WO2016197091A1 - Taxane particles and their use - Google Patents
Taxane particles and their use Download PDFInfo
- Publication number
- WO2016197091A1 WO2016197091A1 PCT/US2016/035993 US2016035993W WO2016197091A1 WO 2016197091 A1 WO2016197091 A1 WO 2016197091A1 US 2016035993 W US2016035993 W US 2016035993W WO 2016197091 A1 WO2016197091 A1 WO 2016197091A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- particles
- composition
- paclitaxel
- docetaxel
- taxane
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/02—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of powders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—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
-
- 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
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- 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
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5192—Processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D46/00—Filters or filtering processes specially modified for separating dispersed particles from gases or vapours
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D46/00—Filters or filtering processes specially modified for separating dispersed particles from gases or vapours
- B01D46/24—Particle separators, e.g. dust precipitators, using rigid hollow filter bodies
-
- 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
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/08—Processes employing the direct application of electric or wave energy, or particle radiation; Apparatus therefor
- B01J19/10—Processes employing the direct application of electric or wave energy, or particle radiation; Apparatus therefor employing sonic or ultrasonic vibrations
-
- 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
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/26—Nozzle-type reactors, i.e. the distribution of the initial reactants within the reactor is effected by their introduction or injection through nozzles
-
- 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
-
- 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
- B01J2/06—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 liquid medium
-
- 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
- B01J3/00—Processes of utilising sub-atmospheric or super-atmospheric pressure to effect chemical or physical change of matter; Apparatus therefor
- B01J3/008—Processes carried out under supercritical conditions
-
- 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
- B01J3/00—Processes of utilising sub-atmospheric or super-atmospheric pressure to effect chemical or physical change of matter; Apparatus therefor
- B01J3/02—Feed or outlet devices therefor
-
- 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
- B01J4/00—Feed or outlet devices; Feed or outlet control devices
- B01J4/001—Feed or outlet devices as such, e.g. feeding tubes
- B01J4/002—Nozzle-type elements
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
- B05B1/00—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means
- B05B1/34—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means designed to influence the nature of flow of the liquid or other fluent material, e.g. to produce swirl
- B05B1/3405—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means designed to influence the nature of flow of the liquid or other fluent material, e.g. to produce swirl to produce swirl
- B05B1/341—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means designed to influence the nature of flow of the liquid or other fluent material, e.g. to produce swirl to produce swirl before discharging the liquid or other fluent material, e.g. in a swirl chamber upstream the spray outlet
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
- B05B1/00—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means
- B05B1/34—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means designed to influence the nature of flow of the liquid or other fluent material, e.g. to produce swirl
- B05B1/3405—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means designed to influence the nature of flow of the liquid or other fluent material, e.g. to produce swirl to produce swirl
- B05B1/341—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means designed to influence the nature of flow of the liquid or other fluent material, e.g. to produce swirl to produce swirl before discharging the liquid or other fluent material, e.g. in a swirl chamber upstream the spray outlet
- B05B1/3489—Nozzles having concentric outlets
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
- B05B13/00—Machines or plants for applying liquids or other fluent materials to surfaces of objects or other work by spraying, not covered by groups B05B1/00 - B05B11/00
- B05B13/02—Means for supporting work; Arrangement or mounting of spray heads; Adaptation or arrangement of means for feeding work
- B05B13/0278—Arrangement or mounting of spray heads
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2271/00—Sealings for filters specially adapted for separating dispersed particles from gases or vapours
- B01D2271/02—Gaskets, sealings
-
- 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
- B01J2204/00—Aspects relating to feed or outlet devices; Regulating devices for feed or outlet devices
- B01J2204/002—Aspects relating to feed or outlet devices; Regulating devices for feed or outlet devices the feeding side being of particular interest
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05D2401/00—Form of the coating product, e.g. solution, water dispersion, powders or the like
- B05D2401/90—Form of the coating product, e.g. solution, water dispersion, powders or the like at least one component of the composition being in supercritical state or close to supercritical state
Definitions
- Dissolution rate is a key parameter in determining the rate and extent of drug absorption and bioavailability. Poor aqueous solubility and poor in vivo dissolution are limiting factors for in vivo bioavailability of many drugs. Thus, in vitro dissolution rates are recognized as an important element in drug development, and methods and compositions for increasing the dissolution rates of poorly soluble drugs are needed.
- compositions comprising particles including at least 95% by weight of a taxane, or a pharmaceutically acceptable salt thereof, wherein the particles have one or both of the following characteristics:
- SSA specific surface area
- the taxane is selected from the group consisting of paclitaxel, docetaxel, cabazitaxel, taxadiene, baccatin HI, taxchinin A, brevifoliol, and taxuspine D, or a pharmaceutically acceptable salt thereof.
- the taxane is selected from the group consisting of paclitaxel, docetaxel, and cabazitaxel, or a pharmaceutically acceptable salt thereof.
- the taxane is paclitaxel or a pharmaceutically acceptable salt thereof, and wherein the particles have a mean bulk density between about 0.050 g/cm 3 and about 0.12 g/cm 3 , or between about 0.060 g/cm 3 and about 0.11 g/cm 3 .
- the paclitaxel particles may have a specific surface area (SSA) of at least 18 m 2 /g, 20 m 2 /g, 25 m 2 /g, 30 m 2 /g, 32 m 2 /g, 34 m 2 /g, or 35 m 2 /g.
- SSA specific surface area
- the paclitaxel particles may have a SSA of between about 22 m 2 /g and about 40 m 2 /g, 25 m 2 /g and about 40 m 2 /g, 30 m 2 /g and about 40 m 2 /g, or between about 35 m 2 /g and about 40 m 2 /g.
- the paclitaxel particles may have a bulk density of between about 0.060 g/cm 3 and about 0.11 g/cm 3 and a SSA of between about 22 mVg and about 40 m 2 /g.
- At least 40% (w/w) of the paclitaxel is dissolved in 30 minutes or less in a solution of 50% methanol /50% water ((v/v)) at 37°C and pH 7.0 in a USP ⁇ paddle apparatus operating at 75 RPM.
- the taxane is docetaxel or a pharmaceutically acceptable salt thereof, and wherein the particles have a mean bulk density between about 0.050 g/cm 3 and about 0.12 g/cm 3 , or between about 0.06 g/cm 3 and about 0.1 g/cm 3 .
- the docetaxel particles may have a SSA of at least 18 m 2 /g, 20 m 2 /g, 25 m 2 /g, 30 m 2 /g, 35 m 2 /g, 40 m 2 /g, or 42 m 2 /g.
- the docetaxel particles may have a SSA of between about 40 m 2 /g and about 50 m 2 /g, or between about 43 m 2 /g and about 46 m 2 /g.
- the docetaxel particles may have a bulk density of between about 0.06 g/cm 3 and about 0.1 g/cm 3 and a SSA of between about 40 m 2 /g and about 50 m 2 /g .
- at least 20% (w/w) of the docetaxel is dissolved in 30 minutes or less in a solution of 15% methanol /85% water (v/v) at 37°C and pH 7.0 in a USP ⁇ paddle apparatus operating at 75 RPM.
- the invention provides compositions comprising particles including at least 95% by weight of paclitaxel, or a pharmaceutically acceptable salt thereof, wherein the particles have a specific surface area (SSA) of at least 12 m 2 /g.
- the paclitaxel particles may have a SSA of at least 12 m 2 /g, 15 m 2 /g, 20 m 2 /g, 25 m 2 /g, 30 m 2 /g, 32 m 2 /g, 34 m 2 /g, or 35 m 2 /g.
- At least 40% (w/w) of the paclitaxel is dissolved in 30 minutes or less in a solution of 50% methanol /50% water (v/v) at 37°C and pH 7.0 in a USP ⁇ paddle apparatus operating at 75 RPM.
- the invention provides compositions comprising particles including at least 95% by weight of paclitaxel, wherein at least 40% (w/w) of the paclitaxel is dissolved in 30 minutes or less in a solution of 50% methanol /50% water (v/v) in a USP II paddle apparatus operating at 75 RPM.
- the invention also provides compositions comprising including at least 95% by weight of docetaxel, wherein at least 20% (w/w) of the docetaxel is dissolved in 30 minutes or less in a solution of 15% methanol /85% water (v/v) at 37°C and pH 7.0 in a USP ⁇ paddle apparatus operating at 75 RPM.
- compositions of the invention may comprise particles have a mean particle size of between about 0.4 um and about 1.2 um, or between about 0.6 um and about 1.0 um.
- the particles may be uncoated and exclude polymer, protein, polyethoxylated castor oil and polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol.
- the compositions may further be incorporated into a suspension, which further comprises a pharmaceutically acceptable aqueous carrier.
- the composition may further comprise one or more components selected from the group consisting of polysorbate, methylcellulose, polyvinylpyrrolidone, mannitol, and
- compositions may comprise by weight at least 96%, 97%, 98%, 99%, or 100% of the compound.
- the invention further provides methods for treating a tumor, comprising
- the tumor may be selected from the group consisting of a breast tumor, an ovarian tumor, a lung tumor, a bladder tumor, a prostate tumor, a bone tumor, a stomach tumor and a pancreatic tumor.
- the composition is administered intraperitoneally, such as by perfusion or as a bolus into the peritoneal cavity.
- the intraperitoneal administration is initiated after removal of ascites fluid from the peritoneal cavity.
- the subject is a human subject.
- the invention further provides methods for making compound particles, comprising: (a) introducing (i) a solution comprising at least one solvent and at least one solute comprising a compound of interest into a nozzle inlet, and (ii) a compressed fluid into an inlet of a vessel defining a pressurizable chamber;
- steps (a), (b), and (c) are carried out under supercritical temperature and pressure for the compressed fluid.
