharmaceutical formulation. These microparticles preferably have a number average size between about 1 and 10 ⁇ m. In one embodiment, the microparticles have a volume average size between 2 and 50 ⁇ m. In another embodiment, the microparticles have an aerodynamic diameter between 1 and 50 ⁇ m.
- the pharmaceutical agent containing particles typically are manufactured to have a size (i.e., diameter) suitable for the intended route of administration. Particle size also can affect RES uptake.
- the particles preferably have a diameter of between 0.5 and 8 ⁇ m.
- the particles preferably have a diameter of between about 1 and 100 ⁇ m.
- the particles For oral administration for delivery to the gastrointestinal tract and for application to other lumens or mucosal surfaces (e.g., rectal, vaginal, buccal, or nasal), the particles preferably have a diameter of between 0.5 ⁇ m and 5 mm.
- a prefened size for administration to the pulmonary system is an aerodynamic diameter of between 1 and 5 ⁇ m, with an actual volume average diameter (or an aerodynamic average diameter) of 5 ⁇ m or less.
- the particles comprise microparticles having voids therein.
- the microparticles have a number average size between 1 and 3 ⁇ m and a volume average size between 3 and 8 ⁇ m.
- the pharmaceutical agent is a therapeutic, diagnostic, or prophylactic agent.
- the pharmaceutical agent is sometimes referred to herein generally as a "drug” or "active agent.”
- the pharmaceutical agent in the final powder may be present in an amorphous state, a crystalline state, or a mixture thereof.
- drugs can be loaded into the microparticles. These can be small molecules, proteins or peptides, carbohydrates, oligosaccharides, nucleic acid molecules, or other synthetic or natural agents. Examples of suitable drugs include the classes and species of drugs described in Martindale, The Extra Pharmacopoeia, 30th Ed. (The Pharmaceutical Press, London 1993). The drug can be in any suitable form, including various salt forms, free acid forms, free base forms, and hydrates.
- the pharmaceutical agent is a contrast agent for diagnostic imaging.
- the agent could be a gas for ultrasound imaging, as described for example in U.S. PatentNo. 5,611,344 to Bernstein et al.
- suitable diagnostic agents useful herein include those agents known in the art for use in positron emission tomography (PET), computer assisted tomography (CAT), single photon emission computerized tomography, x-ray, fluoroscopy, and magnetic resonance imaging (MRI).
- PET positron emission tomography
- CAT computer assisted tomography
- single photon emission computerized tomography single photon emission computerized tomography
- x-ray x-ray
- fluoroscopy fluoroscopy
- MRI magnetic resonance imaging
- the pharmaceutical agent is a therapeutic or prophylactic agent.
- Non-limiting examples of these agents include water soluble drugs, such as ceftriaxone, ketoconazole, ceftazidime, oxaprozin, albuterol, valacyclovir, urofollitropin, famciclovir, flutamide, enalapril, mefformin, itraconazole, buspirone, gabapentin, fosinopril, tramadol, acarbose, lorazepan, follitropin, glipizide, omeprazole, fluoxetine, lisinopril, tramsdol, levofloxacin, zafirlukast, interferon, growth hormone, interleukin, erythropoietin, granulocyte stimulating factor, nizatidine, bupropion, perindopril, erbumine, adenosine, alendronate, alprostadil, benazepril, betax
- hydrophobic drugs such as celecoxib, rofecoxib, paclitaxel, docetaxel, acyclovir, alprazolam, amiodaron, amoxicillin, anagrelide, aripiprazole, bactrim, biaxin, budesonide, bulsulfan, carbamazepine, ceftazidime, cefprozil, ciprofloxicin, clarithromycin, clozapine, cyclosporine, diazepam, estradiol, etodolac, famciclovir, fenofibrate, fexofenadine, gemcitabine, ganciclovir, itraconazole, lamotrigine, loratidine, lorazepam, meloxicam, mesalamine, minocycline, modafinil, nabumetone, nelfinavir mesylate, olanzapin
- the pharmaceutical agent is for pulmonary administration.
- Non-limiting examples include corticosteroids such as budesonide, fluticasone propionate, beclomethasone dipropionate, mometasone, flunisolide, and triamcinolone acetonide; other steroids such as testosterone, progesterone, and estradiol; leukotriene inhibitors such as zafirlukast and zileuton; antibiotics such as cefprozil, amoxicillin; antifungals such as ciprofloxacin, and itraconazole; bronchodilators such as albuterol, formoterol and salmeterol; antineoplastics such as paclitaxel and docetaxel; and peptides or proteins such as insulin, calcitonin, leuprolide, granulocyte colony- stimulating factor, parathyroid hormone-related peptide, and somatostatin.
- corticosteroids such as budesonide, fluticas
- Examples of preferred drugs include aripirazole, risperidone, albuterol, adapalene, doxazosin mesylate, mometasone furoate, ursodiol, amphotericin, enalapril maleate, felodipine, nefazodone hydrochloride, valrubicin, albendazole, conjugated estrogens, medroxyprogesterone acetate, nicardipine hydrochloride, zolpidem tartrate, amlodipine besylate, ethinyl estradiol, omeprazole, rubitecan, amlodipine besylate/ benazepril hydrochloride, etodolac, paroxetine hydrochloride, paclitaxel, atovaquone, felodipine, podofilox, paricalcitol, betamethasone dipropionate, fentanyl, pramipexole
- the shell material can be a synthetic material or a natural material.
- the shell material can be water soluble or water insoluble.
- the particles can be formed of non- biodegradable or biodegradable materials, although biodegradable materials are prefened, particularly for parenteral administration.
- types of shell materials include polymers, amino acids, sugars, proteins, carbohydrates, and lipids.
- Polymeric shell materials can be degradable or non-degradable, erodible or non- erodible, natural or synthetic. Non-erodible polymers may be used for oral administration. In general, synthetic polymers are preferred due to more reproducible synthesis and degradation. Natural polymers also may be used. Natural biopolymers that degrade by hydrolysis, such as polyhydroxybutyrate, may be of particular interest.
- the polymer is selected based on a variety of performance factors, including the time required for in vivo stability, i.e., the time required for distribution to the site where delivery is desired, and the time desired for delivery. Other selection factors may include shelf life, degradation rate, mechanical properties, and glass transition temperature of the polymer.
- Representative synthetic polymers include poly(hydroxy acids) such as poly(lactic acid), poly(glycolic acid), and poly(lactic acid-co-glycolic acid), poly(lactide), poly(glycolide), poly(lactide-co-glycolide), polyanhydrides, polyorthoesters, polyamides, polycarbonates, polyalkylenes such as polyethylene and polypropylene, polyalkylene glycols such as poly(ethylene glycol), polyalkylene oxides such as poly(ethylene oxide), polyalkylene terepthalates such as poly(ethylene terephthalate), polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides such as poly(vinyl chloride), polyvinylpyrrolidone, polysiloxanes, poly(vinyl alcohols), poly(vinyl acetate), polystyrene, polyurethanes and co-polymers thereof, derivativized celluloses such as alkyl
- biodegradable polymers include polymers of hydroxy acids such as lactic acid and glycolic acid, and copolymers with PEG, polyanhydrides, poly(ortho)esters, polyurethanes, poly(butyric acid), poly(valeric acid), poly(lactide-co- caprolactone), blends and copolymers thereof.
- preferred natural polymers include proteins such as albumin and prolamines, for example, zein, and polysaccharides such as alginate, cellulose and polyhydroxyalkanoates, for example, polyhydroxybutyrate.