- the method further comprises:
- step (d) contacting the atomized droplets produced in step (c) with an anti-solvent to cause further depletion of the solvent from the compound particles, wherein step (d) is carried out under supercritical temperature and pressure for the anti-solvent.
- a flow rate of the solution through the nozzle has a range from about 0.5 mL/min to about 30 mL/min.
- the sonic energy source comprises one of a sonic horn, a sonic probe, or a sonic plate.
- the sonic energy source has a frequency between about 18 kHx and about 22 kHz, or about 20 kHz.
- the methods may further comprise:
- the compound is a taxane.
- Exemplary taxanes may include paclitaxel, docetaxel, cabazitaxel, taxadiene, baccatin III, taxchinin A, brevifoliol, and taxuspine D, or a pharmaceutically acceptable salt thereof.
- the taxane is selected from the group consisting of paclitaxel, docetaxel, and cabazitaxel, or a pharmaceutically acceptable salt thereof.
- the solvent is selected from the group consisting of acetone, ethanol, methanol, dichloromethane, ethyl acetate, chloroform, acetonitrile, and suitable combinations thereof.
- the compressed fluid and/or the anti- solvent may be super critical carbon dioxide.
- the compound is paclitaxel and the solvent comprises acetone.
- the compound is docetaxel and the solvent comprises ethanol.
- the method is carried out between 31.1 °C to about 60°C, and at between about 1071 psi and about 1800 psi.
- the invention also provides compound particles prepared by the method of any embodiment or combination of embodiments of the invention.
- Figure 1 is an electron micrograph of exemplary paclitaxel particles of the invention.
- Figure 2 is an electron micrograph of raw paclitaxel particles.
- Figure 3 illustrates a cross-section view of an example nozzle assembly, according to an example embodiment.
- Figure 4 illustrates a cross-section view of another example nozzle assembly, according to an example embodiment.
- Figure 5 illustrates a perspective view of a particle collection device, according to an example embodiment.
- Figure 6 illustrates a top view of the particle collection device, according to an example embodiment.
- Figure 7 illustrates a cross-section view of the particle collection device, according to an example embodiment.
- Figure 8 illustrates another cross-section view of the particle collection device, according to an example embodiment.
- Figure 9 illustrates another cross-section view of the particle collection device, according to an example embodiment.
- Figure 10 illustrates a perspective view of a support frame, according to an example embodiment.
- compositions comprising particles including at least 95% by weight of a taxane, or a pharmaceutically acceptable salt thereof, wherein the particles have one or both of the following characteristics:
- SSA specific surface area
- compositions comprising the recited taxane particles that have a mean bulk density between about 0.050 g/cm 3 and about 0.15 g/cm 3 , and/or a specific surface area (SSA) of at least 18 m 2 /g an SSA using novel methods for producing the particles as described herein.
- SSA specific surface area
- the increased specific surface area and decreased bulk density of the taxane particles result in significant increases in dissolution rate compared to the raw taxane and to milled taxane products used for comparison. Dissolution takes place only at a solid/liquid interface. Therefore, increased specific surface area will increase the dissolution rate due to a larger number of molecules on the surface of the particle having contact with the dissolution media.
- the bulk density takes into account the macrostructure and inter-particle space of a powder. Parameters that contribute to the bulk density include particle size distribution, particle shape, and the affinity of the particles for each other (i.e., agglomeration). Lower powder bulk densities yield faster dissolution rates. This is due to the ability of the dissolution media to more readily penetrate the interstitial or inter-particle spaces and have greater contact with the surface of the particles. Therefore, each of the increased specific surface area and the decreased bulk density result in the significant increase in dissolution rate for the taxane particles of the invention compared to the unprocessed or raw material, and the milled taxane product used for comparison. This provides a significant improvement for use of the taxane particles of the invention in, for example, tumor treatment.
- the "specific surface area” is the total surface area of the paclitaxel particle per unit of paclitaxel mass as measured by the Brunauer-Emmett-Teller ("BET") isotherm (i.e.: the BET SSA).
- BET Brunauer-Emmett-Teller
- the "taxane particles” include both agglomerated taxane particles and non-agglomerated taxane particles; since the SSA is determined on a per gram basis it takes into account both agglomerated and non-agglomerated taxane particles in the composition.
- the BET specific surface area test procedure is a compendial method included in both the United States Pharmaceopeia and the European Pharmaceopeia.
- the bulk density of the taxane particles is the mass of the totality- of particles in the composition divided by the total volume they occupy when poured into a graduated cylinder.
- the total volume includes particle volume, inter-particle void volume, and internal pore volume.
- Taxanes are a class of ditetpenoids containing a taxadiene core that are very poorly soluble in water.
- the taxane particles of the invention may be any suitable taxane, including but not limited to paclitaxel, docetaxel, cabazitaxel, taxadiene, baccatin III, taxchinin A, brevifoliol, and taxuspine D, combinations thereof, or pharmaceutically acceptable salts thereof.
- the taxane is selected from the group consisting of paclitaxel, docetaxel, and cabazitaxel, or a pharmaceutically acceptable salt thereof.
- taxane particles refers to particles of taxane that do not include an added excipient. Taxane particles are different man “particles containing taxane", which are particles that contain taxane and at least one added excipient. Taxane particles of the invention exclude a polymeric, wax or protein excipient and are not embedded, contained, enclosed or encapsulated within a solid excipient. Taxane particles of the invention may, however, contain impurities and byproducts typically found during preparation of taxane. Even so, taxane particles comprise at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% taxane, meaning the taxane particles consist of or consist essentially of substantially pure taxane.
- the taxane particles are uncoated and exclude polymer, protein, polyethoxylated castor oil and polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol.
- the compositions of the invention have a mean particle size of between in the range of about 0.2 um to about 5 um, about 0.4 um to about 3 um or about 0.5 um to about 1.4 um. In a further embodiment, the compositions have a mean particle size of between about 0.4 um and about 1.2 um. In another embodiment the mean particle size is between about 0.4 um and about 1.2 um, or between about 0.6 um and about 1.0 um.
- the taxane is paclitaxel or a pharmaceutically acceptable salt thereof, and the particles have a mean bulk density between about 0.050 g/cm 3 and about 0.12 g/cm 3 . In another embodiment, the paclitaxel particles have a mean bulk density between about 0.060 g/cm 3 and about 0.11 g/cm 3 .
- the taxane is paclitaxel or a pharmaceutically acceptable salt thereof, and wherein the paclitaxel particles have a specific surface area (SSA) of at least 18 m 2 /g.
- the paclitaxel particles have a SSA of at least 20 m 2 /g, 25 m 2 /g, 30 m 2 /g, 32 m 2 /g, 34 m 2 /g, or 35 m 2 /g.
- the paclitaxel particles have a SSA of between about 22 m 2 /g and about 40 m 2 /g, between about 25 m 2 /g and about 40 m 2 /g, between about 30 m 2 /g and about 40 m 2 /g, or between about 35 m 2 /g and about 40 m 2 /g.
- the paclitaxel particles have a mean bulk density of between about between about 0.050 g/cm 3 and about 0.12 g/cm 3 and a SSA of at least 30 m 2 /g. In another preferred embodiment, the paclitaxel particles have a mean bulk density of between about between about 0.050 g/cm 3 and about 0.12 g/cm 3 and a SSA of at least 35 m 2 /g. In one the paclitaxel particles have a mean bulk density of between about between about 0.050 g/cm 3 and about 0.12 g/cm 3 and a SSA of between about 30 m 2 /g and about 40 m 2 /g.
- the paclitaxel particles have a mean bulk density of between about 0.060 g/cm 3 and about 0.11 g/cm 3 and a SSA of between about 30 m 2 /g and about 40 m 2 /g. In another preferred embodiment, the paclitaxel particles have a mean bulk density of between about 0.060 g/cm 3 and about 0.11 g/cm 3 and a SSA of at least 30 m 2 /g. In a further embodiment, the paclitaxel particles have a mean bulk density of between about 0.060 g/cm 3 and about 0.11 g/cm 3 and a SSA of at least 35 m 2 /g.
- the paclitaxel particles may include at least
- At least 40% (w/w) of the paclitaxel in the paclitaxel particles of the composition is dissolved in 30 minutes or less in a solution of 50% methanol/50% water (v/v) in a USP ⁇ paddle apparatus operating at 75 RPM. pH 7 was used, and the solubility of the taxanes are not effected by pH.
- the dissolution studies are carried out at 37°C.
- the taxane is docetaxel or a pharmaceutically acceptable salt thereof, and the docetaxel particles have a mean bulk density between about 0.050 g/cm 3 and about 0.12 g/cm 3 .
- the mean bulk density of the docetaxel particles is between about 0.06 g/cm 3 and about 0.1 g/cm 3 .
- the taxane is docetaxel or a pharmaceutically acceptable salt thereof, and wherein the docetaxel particles have a SSA of at least 18 m 2 /g.
- the docetaxel particles have a SSA of at least 20 m 2 /g, 25 m 2 /g, 30 m 2 /g, 35 m 2 /g, 40 m 2 /g, or 42 m 2 /g.
- the docetaxel particles have a SSA of between about 40 m 2 /g and about 50 m 2 /g.
- the docetaxel particles have a SSA of between about 43 m 2 /g and about 46 m 2 /g.
- the docetaxel particles have a mean bulk density between about 0.050 g/cm 3 and about 0.12 g/cm 3 and a SSA of at least 30 m 2 /g. In another preferred embodiment, the docetaxel particles have a mean bulk density between about 0.050 g/cm 3 and about 0.12 g/cm 3 and a SSA of at least 35 m 2 /g. In a further preferred embodiment, the docetaxel particles have a mean bulk density between about 0.050 g/cm 3 and about 0.12 g/cm 3 and a SSA of at least 40 m 2 /g.