- the in vivo stability of the matrix can be adjusted during the production by using polymers such as polylactide-co- glycolide copolymerized with polyethylene glycol (PEG).
- PEG if exposed on the external surface, may extend the time these materials circulate, as it is hydrophilic and has been demonstrated to mask RES (reticuloendothelial system) recognition.
- non-biodegradable polymers examples include ethylene vinyl acetate, poly(meth)acrylic acid, polyamides, copolymers and mixtures thereof.
- Bioadhesive polymers of particular interest for use in targeting of mucosal surfaces include polyanhydrides, polyacrylic acid, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).
- amino acids that can be used in the shell include both naturally occurring and non-naturally occurring amino acids.
- the amino acids can be hydrophobic or hydrophilic and may be D amino acids, L amino acids or racemic mixtures.
- Amino acids that can be used include glycine, arginine, histidine, threonine, asparagine, aspartic acid, serine, glutamate, proline, cysteine, methionine, valine, leucine, isoleucine, tryptophan, phenylalanine, tyrosine, lysine, alanine, and glutamine.
- the amino acid can be used as a bulking agent, or as an anti-crystallization agent for drugs in the amorphous state, or as a crystal growth inhibitor for drugs in the crystalline state or as a wetting agent.
- Hydrophobic amino acids such as leucine, isoleucine, alanine, glucine, valine, proline, cysteine, methionine, phenylalanine, tryptophan are more likely to be effective as anticrystallization agents or crystal growth inhibitors.
- amino acids can serve to make the shell have a pH dependency that can be used to influence the pharmaceutical properties of the shell such as solubility, rate of dissolution or wetting.
- the shell material can be the same or different from the excipient material, if present.
- the excipient can comprise the same classes or types of material used to form the shell.
- the excipient comprises one or more materials different from the shell material, hi this latter embodiment, the excipient can be a surfactant, wetting agent, salt, bulking agent, etc.
- the formulation comprises (i) microparticles that have a core of a drug and a shell comprising a sugar or amino acid, blended with (ii) another sugar or amino acid that functions as a bulking or tonicity agent.
- excipient refers to any non-active ingredient of the formulation intended to facilitate delivery and administration by the intended route.
- the excipient can comprise amino acids, sugars or other carbohydrates, starches, surfactants, proteins, lipids, or combinations thereof.
- the excipient may enhance handling, stability, aerodynamic properties and dispersibility of the active agent.
- the excipient is a dry powder (e.g., in the form of microparticles), which is blended with drag microparticles.
- the excipient microparticles are larger in size than the pharmaceutical microparticles.
- the excipient microparticles have a volume average size between about 10 and 1000 ⁇ m, preferably between 20 and 200 ⁇ m, more preferably between 40 and 100 ⁇ m.
- amino acids that can be used in the drug matrices include both naturally occurring and non-naturally occurring amino acids.
- the amino acids can be hydrophobic or hydrophilic and may be D amino acids, L amino acids or racemic mixtures.
- Non-limiting examples of amino acids that can be used include glycine, arginine, histidine, threonine, asparagine, aspartic acid, serine, glutamate, proline, cysteine, methionine, valine, leucine, isoleucine, tryptophan, phenylalanine, tyrosine, lysine, alanine, glutamine.
- the amino acid can be used as a bulking agent, or as a crystal growth inhibitor for drugs in the crystalline state or as a wetting agent.
- Hydrophobic amino acids such as leucine, isoleucine, alanine, glucine, valine, proline, cysteine, methionine, phenylalanine, tryptophan are more likely to be effective as crystal growth inhibitors.
- amino acids can serve to make the matrix have a pH dependency that can be used to influence the pharmaceutical properties of the matrix such as solubility, rate of dissolution, or wetting.
- excipients include pharmaceutically acceptable carriers and bulking agents, including sugars such as lactose, mannitol, trehalose, xylitol, sorbitol, dextran, sucrose, and fructose.
- suitable excipients include surface active agents, dispersants, osmotic agents, binders, disintegrants, glidants, diluents, color agents, flavoring agents, sweeteners, and lubricants.
- Examples include sodium desoxycholate; sodium dodecylsulfate; polyoxyethylene sorbitan fatty acid esters, e.g., polyoxyethylene 20 sorbitan monolaurate (TWEENTM 20), polyoxyethylene 4 sorbitan monolaurate (TWEENTM 21), polyoxyethylene 20 sorbitan monopalmitate (TWEENTM 40), polyoxyethylene 20 sorbitan monooleate (TWEENTM 80); polyoxyethylene alkyl ethers, e.g., polyoxyethylene 4 lauryl ether (BRIJTM 30), polyoxyethylene 23 lauryl ether (BPJJTM 35), polyoxyethylene 10 oleyl ether (BRIJTM 97); and polyoxyethylene glycol esters, e.g., poloxyethylene 8 stearate (MYRJTM 45), poloxyethylene 40 stearate (MYRJTM 52), Spans, Tyloxapol or mixtures thereof.
- binders include starch, gelatin, sugars, gums, polyethylene glycol, ethylcellulose, waxes and polyvinylpyrrolidone.
- disintegrants include starch, clay, celluloses, croscarmelose, crospovidone and sodium starch glycolate.
- glidants include colloidal silicon dioxide and talc.
- diluents include dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered sugar.
- lubricants include talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, and polyethylene glycol.
- the amounts of excipient for a particular formulation depend on a variety of factors and can be selected by one skilled in the art. Examples of these factors include the choice of excipient, the type and amount of drug, the microparticle size and morphology, and the desired properties and route of administration of the final formulation.
- TWEENTM 80 is blended with polymeric microspheres.
- the mannitol is provided at between 50 and 200 % w/w, preferably 90 and 130 % w/w, microparticles, while the TWEENTM 80 is provided at between 0.1 and 10 % w/w, preferably 2.0 and 5.1 % w/w microparticles.
- the mannitol is provided with a volume average particle size between 10 and 500 ⁇ m.
- the excipient comprises lactose for an inhaled dosage form.
- the excipient comprises binders, disintegrants, glidants, diluents, color agents, flavoring agents, sweeteners, and lubricants for a solid oral dosage form such as a capsule, a tablet, or a wafer.
- the term "excipient” refers to essentially any material that can be blended with the particles for any purpose. in. Use of the Particles
- Particles made using the processes described herein can be used in a wide variety of applications and industries, including abrasives, agricultural products, biochemical products, chemicals, cosmetics, dyes, foods, metals, pigments, and pharmaceuticals.
- the particles preferably are microparticles.
- the particles are microparticles for use in a pharmaceutical formulation, which can be administered to a human or animal in need thereof, for the delivery of a therapeutic, diagnostic, or prophylactic agent in an effective amount.
- the formulations can be administered in dry form or dispersed in a physiological solution for injection or oral administration.
- the dry form can be aerosolized and inhaled for pulmonary administration. The route of administration depends on the pharmaceutical agent being delivered.
- microparticles or blends of microparticles/excipient are jet milled to deagglomerate the particles and then further processed, using known techniques, into a solid oral dosage form.
- solid oral dosage forms include powder-filled capsules, tablets, and wafers.
- the jet-milling advantageously can provide improved wetting and dispersibility upon oral dosing as a solid oral dosage form formed from these microparticles or microparticle/excipient blends.
- Example 1 Spray Drying of PLGA Microspheres
- This example describes a process for making PLGA microspheres.