- the docetaxel particles have a mean bulk density between about 0.050 g/cm 3 and about 0.12 g/cm 3 and a SSA of between about 40 m 2 /g and about 50 m 2 /g.
- mean bulk density of the docetaxel particles is between about 0.06 g/cm 3 and about 0.1 g/cm 3 and the SSA is between about 40 m 2 /g and about 50 m 2 /g.
- the docetaxel particles may include at least 4.16 x 10 "13 grams docetaxel, or a pharmaceutically acceptable salt thereof per docetaxel particle.
- At least 20% (w/w) of the docetaxel is dissolved in 30 minutes or less in a solution of 15% methanol/85% water (v/v) in a USP II paddle apparatus operating at 75 RPM.
- a neutral pH was used where the solubility of the taxanes are not effected by pH.
- the dissolution studies are carried out at 37°C.
- the invention provides compositions comprising particles including at least 95% by weight of paclitaxel, or a pharmaceutically acceptable salt thereof, wherein the particles have a specific surface area (SSA) of at least 12 m 2 /g.
- SSA specific surface area
- the paclitaxel particles have an SSA of at least 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 m 2 /g.
- the paclitaxel particles have an SSA of between about 12 m 2 /g and about 40 m 2 /g , about 14 m 2 /g and about 40 m 2 /g, about 15 m 2 /g and about 40 m 2 /g, about 16 m 2 /g and about 40 m 2 /g, about 17 m 2 /g and about 40 m 2 /g, about 18 m 2 /g and about 40 m 2 /g, about 19 mVg and about 40 m 2 /g, about 20 m 2 /g and about 40 m 2 /g, about 22 m 2 /g and about 40 m 2 /g, about 26 m 2 /g and about 40 m 2 /g, about 30 m 2 /g and about 40 m 2 /g, between about 20 m 2 /g and about 29 m 2 /g, between about 20 m 2 /g and about 28 m 2 /g, between
- G between 17 m 2 /g and 30 m 2 /g, or > 32 m 2 /g;
- At least 40% (w/w) of the paclitaxel in the paclitaxel particles of the composition is dissolved in 30 minutes or less in a solution of 50% methanol /50% water (v/v) in a USP ⁇ paddle apparatus operating at 75 RPM. pH 7 was used, and the solubility of the taxanes are not effected by pH. In another embodiment, the dissolution studies are carried out at 37°C.
- the present invention provides compositions, comprising particles including at least 95% by weight of paclitaxel, wherein at least 40% (w/w) of the paclitaxel is dissolved in 30 minutes or less in a solution of 50% methanol/50% water (v/v) in a USP II paddle apparatus operating at 75 RPM. pH 7 was used, and the solubility of the taxanes are not effected by pH. In another embodiment, the dissolution studies are carried out at 37°C.
- the present invention provides composition, comprising including at least 95% by weight of docetaxel, wherein at least 20% (w/w) of the docetaxel is dissolved in 30 minutes or less in a solution of 15% methanol/85% water (v/v) in a USP ⁇ paddle apparatus operating at 75 RPM. pH 7 was used, and the solubility of the taxanes are not effected by pH. In another embodiment, the dissolution studies are carried out at 37°C.
- the composition comprises a suspension further comprising a pharmaceutically acceptable aqueous carrier.
- the suspension of the invention comprises taxane particles and a liquid carrier.
- the liquid carrier can be aqueous.
- the suspension excludes a solid excipient within which the paclitaxel is contained and excludes GELUCIRE ® (polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol), and CREMOPHOR ® (polyethoxylated castor oil).
- the liquid carrier of the suspension can comprise water and optionally one or more excipients selected from the group consisting of buffer, tonicity adjusting agent, preservative, demulcent, viscosity modifier, osmotic agent, surfactant, antioxidant, alkalinizing agent, acidifying agent, antifbaming agent, and colorant.
- the suspension can comprise taxane particles, water, buffer and salt. It optionally further comprises a surfactant.
- the suspension consists essentially of or consists of water, taxane particles suspended in the water and buffer.
- the suspension can further contain an osmotic salt.
- the suspension can comprise one or more surfactants.
- Suitable surfactants include by way of example and without limitation polysorbates, lauryl sulfates, acetylated
- the suspension can comprise one or more tonicity adjusting agents.
- Suitable tonicity adjusting agents include by way of example and without limitation, one or more inorganic salts, electrolytes, sodium chloride, potassium chloride, sodium phosphate, potassium phosphate, sodium, potassium sulfates, sodium and potassium bicarbonates and alkaline earth metal salts, such as alkaline earth metal inorganic salts, e.g., calcium salts, and magnesium salts, mannitol, dextrose, glycerin, propylene glycol, and mixtures thereof.
- the suspension may be formulated to be hyperosmolar (hypertonic), hyposmolar (hypotonic) or isosmolar (isotonic) with respect to the fluid(s) of the IP cavity.
- the suspension may be isotonic with respect to fluid in the IP cavity.
- the he osmolality of the suspension can range from about 200 to about 380, about 240 to about 340, about 280 to about 300 or about 290 mOsm/kg.
- the suspension can comprise one or more buffering agents.
- buffering agents include by way of example and without limitation, dibasic sodium phosphate, monobasic sodium phosphate, citric acid, sodium citrate hydrochloric acid, sodium hydroxide, tris(hydroxymethyl)aminomethane, bis(2-hydroxyethyl)iminotris-(hydrox>'methyl)methane, and sodium hydrogen carbonate and others known to those of ordinary skill in the art.
- Buffers are commonly used to adjust the pH to a desirable range for intraperitoneal use. Usually a pH of around 5 to 9, 5 to 8, 6 to 7.4, 6.5 to 7.5, or 6.9 to 7.4 is desired.
- the suspension can comprise one or more demulcents.
- a demulcent is an agent that forms a soothing film over a mucous membrane, such as the membranes lining the peritoneum and organs therein.
- a demulcent may relieve minor pain and inflammation and is sometimes referred to as a mucoprotective agent.
- Suitable demulcents include cellulose derivatives ranging from about 0.2 to about 2.5 % such as carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl methylcellulose, and methylcellulose; gelatin at about 0.01%; polyols in about 0.05 to about 1%, also including about 0.05 to about 1%, such as glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate 80, and propylene glycol; polyvinyl alcohol from about 0.1 to about 4 %; povidone from about 0.1 to about 2%; and dextran 70 from about 0.1% when used with another polymeric demulcent described herein.
- cellulose derivatives ranging from about 0.2 to about 2.5 % such as carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl methylcellulose, and methylcellulose; gelatin at about 0.01%; polyols in about 0.05 to about 1%, also including about 0.05 to about 1%, such as glycerin, polyethylene
- the suspension can comprise one or more alkalinizing agents to adjust the pH.
- alkalizing agent is intended to mean a compound used to provide an alkaline medium.
- Such compounds include, by way of example and without limitation, ammonia solution, ammonium carbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate, and sodium hydroxide and others known to those of ordinary skill in the art
- the suspension can comprise one or more acidifying agents to adjust the pH.
- acidifying agent is intended to mean a compound used to provide an acidic medium. Such compounds include, by way of example and without limitation, acetic acid, amino acid, citric acid, nitric acid, fumaric acid and other alpha hydroxy acids, hydrochloric acid, ascorbic acid, and nitric acid and others known to those of ordinary skill in the art.
- the suspension can comprise one or more antifbaming agents.
- antifbaming agent is intended to mean a compound or compounds that prevents or reduces the amount of foaming that forms on the surface of the fill composition. Suitable antifoaming agents include by way of example and without limitation, dimethicone, SIMETHICONE®, octoxynol and others known to those of ordinary skill in the art.
- the suspension can comprise one or more viscosity modifiers that increase or decrease the viscosity of the suspension.
- Suitable viscosity modifiers include
- the suspension can comprise one or more osmotic agents such as those used for peritoneal dialysis.
- Suitable osmotic agents include icodextrin (a glucose polymer), sodium chloride, potassium chloride, and salts that are also used as buffering agents.
- salts of the taxanes are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the taxanes.
- salts refers to the relatively non-toxic, inorganic and organic acid addition salts of taxanes.
- Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like.
- alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and the like
- non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammomum, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
- the composition comprises a dosage form of taxane in suspension (i.e.: with a pharmaceutically acceptable carrier and any other components), in a dosage deemed suitable by an attending physician for an intended use.
- a dosage form of taxane in suspension i.e.: with a pharmaceutically acceptable carrier and any other components
- Any suitable dosage form may be used; in various non-limiting embodiments, the dosage form is adequate to provide about 0.01 mg/kg to about 50 mg/kg of body weight per day.
- the dosage form is adequate to provide about 0.01 mg/kg to about 45 mg/kg, about 0.01 mg/kg to about 40 mg/kg, about 0.01 mg/kg to about 35 mg/kg, about 0.01 mg/kg to about 30 mg/kg, about 0.01 mg/kg to about 25 mg/kg, about 0.01 mg/kg to about 20 mg/kg, about 0.01 mg/kg to about 15 mg/kg, about 0.01 mg/kg to about 10 mg/kg, about 0.01 mg/kg to about 5 mg/kg, or about 0.01 mg/kg to about 1 mg/kg of body weight per day.
- the suspension can be administered as is or can be diluted with a diluent, e.g.
- volume ratio of suspension to diluent might be in the range of 1 : 1 - 1 : 100 (v/v) or other suitable ratio.
- the invention provides methods for treating a tumor, comprising administering to a subject with a tumor an amount effective to treat the tumor of the composition or suspension of any embodiment or combination of embodiments of the invention.
- the inventors have unexpectedly been able to produce compositions comprising the recited taxane particles that have a mean bulk density between about 0.050 g/cm 3 and about 0.15 g/cm 3 , and/or a specific surface area (SSA) of at least 18 m 2 /g an SSA using novel methods for producing the particles as described herein.
- SSA specific surface area
- Each of the increased specific surface area and the decreased bulk density result in the significant increase in dissolution rate for the taxane particles of the invention compared to the unprocessed or raw material, and the milled taxane product used for comparison. This provides a significant improvement for use of the taxane particles of the invention in, for example, tumor treatment.
- tumor includes benign tumors, pre-malignant tumors, malignant tumors that have not metastasized, and malignant tumors that have metastasized.
- the methods of the invention can be used to treat tumor that is susceptible to taxane treatment, including but not limited to breast tumors, ovarian tumors, lung tumors, bladder tumors, prostate tumors, bone tumors, stomach tumors and pancreatic tumors.
- the tumor is located in whole or in part in the intraperitoneal cavity.
- the subject may be any suitable subject with a tumor, including but not limited to humans, primates, dogs, cats, horses, cattle, etc.
- treat or “treating” means accomplishing one or more of the following: (a) reducing the severity of the disorder; (b) limiting or preventing development of symptoms characteristic of the disorder(s) being treated; (c) inhibiting worsening of symptoms characteristic of the disorders) being treated; (d) limiting or preventing recurrence of the disorders) in patients that have previously had the disorders); and (e) limiting or preventing recurrence of symptoms in patients that were previously symptomatic for the disorder(s).
- an amount effective for these uses depends on factors including, but not limited to, the nature of the taxane (specific activity, etc.), the route of administration, the stage and severity of the disorder, the weight and general state of health of the subject, and the judgment of the prescribing physician. It will be understood that the amount of the composition of suspension of the invention actually administered will be determined by a physician, in the light of the above relevant circumstances. In one non-limiting embodiment, an amount effective is an amount that provides between 0.01 mg/kg to about 50 mg/kg of body weight per day.
- compositions may be administered via any suitable route, including but not limited to orally, pulmonary, intraperitoneally, subcutaneous injection, intramuscular injection, or any other form of injection, as deemed most appropriate by attending medical personnel in light of all factors for a given subject.
- the composition or suspension is administered intraperitoneally, for example, when the tumor is located (at least in part) in the peritoneal cavity.
- the composition or suspension may be administered, for example, by perfusion or as a bolus into the peritoneal cavity.
- the administering may be initiated after removal of ascites fluid from the peritoneal cavity.
- a dosing period is that period of time during which a dose of taxane particles in the composition or suspension is administered.
- the dosing period can be a single period of time during which the entire dose is administered, or it can be divided into two or more periods of time during each of which a portion of the dose is administered.
- a post-dosing period is that period of time beginning after completion of a prior dosing period and ending after initiating a subsequent dosing period.
- the duration of the post-dosing period may vary according to a subject's clinical response to the paclitaxel.
- the suspension is not administered during the post-dosing period.
- a post-dosing period can last at least 7 days, at least 14 days, at least 21 days, at least 28 days, at least 35 days, at least 60 days or at least 90 days or longer.
- the post-dosing period can be kept constant for a subject or two or more different post-dosing periods can be used for a subject.
- a dosing cycle includes a dosing period and a post-dosing period. Accordingly, the duration of a dosing cycle will be the sum of the dosing period and the post-dosing period.
- the dosing cycle can be kept constant for a subject or two or more different dosing cycles can be used for a subject.
- the administering is carried out more than once, and wherein each administration is separated in time by at least 21 days.
- the invention provides methods for making compound particles, comprising:
- steps (a), (b), and (c) are carried out under supercritical temperature and pressure for the compressed fluid.
- the methods of the invention involve contacting a solution, including a solvent with at least one compound of interest (including but not limited to an active pharmaceutical ingredient, such as ataxane) dispersed in the solvent, with a compressed fluid at supercritical conditions for the compressed fluid, so as to cause the compressed fluid to deplete the solvent and precipitate the compound away as extremely small particles.
- a solution including a solvent with at least one compound of interest (including but not limited to an active pharmaceutical ingredient, such as ataxane) dispersed in the solvent, with a compressed fluid at supercritical conditions for the compressed fluid, so as to cause the compressed fluid to deplete the solvent and precipitate the compound away as extremely small particles.
- the methods of the present invention provide a significant improvement over methods such as those disclosed in US Patent Nos. 5,833,891; 5,874,029; 6,113,795; and 8,778,181 (incorporated herein by reference in their entirety) using a compressed fluid in combination with appropriate solvents to reproducibly precipitate compounds as fine particles that have a narrow size distribution.
- the methods of the present invention are capable of producing the particles of the invention with significantly improved bulk density, SSA, and dissolution properties, and thus significantly improved therapeutic benefits.
- the methods provide this significant improvement, at least in part, through use of the sonic energy source external to the nozzle and at the recited distance from the nozzle orifice to provide significantly enhanced sonic energy and enhanced disruption of the solvent-solute flow as it exits the nozzle compared to the methods disclosed U.S. Patent Nos. 5,833,891 and 5,874,029 that use a converging-diverging nozzle to create the sonic energy.
- the methods further comprise:
- step (d) contacting the atomized droplets produced in step (c) with an anti-solvent to cause further depletion of the solvent from the compound particles, wherein step (d) is carried out under supercritical temperature and pressure for the anti-solvent.
- the methods of the invention utilize a sonic energy source located directly in the output stream of the solute dissolved in the solvent.
- a sonic energy source located directly in the output stream of the solute dissolved in the solvent.
- Any suitable source of sonic energy may be used that is compatible with the methods of the invention, including but not limited to sonic horn, a sonic probe, or a sonic plate.
- the nozzle orifice is located between about 2 mm and about 20 mm, about 2 mm and about 18 mm, about 2 mm and about 16 mm, about 2 mm and about 14 mm, about 2 mm and about 12 mm, about 2 mm and about 10 mm, about 2 mm and about 8 mm, about 2 mm and about 6 mm, about 2 mm and about 4 mm, about 4 mm and about 20 mm, about 4 mm and about 18 mm, about 4 mm and about 16 mm, about 4 mm and about 14 mm, about 4 mm and about 12 mm, about 4 mm and about 10 mm, about 4 mm and about 8 mm, about 4 mm and about 6 mm, about 6 mm and about 20 mm, about 6 mm and about 18 mm, about 6 mm and about 16 mm, about 6 mm and about 14 mm, about 6 mm and about 12 mm, about 6 mm and about 10 mm, about 6 mm and about 8 mm, about 4 mm and
- the nozzle assembly 100 includes a vessel 102 defining a pressurizable chamber 104.
- the vessel 102 includes a distal end 106 and a proximal end 108.
- the nozzle assembly 100 further includes an inlet 110 of the pressurizable chamber 104 at the proximal end 108 of the vessel 102.
- the nozzle assembly 100 further includes a nozzle 112 positioned within the pressurizable chamber 104.
- the nozzle 112 includes an inlet tube 114 in fluid communication with the inlet 110 of the pressurizable chamber 104.
- the nozzle 112 includes an outlet aperture 116.
- the nozzle 112 is adjustable to alter a distance 118 between the proximal end 108 of the vessel 102 and the outlet aperture 116 of the nozzle 112. As shown in Figure 3, the nozzle 112 is further adjustable to alter an angle 120 between a longitudinal axis of the vessel 122 and a longitudinal axis of the nozzle 124.
- the nozzle assembly 100 includes an outlet 126 of the pressurizable chamber 104 at the distal end 106 of the vessel 102.
- the nozzle assembly 100 may further include a first reservoir 128 and a second reservoir 130.
- the first reservoir 128 may include a supply of solvent, while the second reservoir 130 may include a supply of anti-solvent.
- the inlet 110 of the pressurizable chamber 104 may be in fluid communication with the first reservoir 128, and a second inlet 132 of the pressurizable chamber 104 may be in fluid communication with the second reservoir 130.
- the first reservoir 128 is in fluid communication with the inlet tube 114 of the nozzle 112, such that the solvent enters the pressurizable chamber 104 through the nozzle 112.
- Other examples are possible as well.
- the outlet aperture 116 of the nozzle 112 may include a plurality of ridges to create a vortex within the nozzle 112 such that the solvent exits the nozzle 112 via turbulent flow.
- the nozzle 112 may include a porous frit interior to the nozzle 112 such that the solvent exits the nozzle 112 via turbulent flow.
- the outlet aperture 116 of the nozzle 112 may have a small diameter (as discussed in additional detail below) such that the solvent exits the nozzle 112 via turbulent flow. These various embodiments that cause turbulent flow may assist in mixing the solvent with the anti-solvent within the pressurizable chamber 104.
- the inlet tube 114 of the nozzle 112 may have an inner diameter with a range from about 1.5875 mm to about 6.35 mm.
- both the angle of the nozzle 112 and the vertical position of the nozzle 112 may be adjusted manually by a user.
- the nozzle 112 may be positioned on a vertical support that can be adj usted to alter the distance 118 between the proximal end 108 of the vessel 102 and the outlet aperture 116 of the nozzle 112. Further, the nozzle 112 may be rotated manually to adjust the angle 120 between the longitudinal axis of the vessel 122 and the longitudinal axis of the nozzle 124.
- the nozzle assembly 100 may include a motor coupled to the nozzle 112.
- the motor may be configured to alter the distance 118 between the proximal end 108 of the vessel 102 and the outlet aperture 116 of the nozzle 112 and/or alter the angle 120 between the longitudinal axis of the vessel 122 and the longitudinal axis of the nozzle 124.
- Such a motor may be an electric motor powered by electrical power, or may be powered by a number of different energy sources, such as a gas-based fuel or solar power.