- the microspheres were made in a batch spray drying process.
- a polymer emulsion was prepared, composed of droplets of an aqueous phase suspended in a continuous polymer/organic solvent phase.
- the polymer was a commercially obtained poly(lactide-co-glycolide) (PLGA) (50:50).
- the organic solvent was methylene chloride.
- the resulting emulsion was spray dried on a custom spray dryer with a dual drying chamber set-up.
- the process conditions resulted in a theoretical solids to drying gas mass flow ratio of 4.77 g solids/min. : 1.6 kg nitrogen/min.
- the outlet temperature of the primary drying chamber was maintained at 12 °C.
- the discharge of the primary drying chamber was connected to a custom secondary drying chamber comprising 100 feet of 1.5" 0 coiled tubing, enveloped by a water-cooled jacket.
- the discharge of the secondary drying chamber was connected to a cyclone collector having a 1" 0 inlet, a 1" 0 exhaust outlet, and a 1.5" 0 dust outlet.
- Three replicate batches were generated. Particle size was measured using a Coulter Multisizer U with a 50 ⁇ m aperture. Table 1 presents the average size results for the three batches.
- Example 2 PLGA Microparticles Formed Using an In-Line Spray Drying / Jet Milling Process
- PLGA microspheres were produced using a batch spray drying process with an in-line jet mill.
- a polymer emulsion was prepared, composed of droplets of an aqueous phase suspended in a continuous polymer/organic solvent phase.
- the polymer was a commercially obtained poly(lactide-co-glycolide) (PLGA) (50:50).
- the organic solvent was methylene chloride.
- the resulting emulsion was spray dried on a custom spray dryer with a dual drying chamber set-up. The process conditions resulted in a theoretical solids to drying gas mass flow ratio of 4.77 g solids/min : 1.6 kg nitrogen/min.
- the outlet temperature of the primary drying chamber was maintained at 12 °C.
- the discharge of the primary drying chamber was connected to a secondary drying chamber comprising 100 feet of 1.5" 0 coiled tubing, enveloped by a water- cooled jacket.
- the discharge of the secondary drying chamber was connected to a concentrating cyclone having a 1" 0 inlet, a 1" 0 exhaust outlet, and a 1.5" 0 dust outlet.
- a 0.2 ⁇ m filter was attached to each of the concentrating cyclone exhausts.
- a jet mill Hosokawa 50AS
- a cyclone collector having a 3/8" 0 inlet, a 3/4" 0 exhaust outlet, and a 3/4" 0 dust outlet, was connected to the discharge of the jet mill to collect the microspheres.
- a 0.2 ⁇ m filter was attached to the jet mill cyclone exhaust. This experiment was conducted in triplicate. An average product yield of 56.5 ⁇ 4.2% was obtained. Particle size was measured using the same method as in Example 1, and the average results for the three batches are shown in Table 2.
- Table 3 provides a comparison of the average size results of the unmilled and in-line milled microspheres from Examples 1 and 2.
- Celecoxib (CXB) microspheres were produced using a batch spray drying process.
- a solution containing CXB in 800 mL of methanol-water (65:35) was spray dried on a custom spray dryer with a single drying chamber.
- the process conditions resulted in a theoretical solids to drying gas mass flow ratio of 0.24 g solids/min : 1.7 kg nitrogen/min.
- the outlet temperature of the drying chamber was set at 20 °C.
- the discharge of the drying chamber was connected to a cyclone collector having a 1" 0 inlet, a 1" 0 exhaust outlet, and a 1.5" 0 dust outlet.
- the powder from Experiment No. 3.1 was fed manually into a Fluid Energy Aljet Jet-O-Mizer jet mill at a feed rate of about 1 g/min. Dry nitrogen gas was used to drive the jet mill.
- the operating parameters were 4 bar grinding gas pressure and 8 bar injection gas pressure.
- the data shows that jet milling reduced the particle size of the CXB powder.
- the final yield of the batch process can be calculated by multiplying the yield for experiment 3.1 times the yield from experiment 3.2. This calculates to a final process yield of 52% for the batch milled product.
- CXB microspheres were produced using a spray drying process with an in-line jet mill.
- a solution containing CXB in 800 mL of methanol-water (65:35) was spray dried on a custom spray dryer with a single drying chamber.
- the process conditions resulted in a theoretical solids to drying gas mass flow ratio of 0.24 g solids/min. : 1.7 kg nitrogen/min.
- the outlet temperature of the drying chamber was set at 20 °C.
- the discharge of the drying chamber was connected to a concentrating cyclone having a 1" 0 inlet, a 1" 0 exhaust outlet, and a 1.5" 0 dust outlet.
- a jet mill Fluid Energy Aljet Jet-O-Mizer
- Table 7 provides a comparison of the average size and yield results of the unmilled, batch milled, and in-line milled CXB microspheres from Examples 3 and 4.
- In-line jet milling was as effective as batch jet milling in reducing particle size.
- Example 5 Batch Processing of Paclitaxel Microspheres (Comparative Example) Paclitaxel (PXL) microspheres were produced using a batch spray drying process. A solution containing PXL in 800 mL of ethanol-water (80:20) was spray dried on a custom spray dryer with a single drying chamber. The process conditions resulted in a theoretical solids to drying gas mass flow ratio of 0.83 g solids/min : 2.0 kg nitrogen/min. The outlet temperature of the drying chamber was set at 57 °C. The discharge of the drying chamber was connected to a cyclone collector having a 1" 0 inlet, a 1" 0 exhaust outlet, and a 1.5" 0 dust outlet.
- the powder from Experiment No. 5.1 was fed manually into a Fluid Energy Aljet Jet-O-Mizer jet mill at a feed rate of about 1 g/min. Dry nitrogen gas was used to drive the jet mill.
- the operating parameters were 4 bar grinding gas pressure and 8 bar injection gas pressure.
- the data shows that, in this case, batch jet milling did not significantly change the particle size of the PXL powder.
- the final yield of the batch process can be calculated by multiplying the yield for Experiment No. 5.1 times the yield from Experiment No. 5.2. This calculates to a final process yield of 49% for the batch milled product.
- Example 6 Paclitaxel Microspheres Formed Using an In-Line Process
- PXL microspheres were produced using a spray drying process with an in-line jet mill.
- a solution containing PXL in 800 mL of ethanol-water (80:20) was spray dried on a custom spray dryer with a single drying chamber.
- the process conditions resulted in a theoretical solids to drying gas mass flow ratio of 0.83 g solids/min : 2.0 kg nitrogen min.
- the outlet temperature of the drying chamber was set at 57 °C.
- the discharge of the drying chamber was connected to a concentrating cyclone having a 1" 0 inlet, a 1" 0 exhaust outlet, and a 1.5" 0 dust outlet.
- a jet mill Fluid Energy Aljet Jet-O-Mizer
- Dry nitrogen was supplied to the jet mill for grinding and injection gas.
- a cyclone collector having a 3/8" 0 inlet, a 3/4" 0 exhaust outlet, and a 3/4" 0 dust outlet, was connected to the discharge of the jet mill to collect the microspheres for Experiment No. 6.1. Yield and particle size were measured using the same methods as in Example 5. Table 10 presents the results.
- Table 11 provides a comparison of the average size and yield results of the unmilled, batch milled, and in-line milled PXL microspheres from Examples 5 and 6.
- In-line jet milling was more effective than batch jet milling in reducing particle size.