- the motor may be coupled directly or indirectly to the nozzle 112, such that when the motor is turned on the distance 118 between the proximal end 108 of the vessel 102 and the outlet aperture 116 of the nozzle 112 increases or decreases depending on the direction the motor rotates.
- the motor may be coupled to a series of gears that adjusts the distance 118 between the proximal end 108 of the vessel 102 and the outlet aperture 116 of the nozzle 112 and/or adjusts the angle 120 between the longitudinal axis of the vessel 122 and the longitudinal axis of the nozzle 124, or the motor may be coupled to a pulley system mat adjusts the distance 118 between the proximal end 108 of the vessel 102 and the outlet aperture 116 of the nozzle 112 and/or adjusts the angle 120 between the longitudinal axis of the vessel 122 and the longitudinal axis of the nozzle 124.
- Other configurations are possible as well.
- the nozzle 112 assembly may include an actuator coupled to the nozzle 112, where the actuator alters the distance 118 between the proximal end 108 of the vessel 120 and the outlet aperture 116 of the nozzle 112 and/or alters the angle 120 between the longitudinal axis of the vessel 122 and the longitudinal axis of the nozzle 124.
- an actuator may be an electro-mechanical actuator, including an electric motor that converts a rotary motion of the electric motor to a linear displacement via a linkage system.
- Other potential actuators are possible as well, such as hydraulic actuators, pneumatic actuators, piezoelectric actuators, linear motors, or telescoping linear actuators, as examples.
- the nozzle assembly further includes a sonic energy source 134 positioned adjacent to the outlet aperture 116 of the nozzle 112.
- the sonic energy source 134 may include a sonic probe extending within the pressurizable chamber 104.
- the sonic energy source 134 may include a sonic surface positioned in the pressurizable chamber 104. The sonic waves from the sonic energy source 134 cause the liquids in the pressurizable chamber 104 to shatter, thereby enhancing mixing of the solvent and anti-solvent solutions to create particles within the pressurizable chamber 104.
- the sonic energy source 134 is positioned at an angle of 45 degrees with respect to the longitudinal axis of the nozzle 124. Other angles are possible as well. In one example, the sonic energy source 134 may be adjustable to alter a distance between the outlet aperture 116 of the nozzle 112 and the sonic energy source 134. Further, the sonic energy source 134 may be adjustable to alter an angle between the sonic energy source 134 and the longitudinal axis of the nozzle 124.
- any suitable source of sonic energy may be used that is compatible with the methods of the invention, including but not limited to sonic horn, a sonic probe, or a sonic plate.
- the sonic energy source produces sonic energy with an amplitude between about 1% and about 100% of the total power that can be generated using the sonic energy source.
- the sonic energy source has a total power output of between about 500 and about 900 watts; in various further embodiments, between about 600 and about 800 watts, about 650-750 watts, or about 700 watts.
- the sonic energy source produces sonic energy with a power output between about 5% and about 100%, about 10% and about 100%, 20% and about 100%, about 30% and about 100%, about 40% and about 100%, about 50% and about 100%, about 60% and about 100%, about 70% and about 100%, about 80% and about 100%, about 90% and about 100%, about 1% and about 90%, about 5% and about 90%, about 10% and about 90%, about 20% and about 90%, about 30% and about 90%, about 40% and about 90%, about 50% and about 90%, about 60% and about 90%, about 70% and about 90%, about 80% and about 90%, about 1% and about 80%, about 5% and about 80%, about 10% and about 80%, about 20% and about 80%, about 30% and about 80%, about 40% and about 80%, about 50% and about 80%, about 60% and about 80%, about 70% and about 80%, about 1% and about 70%, about 5% and about 70%, about 10% and about 70%, about 20% and about 70%, about 30% and about 70%, about 40% and about 70%, about 50% and about 80%, about 60% and
- the sonic energy source produces sonic energy with power output of about l%-80%, 20-80%, 30-70%, 40-60%, or about 60% of the total power that can be generated using the sonic energy source.
- a frequency of between about 18 and about 22 kHz on the sonic energy source is utilized.
- a frequency of between about 19 and about 21 kHz, about 19.5 and about 20.5, or , a frequency of about 20 kHz on the sonic energy source is utilized.
- the nozzle orifice has a diameter of between about 20 um and about 125 um, about 20 um and about 115 um, about 20 um and about 100 um, about 20 um and about 90 um, about 20 um and about 80 um, about 20 um and about 70 um, about 20 um and about 60 um, about 20 um and about 50 um, about 20 um and about 40 um, about 20 um and about 30 um, between about 30 um and about 125 um, about 30 um and about 115 um, about 30 um and about 100 um, about 30 um and about 90 um, about 30 um and about 80 um, about 30 um and about 70 um, about 30 um and about 60 um, about 30 um and about 50 um, about 30 um and about 40 um, between about 40 um and about 125 um, about 40 um and about 115 um, about 40 um and about 100 um, about 40 um and about 90 um, about 40 um and about 80 um, about 40 um and about 70 um, about 40 um and about 60 um, about 40 um and about 50 um, between about 50 um and about 125 um, about 50 um and about 115 um
- the nozzle is inert to both the solvent and the compressed fluid used in the methods.
- the system may include a plurality of nozzles, with each nozzle positioned at a different angle between a longitudinal axis of the vessel and a longitudinal axis of the nozzle and/or a different distance between the nozzle orifice and the sonic energy source.
- a given nozzle of the plurality of nozzles may be chosen for a given production run to produce a certain type of particle having a given SSA.
- the solute/compound comprises a taxane, including those discussed herein.
- the solvent may comprise acetone, ethanol, methanol,
- the solute/compound is paclitaxel and the solvent is acetone.
- the solute/compound is docetaxel and the solvent is ethanol.
- the solvents should comprise at least about 80%, 85%, or 90% by weight of the overall solution.
- the compressed fluid is capable of forming a supercritical fluid under the conditions used, and the solute that forms the particles is poorly soluble or insoluble in the compressed fluid.
- a supercritical fluid is any substance at a temperature and pressure above its critical point, where distinct liquid and gas phases do not exist. Steps (a), (b), and (c) of the methods of the invention are carried out under supercritical temperature and pressure for the compressed fluid, such that the compressed fluid is present as a supercritical fluid during these processing steps.
- the compressed fluid can serve as a solvent for and can be used to remove unwanted components in the particles.
- Any suitable compressed fluid may be used in the methods of the invention; exemplary such compressed fluids are disclosed in U.S. Patent Nos. 5833891 and 5874029.
- suitable supercritical fluid-forming compressed fluids and/or anti-solvents can comprise carbon dioxide, ethane, propane, butane, isobutane, nitrous oxide, xenon, sulfur hexafluoride and trifluoromethane.
- the anti-solvent recited in step (d) to cause further solvent depletion is a compressed fluid as defined above, and may be the same compressed fluid used in steps (a-c), or may be different.
- the anti-solvent used in step (d) is the same as the compressed fluid used in steps (a-c).
- the compressed fluid and the anti-solvent are both super-critical carbon dioxide.
- the compressed fluid and anti-solvent should be substantially miscible with the solvent while the compound to be precipitated should be substantially insoluble in the compressed fluid, i.e., the compound, at the selected solvent/compressed fluid contacting conditions, should be no more than about 5% by weight soluble in the compressed fluid or anti-solvent, and preferably is essentially completely insoluble.
- the supercritical conditions used in the methods of the invention are typically in the range of from IX to about 1.4X, or IX to about 1.2X of the critical temperature of the supercritical fluid, and from IX to about 7X, or IX to about 2X, of the of the supercritical pressure for the compressed fluid.
- the critical temperature and pressure are both super critical carbon dioxide, and the critical temperature is at least 31.1 °C and up to about 60°C, and the critical pressure is at least 1071 psi and up to about 1800 psi.
- the compressed fluid and anti-solvent are both super critical carbon dioxide, and the critical temperature is at least 35°C and up to about S5°C, and the critical pressure is at least 1070 psi and up to about 1500 psi. It will be understood by those of skill in the art that the specific critical temperature and pressure may be different at different steps during the processing.
- any suitable pressurizable chamber may be used, including but not limited to those disclosed in U.S. Patent Nos. 5,833,891 and 5,874,029.
- the steps of contacting the atomized droplets with the compressed fluid to cause depletion of the solvent from the droplets; and contacting the droplets with an anti-solvent to cause further depletion of the solvent from the droplets, to produce particles of the compound can be carried out under any suitable conditions, including but not limited to those disclosed in U.S. Patent Nos. 5,833,891 and 5,874,029.
- the flow rate can be adjusted as high as possible to optimize output but below the pressure limitations for the equipment, including the nozzle orifice.
- the flow rate of the solution through the nozzle has a range from about 0.5 mL/min to about 30 mlJmin.
- the flow rate is between about 0.5 mL/min to about 25 mL/min, 0.5 mL/min to about 20 mL/min, 0.5 mL/min to about 15 mL/min, 0.5 mL/min to about 10 mL/min, 0.5 mL/min to about 4 mL/min, about 1 mL/min to about 30 mL/min, about 1 mL/min to about 25 mL/min, about 1 mL/min to about 20 mL/min, 1 mL/min to about 15 mL/min, about 1 mL/min to about 10 mL/min, about 2 mL/min to about 30 mL/min, about 2 mL/min to about 25 mL/min, about 2 mL/min to about 20 mL/min, about 2 mL/min to about 15 mL/min, or about 2 mL/min to about 10 mL/min.
- the solution of drug subject to the flow rate can be any suitable concentration, such as between about 1 mg/ml and about 80 mg/ml.
- the methods further comprise receiving the plurality of particles through the outlet of the pressurizable chamber; and collecting the plurality of particles in a collection device.
- the invention comprises a collection device 200 including a vessel 202 defining a chamber 204.
- the vessel 202 includes a distal end 206 and a proximal end 208.
- the outer diameter of the vessel 202 may range from about 152.4 mm to about 914.4 mm.
- the collection device 200 further includes an inlet port 210 extending from the proximal end 208 of the vessel 202.
- the inlet port 210 is in fluid communication with the chamber 204.
- the inlet port 210 may have an outer diameter ranging from about 12.7 mm to about 101.6 mm.
- the collection device 200 includes an outlet port 212 extending from the proximal end 208 of the vessel 202.
- the outlet port 212 is in fluid communication with the chamber 204, and the outlet port 212 includes a porous material 214 positioned between the chamber 204 and the outlet port 212.
- the outer diameter of the outlet port may range from about 12.7 mm to about 50.8 mm.
- the collection device 200 may further include a sampling tube 216 having a distal end 218 and a proximal end 220.
- the outer diameter of the sampling tube 216 may range from about 6.35 mm to about 25.4 mm.
- the proximal end 220 of the sampling tube 216 extends from the proximal end 208 of the vessel 202, and the distal end 218 of the sampling tube 216 extends into the chamber 204.
- the sampling tube 216 may be configured to remove a small sample of particles from the chamber 204 during a particle production run in which additional particles are being formed.
- the sampling tube 216 may include a sample thief that enables an operator to remove a small sample of particles without opening the chamber 204 or removing the sampling tube 216 from the rest of the collection device 200 during processing. This enables an operator to test a small sample of particles to ensure that the product is within
- the operating parameters of the particle formation process may be suitably adjusted to correct the situation before an entire batch of product with undesirable characteristics is created.
- the porous material 214 positioned between the chamber 204 and the outlet port 212 may take a variety of forms.
- the porous material 214 is selected from the group consisting of a frit, a mesh, a cloth.
- the porous material 214 may comprise a high-efficiency particulate arre stance (HEPA) filter.
- HEPA high-efficiency particulate arre stance
- An example HEP A filter may include a mat of randomly arranged fibers, the fibers composed of fiberglass and possessing diameters between about 0.S micrometers and about 2.0 micrometers.
- the porous material 214 comprises a sintered filter having a distal end 222 and a proximal end 224.
- the proximal end 224 of the sintered filter extends from the proximal end 208 of the vessel 202 and is coupled to the outlet port 212, and the distal end 222 of the sintered filter extends into the chamber 204.
- a sintered filter may include a porous stainless steel filter cartridge, as an example. Other porous materials are possible as well.
- the inlet port 210 may include a coupling mechanism connects an outlet of a particle filtration system to the inlet pott 210.
- the coupling mechanism comprises one or more sanitary fittings.
- the coupling mechanism comprises a threaded connection between the outlet of the particle filtration system to the inlet port 210.
- the coupling mechanism comprises one or more compression fittings. Other example coupling mechanisms are possible as well.
- the collection device 200 may further include a collection insert 226 positioned within the chamber 204 of the vessel 202, and a support frame 228 positioned between an interior wall 230 of the chamber 204 and the collection insert 226.
- the collection insert 226 may be a plastic bag, as an example.
- the support frame 228 may include a distal ring 232, a proximal ring 234, one or more support legs 236 connecting the distal ring 232 to the proximal ring 234, and a gasket 238 positioned adjacent to the proximal ring 234.
- the gasket 238 may comprise a neoprene gasket.
- the vessel 202 may include a removable lid 240 that can be removed to access the collection insert 226 once particle collection is completed.
- the collection insert 226 may be positioned within the chamber 204 of the vessel 202 such that top edge of the collection insert 226 folds over the top of the support frame 228 and is sealed between the gasket 238 and the removable lid 240 when the lid is in the closed position.
- Other arrangements are possible as well.
- a solution of 65 mg/ml of paclitaxel is prepared in acetone.
- the nozzle and a sonic probe are positioned in the pressurizable chamber approximately 8mm apart.
- a stainless steel mesh filter with approximately 100 nm holes is attached to the pressurizable chamber to collect the precipitated paclitaxel nanoparticles.
- the supercritical carbon dioxide is placed in the pressurizable chamber of the manufacturing equipment and brought to approximately 1200 psi at about 37°C and a flow rate of 18kg per hour.
- the sonic probe is adjusted to an amplitude of 60% of maximum output at a frequency of 20 kHz.
- the acetone solution containing the paclitaxel is pumped through the nozzle at a flow rate of 2mL/minute for approximately 60 minutes.
- the precipitated paclitaxel agglomerates and particles are then collected from the supercritical carbon dioxide as the mixture is pumped through the stainless steel mesh filter.
- the filter containing the nanoparticles of paclitaxel is opened and the resulting product is collected from the filter.
- a solution of 79.32 mg /ml of docetaxel is prepared in ethanol.
- the nozzle and a sonic probe are positioned in the pressurizable chamber approximately 9mm apart.
- a stainless steel mesh filter with approximately 100 nm holes is attached to the pressurizable chamber to collect the precipitated docetaxel nanoparticles.
- the supercritical carbon dioxide is placed in the pressurizable chamber of the manufacturing equipment and brought to approximately 1200 psi at about 38°C and a flow rate of 63 slpm (standard liters per minute).
- the sonic probe is adjusted to 60% of total output power at a frequency of 20 kHz.
- the ethanol solution containing the docetaxel is pumped through the nozzle at a flow rate of 2 mlVminute for approximately 95 minutes, until the drug solution is consumed.
- the precipitated docetaxel agglomerates and particles are then collected from the supercritical carbon dioxide as the mixture is pumped through the stainless steel mesh filter.
- the filter containing the nanoparticles of docetaxel is opened and the resulting product is collected from the filter.
- the system described above may be a component of a larger particle production system.
- a particle production system may include one or more nozzle assemblies such as those described above, a sonic energy source positioned adjacent to the orifice of each nozzle, one or more particle filtration systems in communication with one or more nozzle assemblies, and one or more particle collection devices in communication with the one or more particle filtration systems.
- the one or more particle filtration systems comprise a tandem particle filtration system including at least one high pressure harvesting filter system and at least one low pressure collection filter system in tandem and downstream to the harvesting filter.
- the particle production system may include at least two particle harvesting filters, two particle collection filters and two collection devices.
- the invention provides compound particles prepared by the method of any embodiment or combination of embodiments of the invention.
- Raw paclitaxel and docctaxel were purchased from Phyton Biotech (British).
- a solution of 65 mg/ml of paclitaxel was prepared in acetone.
- a BETE MicroWhirl ® fog nozzle (BETE Fog Nozzle, Inc )and a sonic probe (Qsonica, model number Q700) were positioned in the crystallization chamber approximately 8 mm apart.
- a stainless steel mesh filter with approximately 100 nm holes was attached to the crystallization chamber to collect the precipitated paclitaxel nanoparticles.
- the supercritical carbon dioxide was placed in the crystallization chamber of the manufacturing equipment and brought to approximately 1200 psi at about 38 °C and a flow rate of 24 kg/hour.
- the sonic probe was adjusted to 60% of total output power at a frequency of 20 kHz.
- Paclitaxel nanoparticles produced had an average number-weighted mean size of 0.81 um with an average standard deviation of 0.74 um over three separate runs.
- a solution of 79.32 mg/ml of docetaxel was prepared in ethanol.
- the nozzle and a sonic probe were positioned in the pressurizable chamber approximately 9 mm (apart.
- a stainless steel mesh filter with approximately 100 nm holes was attached to the pressurizable chamber to collect the precipitated docetaxel nanoparticles.
- the supercritical carbon dioxide was placed in the pressurizable chamber of the manufacturing equipment and brought to approximately 1200 psi at about 38 °C and a flow rate of 68 slpm.
- the sonic probe was adjusted to 60% of total output power at a frequency of 20 kHz.
- the ethanol solution containing the docetaxel was pumped through the nozzle at a flow rate of 2 mlJminute for approximately 95 minutes).
- the precipitated docetaxel agglomerates and particles were then collected from the supercritical carbon dioxide as the mixture is pumped through the stainless steel mesh filter.
- the filter containing the nanoparticles of docetaxel
- Docetaxel nanoparticles produced had an average number-weighted mean size of 0.82 um with an average standard deviation of 0.66 um over three separate ethanol runs.
- Particle size was analyzed by both light obscuration and laser diffraction methods.
- An Particle Sizing Systems AccuSizer 780 SIS system was used for the light obscuration method and Shimadzu SALD-7101 was used for the laser diffraction method.
- Paclitaxel nanoparticles were analyzed using 0.10% (w/v) sodium dodecyl sulfate (SDS) in water as the dispersant.
- Docetaxel nanoparticles were analyzed using isopar G as the dispersant.
- Paclitaxel suspensions were prepared by adding approximately 7 mL of filtered dispersant to a glass vial containing approximately 4 mg of paclitaxel particles. The vials were vortexed for approximately 10 seconds and then sonicated in a sonic bath approximately 1 minute. If the sample was already suspended, 1 : 1 solution of paclitaxel suspension to 0.1 % SDS solution was made, vortexed for 10 seconds, and sonicated in the sonic bath for 1 minute.
- Docetaxel suspensions were prepared by adding approximately 7 mL of filtered dispersant to a plastic vial containing approximately 4 mg of docetaxel particles. The vial was vortexed for approximately 10 seconds and then sonicated in a sonic bath for approximately 2 minutes. This suspension was used for laser diffraction analysis. Unused suspension was poured into a 125mL particle-free plastic bottle, which was then filled to approximately 100 mL with filtered dispersant. The suspension was vortex for
- a background test was first performed prior to analyzing particles on the AccuSizer 780 SIS,.