- the in-line process resulted in a higher product yield (66%) than the combination of the batch processes (49%).
- Example 7 PLGA Micro articles Formed, Blended with Mannitol/Tween 80, And Jet Milled Using an In-Line Process
- PLGA microspheres were produced using a single in-line process involving spray drying, blending with mannitol/Tween 80 powder, and jet-milling using the Hosokawa 50AS jet-mill.
- a polymer emulsion was prepared, composed of droplets of an aqueous phase suspended in a continuous polymer/organic solvent phase.
- the polymer was a commercially obtained poly(lactide-co-glycolide) (PLGA) (50:50).
- the organic solvent was methylene chloride.
- the resulting emulsion was spray dried on a custom spray dryer with a dual drying chamber set-up.
- the mannitol/Tween 80 powder was injected at the discharge of the secondary drying chamber (which is upstream from the concentrating cyclone having a 1" 0 inlet, a 1" 0 exhaust outlet, and a 1.5" 0 dust outlet) using a nitrogen feed.
- the dust outlet of the concentrating cyclone was connected to the inlet of the jet-mill.
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
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AU2003295704A AU2003295704B2 (en) | 2002-12-19 | 2003-11-20 | Methods and apparatus for making particles using spray dryer and in-line jet mill |
JP2004565053A JP2006514879A (en) | 2002-12-19 | 2003-11-20 | Method and apparatus for producing particles using a spray dryer and an in-line jet mill |
BR0317595-2A BR0317595A (en) | 2002-12-19 | 2003-11-20 | Method and apparatus for producing particles, method for producing a mixture of dry powder and pharmaceutical composition. |
CA002511376A CA2511376A1 (en) | 2002-12-19 | 2003-11-20 | Methods and apparatus for making particles using spray dryer and in-line jet mill |
EP03786905A EP1575696A1 (en) | 2002-12-19 | 2003-11-20 | Methods and apparatus for making particles using spray dryer and in-line jet mill |
IL168746A IL168746A (en) | 2002-12-19 | 2005-05-23 | Methods and apparatus for making particles using spray dryer and in-line jet mill |
IL188086A IL188086A (en) | 2002-12-19 | 2007-12-12 | Method and apparatus for making particles using spray dryer and in-line jet mill |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007091688A (en) * | 2005-09-30 | 2007-04-12 | Kurimoto Ltd | Method for producing fine powder for coating of solid preparation |
CN102374759A (en) * | 2010-08-11 | 2012-03-14 | 焦作健康元生物制品有限公司 | Mushroom scrap spray-drying system |
Families Citing this family (138)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9006175B2 (en) | 1999-06-29 | 2015-04-14 | Mannkind Corporation | Potentiation of glucose elimination |
CA2479751C (en) | 2002-03-20 | 2008-06-03 | Trent Poole | Inhalation apparatus |
US20040121003A1 (en) * | 2002-12-19 | 2004-06-24 | Acusphere, Inc. | Methods for making pharmaceutical formulations comprising deagglomerated microparticles |
US6962006B2 (en) * | 2002-12-19 | 2005-11-08 | Acusphere, Inc. | Methods and apparatus for making particles using spray dryer and in-line jet mill |
US6669929B1 (en) | 2002-12-30 | 2003-12-30 | Colgate Palmolive Company | Dentifrice containing functional film flakes |
WO2004096113A2 (en) | 2003-04-28 | 2004-11-11 | Medical Instill Technologies, Inc. | Container with valve assembly for filling and dispensing substances, and apparatus and method for filling |
US20050266298A1 (en) * | 2003-07-09 | 2005-12-01 | Maxwell Technologies, Inc. | Dry particle based electro-chemical device and methods of making same |
US7791860B2 (en) | 2003-07-09 | 2010-09-07 | Maxwell Technologies, Inc. | Particle based electrodes and methods of making same |
US20050250011A1 (en) * | 2004-04-02 | 2005-11-10 | Maxwell Technologies, Inc. | Particle packaging systems and methods |
US20070122698A1 (en) * | 2004-04-02 | 2007-05-31 | Maxwell Technologies, Inc. | Dry-particle based adhesive and dry film and methods of making same |
US7295423B1 (en) * | 2003-07-09 | 2007-11-13 | Maxwell Technologies, Inc. | Dry particle based adhesive electrode and methods of making same |
US20060147712A1 (en) * | 2003-07-09 | 2006-07-06 | Maxwell Technologies, Inc. | Dry particle based adhesive electrode and methods of making same |
US7352558B2 (en) * | 2003-07-09 | 2008-04-01 | Maxwell Technologies, Inc. | Dry particle based capacitor and methods of making same |
US7342770B2 (en) | 2003-07-09 | 2008-03-11 | Maxwell Technologies, Inc. | Recyclable dry particle based adhesive electrode and methods of making same |
US7920371B2 (en) | 2003-09-12 | 2011-04-05 | Maxwell Technologies, Inc. | Electrical energy storage devices with separator between electrodes and methods for fabricating the devices |
GB0327723D0 (en) * | 2003-09-15 | 2003-12-31 | Vectura Ltd | Pharmaceutical compositions |
US7495349B2 (en) | 2003-10-20 | 2009-02-24 | Maxwell Technologies, Inc. | Self aligning electrode |
ES2234420B1 (en) * | 2003-12-03 | 2006-11-01 | Tolsa, S.A. | PROCEDURE TO PREPARE A PRODUCT OF EASY RHEOLOGICAL GRADE DISPERSION OF A PSEUDOLAMINARY SILICATE, PRODUCT AS OBTAINED, AND METHODS OF USE OF THE PRODUCT. |
DE102004007526A1 (en) * | 2004-02-17 | 2005-09-01 | Oetjen, Georg-Wilhelm, Dr. | Method and device for the freeze-drying of products |
US7090946B2 (en) | 2004-02-19 | 2006-08-15 | Maxwell Technologies, Inc. | Composite electrode and method for fabricating same |
US7384433B2 (en) | 2004-02-19 | 2008-06-10 | Maxwell Technologies, Inc. | Densification of compressible layers during electrode lamination |
US7227737B2 (en) | 2004-04-02 | 2007-06-05 | Maxwell Technologies, Inc. | Electrode design |
US20060109608A1 (en) * | 2004-04-02 | 2006-05-25 | Maxwell Technologies, Inc. | Dry-particle based capacitor and methods of making same |
US7245478B2 (en) | 2004-08-16 | 2007-07-17 | Maxwell Technologies, Inc. | Enhanced breakdown voltage electrode |
ES2385934T3 (en) | 2004-08-20 | 2012-08-03 | Mannkind Corporation | CATALYSIS OF THE SYNTHESIS OF DICETOPIPERAZINA. |
KR101644250B1 (en) | 2004-08-23 | 2016-07-29 | 맨카인드 코포레이션 | Diketopiperazine salts, diketomorpholine salts or diketodioxane salts for drug delivery |
US20090104274A1 (en) * | 2005-03-01 | 2009-04-23 | Ajay Khopade | Process of making microspheres |
US7440258B2 (en) | 2005-03-14 | 2008-10-21 | Maxwell Technologies, Inc. | Thermal interconnects for coupling energy storage devices |
US20060286378A1 (en) * | 2005-05-23 | 2006-12-21 | Shivkumar Chiruvolu | Nanostructured composite particles and corresponding processes |
US7276231B2 (en) * | 2005-05-23 | 2007-10-02 | E I Du Pont De Nemours And Company | Lower-energy process for preparing passivated inorganic nanoparticles |
DK1928423T3 (en) | 2005-09-14 | 2016-02-29 | Mannkind Corp | A method for drug formulation based on increasing the affinity of the active substances to the crystalline microparticle surfaces |
WO2007035348A2 (en) * | 2005-09-15 | 2007-03-29 | Elan Pharma International, Limited | Nanoparticulate aripiprazole formulations |
EP1928589A2 (en) * | 2005-09-28 | 2008-06-11 | University of Massachusetts | Encapsulated emulsions and methods of preparation |
EP1951197A4 (en) * | 2005-11-10 | 2011-12-21 | Alphapharm Pty Ltd | Process to control particle size |
EP1978933A2 (en) * | 2005-12-15 | 2008-10-15 | Acusphere, Inc. | Processes for making particle-based pharmaceutical formulations for oral administration |
US8540666B2 (en) * | 2005-12-21 | 2013-09-24 | Boston Scientific Scimed, Inc. | Echogenic occlusive balloon and delivery system |
US8039431B2 (en) | 2006-02-22 | 2011-10-18 | Mannkind Corporation | Method for improving the pharmaceutic properties of microparticles comprising diketopiperazine and an active agent |
ES2683919T3 (en) | 2006-04-24 | 2018-09-28 | Medical Instill Technologies, Inc. | Freeze-drying device that can be pierced with a needle and resealed, and related method |
KR100780337B1 (en) * | 2006-04-27 | 2007-11-29 | 주식회사 케미랜드 | A Milling Machine For Powder-type Material |
US8067047B2 (en) * | 2006-06-27 | 2011-11-29 | James Fajt | Method and devices for forming articles |
US8518573B2 (en) | 2006-09-29 | 2013-08-27 | Maxwell Technologies, Inc. | Low-inductive impedance, thermally decoupled, radii-modulated electrode core |
CN101167697B (en) * | 2006-10-26 | 2011-03-30 | 中国科学院上海药物研究所 | Donepezils compound long-acting slow-releasing and controlled-releasing composition and preparation method thereof |
DE102006053375A1 (en) * | 2006-11-10 | 2008-05-15 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Process for mixing powders |
US20080204973A1 (en) * | 2007-02-28 | 2008-08-28 | Maxwell Technologies, Inc. | Ultracapacitor electrode with controlled iron content |
US20080201925A1 (en) | 2007-02-28 | 2008-08-28 | Maxwell Technologies, Inc. | Ultracapacitor electrode with controlled sulfur content |
CA2678739A1 (en) * | 2007-03-15 | 2008-09-18 | Janssen Pharmaceutica N.V. | Filter assembly containing metal fiber filter elements |
DK2158029T3 (en) * | 2007-04-10 | 2019-08-19 | Gea Process Eng Inc | Process gas filter and method of cleaning this |
US8075740B2 (en) * | 2007-07-20 | 2011-12-13 | Aht Solutions, Llc | Method and system for treating feedwater |
US20090020481A1 (en) * | 2007-07-20 | 2009-01-22 | Bailie Robert E | Method and system for treating feedwater |
US20090020411A1 (en) * | 2007-07-20 | 2009-01-22 | Holunga Dean M | Laser pyrolysis with in-flight particle manipulation for powder engineering |
US8083162B2 (en) * | 2007-08-23 | 2011-12-27 | Liquajet L.L.C. | Method for micro-sizing organic, inorganic and engineered compounds |
WO2009039281A2 (en) * | 2007-09-19 | 2009-03-26 | Amgen Inc. | Particle drying apparatus and methods for forming dry particles |
SG185257A1 (en) * | 2007-10-10 | 2012-11-29 | Avantor Performance Mat Inc | Directly compressible high functionality granular microcrystalline cellulose based excipient, manufacturing process and use thereof |
US20100055180A1 (en) * | 2007-10-10 | 2010-03-04 | Mallinckrodt Baker, Inc. | Directly Compressible Granular Microcrystalline Cellulose Based Excipient, Manufacturing Process and Use Thereof |
US20090165974A1 (en) * | 2007-12-28 | 2009-07-02 | Weyerhaeuser Co. | Methods for blending dried cellulose fibers |
US20090197780A1 (en) * | 2008-02-01 | 2009-08-06 | Weaver Jimmie D | Ultrafine Grinding of Soft Materials |
US8337867B2 (en) * | 2008-02-08 | 2012-12-25 | Purac Biochem B.V. | Metal lactate powder and method for preparation |
PL220269B1 (en) * | 2008-04-21 | 2015-09-30 | Przedsiębiorstwo Produkcji Farmaceutycznej Hasco Lek Spółka Akcyjna | Composite carrier of powdered medicines, method of production the medicine carrier and equipment for production of particles of composite carrier |
AR071375A1 (en) * | 2008-04-22 | 2010-06-16 | Solvay Pharm Gmbh | FORMULATIONS FOR ACTIVE PHARMACEUTICAL INGREDIENTS OF DEFICIENT PERMEABILITY, PREPARATION AND PRODUCT PROCESS |
US8697098B2 (en) | 2011-02-25 | 2014-04-15 | South Dakota State University | Polymer conjugated protein micelles |
AU2009257311B2 (en) | 2008-06-13 | 2014-12-04 | Mannkind Corporation | A dry powder inhaler and system for drug delivery |
US8485180B2 (en) | 2008-06-13 | 2013-07-16 | Mannkind Corporation | Dry powder drug delivery system |
US8632805B2 (en) * | 2008-06-20 | 2014-01-21 | Mutual Pharmaceutical Company, Inc. | Controlled-release formulations, method of manufacture, and use thereof |
US7794750B2 (en) * | 2008-06-20 | 2010-09-14 | Mutual Pharmaceutical Company, Inc. | Controlled-release formulations, method of manufacture, and use thereof |
US9364619B2 (en) | 2008-06-20 | 2016-06-14 | Mannkind Corporation | Interactive apparatus and method for real-time profiling of inhalation efforts |
TWI532497B (en) | 2008-08-11 | 2016-05-11 | 曼凱公司 | Use of ultrarapid acting insulin |
KR100901741B1 (en) * | 2008-10-24 | 2009-06-10 | 김성우 | Air dryer using vortex tube |
US8176655B2 (en) * | 2008-12-16 | 2012-05-15 | Spx Flow Technology Danmark A/S | Vapor atmosphere spray dryer |
US8314106B2 (en) | 2008-12-29 | 2012-11-20 | Mannkind Corporation | Substituted diketopiperazine analogs for use as drug delivery agents |
CA2691712A1 (en) * | 2009-02-16 | 2010-08-16 | Honda Motor Co., Ltd. | Electrostatic coating method and electrostatic coating apparatus |
JP5667095B2 (en) | 2009-03-11 | 2015-02-12 | マンカインド コーポレイション | Apparatus, system and method for measuring inhaler resistance |