- a new particle-free plastic bottle was filled with blank suspension solution by pumping from a reservoir, using a peristaltic pump, through a 0.22 um Millipore filter and into the bottle.
- a background analysis was run to ensure the particle/mL count was below 100 particles/mL.
- a known mass between 200 and 300 mg of the analyte was added to a 30 mL sample tube.
- the loaded tube was then mounted to a Porous Materials Inc. SORPTOMETER ® , model BET-202A.
- SORPTOMETER ® a Porous Materials Inc.
- the automated test was then carried out using the BETWIN ® software package and the surface area of each sample was subsequently calculated.
- Paclitaxel or docetaxel particle preparations were added to a 10 mL tared graduated cylinder through a plastic weigh funnel at room temperature. The mass of the drug was measured to a nearest 0.1 mg, the volume was determined to the nearest 0.1 mL and the density calculated.
- the BET surface area of particles produced using the above protocol and variations thereof ranged between 22 and 39 m 2 /g.
- Figure 1 shows exemplary particles produced using the methods of the invention.
- the BET surface area of raw paclitaxel was measured at 7.25 m 2 /g( Figure 2), while paclitaxel particles made according to the methods of US patents 5833891 and 5874029 ranged from 11.3 to 15.58 m 2 /g .
- Exemplary particle sizes produced using the methods of the invention are shown in Table 1. Table 1
Abstract
Description
Claims
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP16732387.2A EP3302431B1 (en) | 2015-06-04 | 2016-06-06 | Taxane particles and their use |
CN201680032549.6A CN107683131B (en) | 2015-06-04 | 2016-06-06 | Taxane particles and uses thereof |
KR1020207004878A KR102317107B1 (en) | 2015-06-04 | 2016-06-06 | Taxane Particles and Their Use |
JP2017560744A JP6758325B2 (en) | 2015-06-04 | 2016-06-06 | Taxane particles and their use |
ES16732387T ES2833749T3 (en) | 2015-06-04 | 2016-06-06 | Taxane particles and their use |
KR1020207033764A KR20200134347A (en) | 2015-06-04 | 2016-06-06 | Taxane particles and their use |
KR1020177033970A KR102337080B1 (en) | 2015-06-04 | 2016-06-06 | Taxane particles and uses thereof |
AU2016270549A AU2016270549B2 (en) | 2015-06-04 | 2016-06-06 | Taxane particles and their use |
RU2017140678A RU2750163C2 (en) | 2015-06-04 | 2016-06-06 | Taxan particles and their application |
CA2988132A CA2988132C (en) | 2015-06-04 | 2016-06-06 | Taxane particles and their use |
BR112017025815-3A BR112017025815B1 (en) | 2015-06-04 | 2016-06-06 | TAXANE PARTICLES, COMPOSITIONS COMPRISING TAXANE PARTICLES, USE OF THE COMPOSITION COMPRISING TAXANE PARTICLES AND METHODS OF MANUFACTURING THE TAXANE PARTICLES |
DK16732387.2T DK3302431T3 (en) | 2015-06-04 | 2016-06-06 | TAXAN PARTICLES AND THEIR USE |
EP20206804.5A EP3838264A1 (en) | 2015-06-04 | 2016-06-06 | Taxane particles and their use |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562171060P | 2015-06-04 | 2015-06-04 | |
US201562171001P | 2015-06-04 | 2015-06-04 | |
US201562171008P | 2015-06-04 | 2015-06-04 | |
US62/171,060 | 2015-06-04 | ||
US62/171,001 | 2015-06-04 | ||
US62/171,008 | 2015-06-04 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2016197091A1 true WO2016197091A1 (en) | 2016-12-08 |
Family
ID=56194575
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2016/036013 WO2016197101A1 (en) | 2015-06-04 | 2016-06-06 | Collection device and methods for use |
PCT/US2016/036012 WO2016197100A1 (en) | 2015-06-04 | 2016-06-06 | Nozzle assembly and methods for use |
PCT/US2016/035993 WO2016197091A1 (en) | 2015-06-04 | 2016-06-06 | Taxane particles and their use |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2016/036013 WO2016197101A1 (en) | 2015-06-04 | 2016-06-06 | Collection device and methods for use |
PCT/US2016/036012 WO2016197100A1 (en) | 2015-06-04 | 2016-06-06 | Nozzle assembly and methods for use |
Country Status (14)
Country | Link |
---|---|
US (11) | US9814685B2 (en) |
EP (4) | EP3302423B1 (en) |
JP (5) | JP6921759B2 (en) |
KR (5) | KR102077518B1 (en) |
CN (4) | CN107743418A (en) |
AU (3) | AU2016270558B2 (en) |
CA (3) | CA3026452C (en) |
DK (1) | DK3302431T3 (en) |
ES (1) | ES2833749T3 (en) |
HK (3) | HK1253020A1 (en) |
PT (1) | PT3302431T (en) |
RU (1) | RU2750163C2 (en) |
SG (2) | SG10201913947RA (en) |
WO (3) | WO2016197101A1 (en) |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018170207A1 (en) | 2017-03-15 | 2018-09-20 | Dfb Soria, Llc | Topical therapy for the treatment of skin keratoses using nanoparticles of taxanes |
WO2018170210A1 (en) | 2017-03-15 | 2018-09-20 | Dfb Soria, Llc | Topical therapy for the treatment of vulvar intraepithelial neoplasia (vin) and genital warts using nanoparticles of taxanes |
WO2018170196A1 (en) | 2017-03-15 | 2018-09-20 | Dfb Soria, Llc | Topical therapy for the treatment of skin malignancies using nanoparticles of taxanes |
WO2018227037A1 (en) | 2017-06-09 | 2018-12-13 | Crititech, Inc. | Treatment of epithelial cysts by intracystic injection of antineoplastic particles |
WO2018231908A1 (en) | 2017-06-14 | 2018-12-20 | Crititech, Inc. | Methods for treating lung disorders |
WO2019067851A1 (en) | 2017-09-29 | 2019-04-04 | Crititech, Inc. | Ciprofloxacin polymorph and its use |
WO2019070850A1 (en) | 2017-10-03 | 2019-04-11 | Crititech, Inc. | Local delivery of antineoplastic particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer |
WO2019136188A1 (en) | 2018-01-05 | 2019-07-11 | Crititech, Inc. | Treatment of bladder cancer by intratumoral injection of taxane particles |
US10449162B2 (en) | 2015-09-16 | 2019-10-22 | Dfb Soria Llc | Delivery of drug nanoparticles and methods of use thereof |
WO2019231499A1 (en) | 2018-05-31 | 2019-12-05 | Crititech, Inc. | Use of antineoplastic agents to stimulate the immune system for treatment of cancer |
WO2019231567A1 (en) | 2018-05-31 | 2019-12-05 | Crititech, Inc. | Methods for isolating tumor-specific immune cells from a subject for adoptive cell therapy and cancer vaccines |
WO2019231498A1 (en) | 2018-05-31 | 2019-12-05 | Crititech, Inc. | Treatment of kidney tumors by intratumoral injection of taxane particles |
US10507195B2 (en) | 2015-06-04 | 2019-12-17 | Crititech, Inc. | Taxane particles and their use |
WO2020072090A1 (en) | 2018-10-03 | 2020-04-09 | Crititech, Inc. | Use of antineoplastic agents to stimulate the immune system for production of tertiary lymphoid structures (tls) |
US10874660B2 (en) | 2016-04-04 | 2020-12-29 | CritlTech, Inc. | Methods for solid tumor treatment |
WO2022020455A1 (en) | 2020-07-23 | 2022-01-27 | Crititech, Inc. | Lapatinib particles and uses thereof |
WO2022020449A1 (en) | 2020-07-23 | 2022-01-27 | Crititech, Inc. | Sorafenib particles and uses thereof |
US11497726B2 (en) | 2018-03-16 | 2022-11-15 | Dfb Soria, Ll. | Topical therapy for the treatment of cervical intraepithelial neoplasia (CIN) and cervical cancer using nanoparticles of taxanes |
WO2023086779A1 (en) | 2021-11-10 | 2023-05-19 | Crititech, Inc. | Niraparib particles and uses thereof |
WO2023086784A1 (en) | 2021-11-10 | 2023-05-19 | Crititech, Inc. | Rucaparib particles and uses thereof |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017194145A1 (en) * | 2016-05-12 | 2017-11-16 | Hewlett-Packard Development Company, L.P. | Build material container |
WO2019010316A1 (en) * | 2017-07-07 | 2019-01-10 | Dfb Pharmaceuticals, Llc | Treatment of hyperplastic tissue growths including benign prostatic hyperplasia (bph) by direct injection of an antineoplastic agent |
EP3687500A1 (en) | 2017-09-29 | 2020-08-05 | Crititech, Inc. | Glucocorticoid particles and their use |
CN108970835B (en) * | 2018-09-20 | 2020-11-17 | 马鞍山纽泽科技服务有限公司 | High-temperature-resistant injection device |
US11911499B2 (en) | 2019-11-07 | 2024-02-27 | Resurge Therapeutics, Inc. | System and method for prostate treatment |
EP4099999A4 (en) * | 2020-02-04 | 2023-07-12 | Zhuhai Beihai Biotech Co., Ltd. | Formulations of docetaxel |
CN113447635B (en) * | 2021-05-11 | 2023-09-29 | 江西农业大学 | Potted plant soil greenhouse gas release rate measuring device with different depths |
US11957654B2 (en) | 2022-01-29 | 2024-04-16 | Resurge Therapeutics, Inc. | Treating benign prostatic hyperplasia |
US11602516B1 (en) | 2022-01-29 | 2023-03-14 | Resurge Therapeutics Inc. | Treating benign prostatic hyperplasia |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000072827A2 (en) * | 1999-05-27 | 2000-12-07 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