CA2764505C (en) | 2009-06-12 | 2018-09-25 | Mannkind Corporation | Diketopiperazine microparticles with defined specific surface areas |
MX353186B (en) | 2009-09-03 | 2018-01-05 | Genentech Inc | Methods for treating, diagnosing, and monitoring rheumatoid arthritis. |
DE102009045116A1 (en) * | 2009-09-29 | 2011-03-31 | Evonik Degussa Gmbh | Niederdruckvermahlungsverfahren |
WO2011056889A1 (en) | 2009-11-03 | 2011-05-12 | Mannkind Corporation | An apparatus and method for simulating inhalation efforts |
GB0921481D0 (en) * | 2009-12-08 | 2010-01-20 | Vectura Ltd | Process and product |
CN104997634A (en) * | 2010-04-09 | 2015-10-28 | 帕西拉制药有限公司 | Method for formulating large diameter synthetic membrane vesicles |
RU2571331C1 (en) | 2010-06-21 | 2015-12-20 | Маннкайнд Корпорейшн | Systems and methods for dry powder drug delivery |
US8939388B1 (en) | 2010-09-27 | 2015-01-27 | ZoomEssence, Inc. | Methods and apparatus for low heat spray drying |
US9332776B1 (en) | 2010-09-27 | 2016-05-10 | ZoomEssence, Inc. | Methods and apparatus for low heat spray drying |
EP2627325A1 (en) | 2010-10-12 | 2013-08-21 | Cipla Limited | Pharmaceutical composition |
FR2970713B1 (en) * | 2011-01-20 | 2014-04-25 | Arkema France | BIORESSOURCE ALIPHATIC POLYESTER FINE POWDER AND PROCESS FOR PRODUCING SUCH POWDER |
WO2012106592A2 (en) * | 2011-02-04 | 2012-08-09 | Climax Molybdenum Company | Molybdenum disulfide powders and methods and apparatus for producing the same |
US8708159B2 (en) | 2011-02-16 | 2014-04-29 | Oakwood Laboratories, Llc | Manufacture of microspheres using a hydrocyclone |
EP2678001B1 (en) | 2011-02-25 | 2017-04-05 | South Dakota State University | Polymer conjugated protein micelles |
CN105667994B (en) | 2011-04-01 | 2018-04-06 | 曼金德公司 | Blister package for pharmaceutical kit |
WO2012174472A1 (en) | 2011-06-17 | 2012-12-20 | Mannkind Corporation | High capacity diketopiperazine microparticles |
EP2732945B1 (en) * | 2011-08-15 | 2016-11-23 | University of Yamanashi | Method of and apparatus for manufacturing micro-beads comprising thermoplastic micro-particles |
CN102357308B (en) * | 2011-10-19 | 2013-10-23 | 江西稀有稀土金属钨业集团有限公司 | Method for directly preparing anhydrous cobalt chloride powder from cobalt chloride solution |
CA2852536A1 (en) | 2011-10-24 | 2013-05-02 | Mannkind Corporation | Methods and compositions for treating pain |
PT106237B (en) | 2012-03-30 | 2015-03-19 | Hovione Farmaci Ncia S A | PRODUCTION OF SUBSTANCIALLY MONO-BUILT PARTICLES USING GRINDING AND MEMBRANE SEPARATION |
CN103374241A (en) * | 2012-04-17 | 2013-10-30 | 鲍联 | Integrated powder modification production process |
JP5827178B2 (en) * | 2012-06-05 | 2015-12-02 | 北越紀州製紙株式会社 | Cellulose porous body and method for producing the same |
CN102728841B (en) * | 2012-07-10 | 2014-06-04 | 交城县融和磁材有限公司 | Airflow powder grinding device and method for sintered neodymium iron boron (NdFeB) permanent magnet material |
US9802012B2 (en) | 2012-07-12 | 2017-10-31 | Mannkind Corporation | Dry powder drug delivery system and methods |
JP6246712B2 (en) * | 2012-07-12 | 2017-12-13 | 武田薬品工業株式会社 | Method for producing microcapsule powder |
CN102788488A (en) * | 2012-08-03 | 2012-11-21 | 梁首强 | High-speed centrifugal drying method and drying system for implementing method |
US8968693B2 (en) * | 2012-08-30 | 2015-03-03 | Honeywell International Inc. | Internal cyclone for fluidized bed reactor |
US10159644B2 (en) | 2012-10-26 | 2018-12-25 | Mannkind Corporation | Inhalable vaccine compositions and methods |
ES2754388T3 (en) | 2013-03-15 | 2020-04-17 | Mannkind Corp | Compositions and methods of microcrystalline dicetopiperazine |
US9925144B2 (en) | 2013-07-18 | 2018-03-27 | Mannkind Corporation | Heat-stable dry powder pharmaceutical compositions and methods |
EP3030294B1 (en) | 2013-08-05 | 2020-10-07 | MannKind Corporation | Insufflation apparatus |
IN2013CH04500A (en) | 2013-10-04 | 2015-04-10 | Kennametal India Ltd | |
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 |
US10307464B2 (en) | 2014-03-28 | 2019-06-04 | Mannkind Corporation | Use of ultrarapid acting insulin |
PT107568B (en) * | 2014-03-31 | 2018-11-05 | Hovione Farm S A | ATOMIZATION DRYING PROCESS FOR PRODUCTION OF POWDER WITH IMPROVED PROPERTIES. |
PT107567B (en) * | 2014-03-31 | 2019-02-13 | Hovione Farm S A | ATOMIZATION DRYER WITH MULTIPLE ATOMIZER, METHOD FOR INCREASING DRIAL POWDER SCALE BY MULTIPLE ATOMIZATION DEVICE AND USE OF VARIOUS ATOMIZERS IN ONE ATOMIZATION DRYER |
CN104251603A (en) * | 2014-09-03 | 2014-12-31 | 嘉善圣莱斯绒业有限公司 | Powder drying device |
US10561806B2 (en) | 2014-10-02 | 2020-02-18 | Mannkind Corporation | Mouthpiece cover for an inhaler |
CN104353396B (en) * | 2014-11-06 | 2016-02-03 | 四川旭华制药有限公司 | A kind of electrostatic adsorption type spray-drying pelleting machine |
SI3346990T1 (en) * | 2015-09-09 | 2020-07-31 | Vectura Limited | Jet milling method |
FR3042987B1 (en) * | 2015-11-04 | 2017-12-15 | Commissariat Energie Atomique | DEVICE FOR GRANULATING POWDERS BY CRYOGENIC ATOMIZATION |
US20190133940A1 (en) * | 2016-06-30 | 2019-05-09 | Philip Morris Products S.A. | Nicotine particles and compositions |
BR112018075017A2 (en) * | 2016-06-30 | 2019-03-19 | Philip Morris Products S.A. | nicotine particles |
CN107188211B (en) * | 2016-08-16 | 2019-04-05 | 上海奉坤新材料有限公司 | The production method of improved powdered whiting |
CN106496082B (en) * | 2016-10-31 | 2018-03-06 | 荆门市欣胱生物工程股份有限公司 | A kind of production method of compound amino acid powder spraying system and amino acid powder |
WO2018112408A1 (en) * | 2016-12-15 | 2018-06-21 | Flexion Therapeutics, Inc. | Fluticasone formulations and methods of use thereof |
CA3153745C (en) | 2017-08-04 | 2024-01-02 | ZoomEssence, Inc. | Ultrahigh efficiency spray drying apparatus and process |
US9993787B1 (en) | 2017-08-04 | 2018-06-12 | ZoomEssence, Inc. | Ultrahigh efficiency spray drying apparatus and process |
US10155234B1 (en) | 2017-08-04 | 2018-12-18 | ZoomEssence, Inc. | Ultrahigh efficiency spray drying apparatus and process |
US9861945B1 (en) | 2017-08-04 | 2018-01-09 | ZoomEssence, Inc. | Ultrahigh efficiency spray drying apparatus and process |
US10486173B2 (en) | 2017-08-04 | 2019-11-26 | ZoomEssence, Inc. | Ultrahigh efficiency spray drying apparatus and process |
CN107510600A (en) * | 2017-08-07 | 2017-12-26 | 苏州大学 | A kind of device and method for preparing medicinal solid particulate |
CN107940900A (en) * | 2017-10-12 | 2018-04-20 | 浙江工业大学 | The multilevel drying method and drying device of a kind of potassium fluoride in high activity |
US10955189B2 (en) * | 2017-12-18 | 2021-03-23 | Oliver Manufacturing Company, Inc. | Vibratory fluidized bed dryer |
US10569244B2 (en) | 2018-04-28 | 2020-02-25 | ZoomEssence, Inc. | Low temperature spray drying of carrier-free compositions |
CN108672014B (en) * | 2018-05-15 | 2020-01-21 | 安徽省华腾农业科技有限公司 | Production system and production method of granules and granules |
CN109126495B (en) * | 2018-07-09 | 2021-06-01 | 山东微研生物科技有限公司 | Energy-concerving and environment-protective type vitamin B2 drying device |
US11121354B2 (en) * | 2019-06-28 | 2021-09-14 | eJoule, Inc. | System with power jet modules and method thereof |
CN110327642A (en) * | 2019-07-08 | 2019-10-15 | 浙江正裕化学工业有限公司 | A kind of spray dryer of solid dye production |
CN111515000B (en) * | 2020-04-30 | 2022-02-01 | 厦门高容纳米新材料科技有限公司 | Method for dispersing nano powder |
CN111624071A (en) * | 2020-06-17 | 2020-09-04 | 北京雪迪龙科技股份有限公司 | Generation device and method for standard particles with various particle sizes |
CN111790484A (en) * | 2020-07-20 | 2020-10-20 | 袁静 | Movable potato starch processing unit |
CN114497548B (en) * | 2022-01-28 | 2023-10-03 | 佛山市德方纳米科技有限公司 | Nanoscale positive electrode material, preparation method and preparation device thereof and lithium ion battery |
CN114669085A (en) * | 2022-01-28 | 2022-06-28 | 南京宁源科生物技术有限公司 | Organic solvent removing device for medicinal particles |
CN114575417B (en) * | 2022-03-28 | 2022-11-04 | 哈尔滨工业大学 | Liquid water collector adopting valve control active air supply |
CN117208888B (en) * | 2023-09-04 | 2024-02-27 | 博路天成新能源科技有限公司 | Manufacturing process of hard carbon negative electrode material for sodium ion battery |
CN117772382A (en) * | 2024-02-28 | 2024-03-29 | 中科雅丽科技有限公司 | Fine control adjustment method for fineness of glass microsphere grinding powder |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5741478A (en) * | 1994-11-19 | 1998-04-21 | Andaris Limited | Preparation of hollow microcapsules by spray-drying an aqueous solution of a wall-forming material and a water-miscible solvent |
WO1999053901A1 (en) * | 1998-04-18 | 1999-10-28 | Glaxo Group Limited | Pharmaceutical aerosol formulation |
US6223455B1 (en) * | 1999-05-03 | 2001-05-01 | Acusphere, Inc. | Spray drying apparatus and methods of use |
Family Cites Families (52)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3215572A (en) * | 1963-10-09 | 1965-11-02 | Papell Solomon Stephen | Low viscosity magnetic fluid obtained by the colloidal suspension of magnetic particles |
US4420441A (en) * | 1982-02-23 | 1983-12-13 | National Research Development Corp. | Method of making a two-phase or multi-phase metallic material |
DE3702787A1 (en) * | 1987-01-30 | 1988-08-11 | Bayer Ag | METHOD AND DEVICE FOR MICRONIZING SOLIDS IN JET MILLS |
US5205290A (en) * | 1991-04-05 | 1993-04-27 | Unger Evan C | Low density microspheres and their use as contrast agents for computed tomography |
GB9107628D0 (en) | 1991-04-10 | 1991-05-29 | Moonbrook Limited | Preparation of diagnostic agents |
US5438573A (en) * | 1991-09-13 | 1995-08-01 | Sundisk Corporation | Flash EEPROM array data and header file structure |
EP0535937B2 (en) * | 1991-10-01 | 2008-05-21 | Takeda Chemical Industries, Ltd. | Prolonged release microparticle preparation and production of the same |
GB9221329D0 (en) | 1992-10-10 | 1992-11-25 | Delta Biotechnology Ltd | Preparation of further diagnostic agents |
DK0669128T3 (en) | 1992-11-17 | 2000-06-19 | Yoshitomi Pharmaceutical | Sustained-release microsphere containing antipsychotics and method of producing same |
DE4319990A1 (en) * | 1993-06-17 | 1994-12-22 | Messer Griesheim Gmbh | Process for producing particles from plastics |
TW402506B (en) | 1993-06-24 | 2000-08-21 | Astra Ab | Therapeutic preparation for inhalation |
IS1796B (en) | 1993-06-24 | 2001-12-31 | Ab Astra | Inhaled polypeptide formulation composition which also contains an enhancer compound |
ES2231775T5 (en) * | 1993-07-30 | 2011-02-02 | Imcor Pharmaceutical Co. | COMPOSITION OF STABILIZED MICROBUBBLES FOR ECOGRAPHY. |
US5667927A (en) | 1993-08-30 | 1997-09-16 | Shimadu Corporation | Toner for electrophotography and process for the production thereof |
US5596815A (en) * | 1994-06-02 | 1997-01-28 | Jet-Pro Company, Inc. | Material drying process |
US6165976A (en) | 1994-06-23 | 2000-12-26 | Astra Aktiebolag | Therapeutic preparation for inhalation |
US6117455A (en) | 1994-09-30 | 2000-09-12 | Takeda Chemical Industries, Ltd. | Sustained-release microcapsule of amorphous water-soluble pharmaceutical active agent |
US5983956A (en) * | 1994-10-03 | 1999-11-16 | Astra Aktiebolag | Formulation for inhalation |
SE9501384D0 (en) * | 1995-04-13 | 1995-04-13 | Astra Ab | Process for the preparation of respirable particles |
US6045913A (en) | 1995-11-01 | 2000-04-04 | Minnesota Mining And Manufacturing Company | At least partly fused particulates and methods of making them by flame fusion |
US6254981B1 (en) | 1995-11-02 | 2001-07-03 | Minnesota Mining & Manufacturing Company | Fused glassy particulates obtained by flame fusion |
DK0904113T3 (en) | 1996-03-05 | 2004-08-30 | Acusphere Inc | Microencapsulated fluorinated gases for use as imaging agents |
US5611344A (en) | 1996-03-05 | 1997-03-18 | Acusphere, Inc. | Microencapsulated fluorinated gases for use as imaging agents |
US6096339A (en) | 1997-04-04 | 2000-08-01 | Alza Corporation | Dosage form, process of making and using same |
US5855913A (en) * | 1997-01-16 | 1999-01-05 | Massachusetts Instite Of Technology | Particles incorporating surfactants for pulmonary drug delivery |
US5833892A (en) * | 1996-07-12 | 1998-11-10 | Kemira Pigments, Inc. | Formation of TiO2 pigment by spray calcination |
US6139872A (en) * | 1996-08-14 | 2000-10-31 | Henkel Corporation | Method of producing a vitamin product |
EP0930874A2 (en) | 1996-10-09 | 1999-07-28 | Takeda Chemical Industries, Ltd. | A method for producing a microparticle |
US6068600A (en) | 1996-12-06 | 2000-05-30 | Quadrant Healthcare (Uk) Limited | Use of hollow microcapsules |
EP0971698A4 (en) * | 1996-12-31 | 2006-07-26 | Nektar Therapeutics | Aerosolized hydrophobic drug |
SE9700135D0 (en) * | 1997-01-20 | 1997-01-20 | Astra Ab | New formulation |
GB9702799D0 (en) * | 1997-02-12 | 1997-04-02 | Scherer Corp R P | Process for preparing solid pharmaceutical dosage forms |
DE19728382C2 (en) | 1997-07-03 | 2003-03-13 | Hosokawa Alpine Ag & Co | Method and device for fluid bed jet grinding |
SE9703407D0 (en) * | 1997-09-19 | 1997-09-19 | Astra Ab | New use |
IT1295226B1 (en) * | 1997-10-14 | 1999-05-04 | Magneti Marelli Spa | PLANT FOR THE PRODUCTION OF PRESSED OR INJECTION-PRINTED PRODUCTS USING SALT CORE. |
US6187345B1 (en) | 1998-04-14 | 2001-02-13 | Jack Lawrence James | Flutamide compositions and preparations |
US6423345B2 (en) | 1998-04-30 | 2002-07-23 | Acusphere, Inc. | Matrices formed of polymer and hydrophobic compounds for use in drug delivery |
US6451349B1 (en) * | 1998-08-19 | 2002-09-17 | Quadrant Healthcare (Uk) Limited | Spray-drying process for the preparation of microparticles |
US6560897B2 (en) | 1999-05-03 | 2003-05-13 | Acusphere, Inc. | Spray drying apparatus and methods of use |
US6395300B1 (en) | 1999-05-27 | 2002-05-28 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
US6443376B1 (en) | 1999-12-15 | 2002-09-03 | Hosokawa Micron Powder Systems | Apparatus for pulverizing and drying particulate matter |
EP1129705A1 (en) * | 2000-02-17 | 2001-09-05 | Rijksuniversiteit te Groningen | Powder formulation for inhalation |
GB0012260D0 (en) * | 2000-05-19 | 2000-07-12 | Astrazeneca Ab | Novel composition |
GB0012261D0 (en) * | 2000-05-19 | 2000-07-12 | Astrazeneca Ab | Novel process |
US20040022862A1 (en) * | 2000-12-22 | 2004-02-05 | Kipp James E. | Method for preparing small particles |
US6962071B2 (en) * | 2001-04-06 | 2005-11-08 | Bracco Research S.A. | Method for improved measurement of local physical parameters in a fluid-filled cavity |
WO2003090717A1 (en) * | 2002-04-23 | 2003-11-06 | Nanotherapeutics, Inc | Process of forming and modifying particles and compositions produced thereby |
US6919068B2 (en) * | 2002-05-17 | 2005-07-19 | Point Biomedical Corporation | Method of preparing gas-filled polymer matrix microparticles useful for echographic imaging |
US6962006B2 (en) * | 2002-12-19 | 2005-11-08 | Acusphere, Inc. | Methods and apparatus for making particles using spray dryer and in-line jet mill |
US20040121003A1 (en) * | 2002-12-19 | 2004-06-24 | Acusphere, Inc. | Methods for making pharmaceutical formulations comprising deagglomerated microparticles |
US7511079B2 (en) * | 2003-03-24 | 2009-03-31 | Baxter International Inc. | Methods and apparatuses for the comminution and stabilization of small particles |
US7485283B2 (en) * | 2004-04-28 | 2009-02-03 | Lantheus Medical Imaging | Contrast agents for myocardial perfusion imaging |
-
2002
- 2002-12-19 US US10/324,943 patent/US6962006B2/en not_active Expired - Fee Related
-
2003
- 2003-11-20 AU AU2003295704A patent/AU2003295704B2/en not_active Ceased
- 2003-11-20 JP JP2004565053A patent/JP2006514879A/en active Pending
- 2003-11-20 KR KR1020057011660A patent/KR20050094410A/en not_active Application Discontinuation
- 2003-11-20 BR BR0317595-2A patent/BR0317595A/en not_active IP Right Cessation
- 2003-11-20 RU RU2005122655/15A patent/RU2324533C2/en not_active IP Right Cessation
- 2003-11-20 CA CA002511376A patent/CA2511376A1/en not_active Abandoned
- 2003-11-20 CN CNB2003801064373A patent/CN100500275C/en not_active Expired - Fee Related
- 2003-11-20 EP EP03786905A patent/EP1575696A1/en not_active Withdrawn
- 2003-11-20 WO PCT/US2003/037108 patent/WO2004060547A1/en active Application Filing
-
2004
- 2004-01-07 US US10/752,861 patent/US6921458B2/en not_active Expired - Fee Related
- 2004-01-07 US US10/752,910 patent/US6918991B2/en not_active Expired - Fee Related
-
2005
- 2005-05-23 IL IL168746A patent/IL168746A/en not_active IP Right Cessation
- 2005-05-26 ZA ZA200504300A patent/ZA200504300B/en unknown
- 2005-06-02 US US11/142,917 patent/US20050209099A1/en not_active Abandoned
-
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- 2007-12-12 IL IL188086A patent/IL188086A/en not_active IP Right Cessation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5741478A (en) * | 1994-11-19 | 1998-04-21 | Andaris Limited | Preparation of hollow microcapsules by spray-drying an aqueous solution of a wall-forming material and a water-miscible solvent |
WO1999053901A1 (en) * | 1998-04-18 | 1999-10-28 | Glaxo Group Limited | Pharmaceutical aerosol formulation |
US6223455B1 (en) * | 1999-05-03 | 2001-05-01 | Acusphere, Inc. | Spray drying apparatus and methods of use |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007091688A (en) * | 2005-09-30 | 2007-04-12 | Kurimoto Ltd | Method for producing fine powder for coating of solid preparation |
CN102374759A (en) * | 2010-08-11 | 2012-03-14 | 焦作健康元生物制品有限公司 | Mushroom scrap spray-drying system |
CN102374759B (en) * | 2010-08-11 | 2014-08-13 | 焦作健康元生物制品有限公司 | Mushroom scrap spray-drying system |
Also Published As
Publication number | Publication date |
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US20040118007A1 (en) | 2004-06-24 |
CN100500275C (en) | 2009-06-17 |
RU2005122655A (en) | 2006-01-20 |
US20040134091A1 (en) | 2004-07-15 |
RU2324533C2 (en) | 2008-05-20 |
ZA200504300B (en) | 2005-11-28 |
JP2006514879A (en) | 2006-05-18 |
EP1575696A1 (en) | 2005-09-21 |
US6962006B2 (en) | 2005-11-08 |
AU2003295704A1 (en) | 2004-07-29 |
US20040139624A1 (en) | 2004-07-22 |
BR0317595A (en) | 2005-11-22 |
AU2003295704B2 (en) | 2008-05-08 |
US20050209099A1 (en) | 2005-09-22 |
IL188086A (en) | 2009-12-24 |
KR20050094410A (en) | 2005-09-27 |
US6921458B2 (en) | 2005-07-26 |
US6918991B2 (en) | 2005-07-19 |
CA2511376A1 (en) | 2004-07-22 |
IL168746A (en) | 2008-08-07 |
IL188086A0 (en) | 2008-03-20 |
CN1726076A (en) | 2006-01-25 |
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