WO2003032906A2 (en) * | 2001-10-15 | 2003-04-24 | Crititech, Inc. | Delivery of poorly soluble drugs |
US20060078619A1 (en) * | 2002-11-13 | 2006-04-13 | Hanmi Pharm Co., Ltd. | Method for the preparatin of paclitaxel solid dispersion by using the supercritical fluid process and paclitaxel solid dispersion prepared thereby |
US20120237768A1 (en) * | 2007-04-06 | 2012-09-20 | Activus Pharma Co., Ltd. | Method for producing pulverized organic compound particle |
US8778181B1 (en) * | 2013-03-14 | 2014-07-15 | Crititech, Inc. | Equipment assembly for and method of processing particles |
Family Cites Families (149)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3648698A (en) * | 1969-05-23 | 1972-03-14 | George O Doherty | Surgical collection unit |
DE3120047C2 (en) * | 1981-05-20 | 1984-03-29 | Sterimed Gesellschaft für medizinischen Bedarf mbH, 6600 Saarbrücken | Suction device for sucking in body secretions |
JPS5958019U (en) | 1982-10-08 | 1984-04-16 | 松下電器産業株式会社 | electric dust collector |
US4780138A (en) * | 1986-10-27 | 1988-10-25 | Bodine Albert G | Sonic apparatus and method for facilitating the extraction of minerals from ore in a leachant |
US5143528A (en) * | 1990-02-14 | 1992-09-01 | Challenge Industries | Lint collector |
US5399363A (en) * | 1991-01-25 | 1995-03-21 | Eastman Kodak Company | Surface modified anticancer nanoparticles |
US6749868B1 (en) | 1993-02-22 | 2004-06-15 | American Bioscience, Inc. | Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof |
US5409833A (en) * | 1993-07-01 | 1995-04-25 | Baxter International Inc. | Microvessel cell isolation apparatus |
GB9313642D0 (en) * | 1993-07-01 | 1993-08-18 | Glaxo Group Ltd | Method and apparatus for the formation of particles |
US5994341A (en) | 1993-07-19 | 1999-11-30 | Angiogenesis Technologies, Inc. | Anti-angiogenic Compositions and methods for the treatment of arthritis |
GB9413202D0 (en) | 1994-06-30 | 1994-08-24 | Univ Bradford | Method and apparatus for the formation of particles |
US5626862A (en) | 1994-08-02 | 1997-05-06 | Massachusetts Institute Of Technology | Controlled local delivery of chemotherapeutic agents for treating solid tumors |
US5480540A (en) | 1994-10-17 | 1996-01-02 | General Electric Company | Spray apparatus for separating solids from fluids |
US5874481A (en) | 1995-06-07 | 1999-02-23 | Alliance Pharmaceutical Corp. | Fluorochemical solutions for the delivery of lipophilic pharmaceutical agents |
US5874029A (en) | 1996-10-09 | 1999-02-23 | The University Of Kansas | Methods for particle micronization and nanonization by recrystallization from organic solutions sprayed into a compressed antisolvent |
US5833891A (en) | 1996-10-09 | 1998-11-10 | The University Of Kansas | Methods for a particle precipitation and coating using near-critical and supercritical antisolvents |
US6495579B1 (en) | 1996-12-02 | 2002-12-17 | Angiotech Pharmaceuticals, Inc. | Method for treating multiple sclerosis |
WO1998029110A2 (en) | 1996-12-30 | 1998-07-09 | Battelle Memorial Institute | Formulation and method for treating neoplasms by inhalation |
HU230338B1 (en) | 1997-06-27 | 2016-02-29 | Abraxis Bioscience Llc | Novel formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof |
US6117949A (en) | 1998-10-01 | 2000-09-12 | Macromed, Inc. | Biodegradable low molecular weight triblock poly (lactide-co-glycolide) polyethylene glycol copolymers having reverse thermal gelation properties |
JPH11189403A (en) * | 1997-12-25 | 1999-07-13 | Tic:Kk | Device for producing layer structure composite particle |
JP3418751B2 (en) | 1998-01-22 | 2003-06-23 | 参天製薬株式会社 | Fluorometholone suspension ophthalmic solution |
IL131217A0 (en) | 1998-03-10 | 2001-01-28 | Napro Biotherapeutics Inc | Novel methods and compositions for delivery of taxanes |
US6221153B1 (en) | 1998-06-09 | 2001-04-24 | Trevor Percival Castor | Method for producing large crystals of complex molecules |
US7521068B2 (en) | 1998-11-12 | 2009-04-21 | Elan Pharma International Ltd. | Dry powder aerosols of nanoparticulate drugs |
US6113795A (en) | 1998-11-17 | 2000-09-05 | The University Of Kansas | Process and apparatus for size selective separation of micro- and nano-particles |
AU1556800A (en) | 1998-11-25 | 2000-06-13 | Universitatsklinikum Freiburg | Hyperforin as cytostatic agent and hyperforin ointment or cream as application form |
US6537585B1 (en) | 1999-03-26 | 2003-03-25 | Guilford Pharmaceuticals, Inc. | Methods and compositions for treating solid tumors |
US7217735B1 (en) | 1999-04-09 | 2007-05-15 | Au Jessie L-S | Methods and compositions for enhancing delivery of therapeutic agents to tissues |
US6610317B2 (en) | 1999-05-27 | 2003-08-26 | Acusphere, Inc. | Porous paclitaxel matrices and methods of manufacture thereof |
US6858199B1 (en) | 2000-06-09 | 2005-02-22 | Advanced Inhalation Research, Inc. | High efficient delivery of a large therapeutic mass aerosol |
US6616849B1 (en) | 1999-08-25 | 2003-09-09 | Shimadzu Corporation | Method of and system for continuously processing liquid materials, and the product processed thereby |
EP1235598A2 (en) | 1999-11-12 | 2002-09-04 | Angiotech Pharmaceuticals, Inc. | Compositions of a combination of radioactive therapy and cell-cycle inhibitors |
SE515604C2 (en) * | 2000-04-28 | 2001-09-10 | Bst Ab | Method and apparatus for suction and transport of liquids, preferably blood |
US6620351B2 (en) | 2000-05-24 | 2003-09-16 | Auburn University | Method of forming nanoparticles and microparticles of controllable size using supercritical fluids with enhanced mass transfer |
US6562952B1 (en) | 2000-10-31 | 2003-05-13 | The University Of Kansas | Precipitation of proteins from organic solutions |
US20020081339A1 (en) | 2000-12-22 | 2002-06-27 | Philippe Menei | Treatment of inoperable tumors by stereotactic injection of microspheres |
JP2004529934A (en) | 2001-05-01 | 2004-09-30 | アンジオテック ファーマシューティカルズ,インコーポレイテッド | Compositions comprising anti-microtubule agents and polypeptides or polysaccharides, and uses of those compositions for the preparation of a medicament for treating inflammatory conditions |
DE60118983T3 (en) | 2001-07-02 | 2016-07-07 | Micro & Nano Materials Sagl | Process for the preparation of nano and micro particles |
US20030054042A1 (en) | 2001-09-14 | 2003-03-20 | Elaine Liversidge | Stabilization of chemical compounds using nanoparticulate formulations |
US20030134810A1 (en) | 2001-10-09 | 2003-07-17 | Chris Springate | Methods and compositions comprising biocompatible materials useful for the administration of therapeutic agents |
AU2002364701B8 (en) | 2001-11-20 | 2006-06-22 | Alkermes, Inc. | Compositions for sustained action product delivery |
JP2005519129A (en) | 2002-03-05 | 2005-06-30 | クリーブランド ステート ユニバーシティー | Agglomerated particles for aerosol drug delivery |
JP2003251127A (en) * | 2002-03-06 | 2003-09-09 | Kazuo Hirakawa | Dust collector |
DE60309300T3 (en) | 2002-03-20 | 2011-02-24 | Elan Pharma International Ltd. | NANOPARTICLE COMPOSITIONS OF ANGIOGENIC INHIBITORS |
EP1501483A2 (en) * | 2002-04-25 | 2005-02-02 | Nektar Therapeutics UK Ltd | Particulate materials |
AU2003231134A1 (en) | 2002-04-26 | 2003-11-10 | Teva Pharmaceutical Industries, Ltd. | Microparticle pharmaceutical compositions for intratumoral delivery |
US9339459B2 (en) * | 2003-04-24 | 2016-05-17 | Nektar Therapeutics | Particulate materials |
CN1255394C (en) | 2002-06-24 | 2006-05-10 | 成都思摩纳米技术有限公司 | Process for the manufacture of pacilitaxel nano granule |
KR100573289B1 (en) | 2002-07-20 | 2006-04-24 | 대화제약 주식회사 | Paclitaxel composition for the intravesical treatment of bladder tumor and preparation method thereof |
US6916389B2 (en) * | 2002-08-13 | 2005-07-12 | Nanotechnologies, Inc. | Process for mixing particulates |
CN2578811Y (en) * | 2002-10-24 | 2003-10-08 | 陆纪清 | Closed coal powder sampler |
US20040220081A1 (en) * | 2002-10-30 | 2004-11-04 | Spherics, Inc. | Nanoparticulate bioactive agents |
TR200502189T1 (en) | 2002-12-09 | 2007-01-22 | American Bioscience, Inc. | Compositions and methods for the transfer of pharmacologically active substances. |
US7455797B2 (en) | 2003-02-28 | 2008-11-25 | Ferro Corporation | Method and apparatus for producing particles using supercritical fluid |
JP4927535B2 (en) | 2003-04-03 | 2012-05-09 | ジェシー エル エス オウ | Particles encapsulating drugs that target tumors |
US20060147535A1 (en) | 2003-04-16 | 2006-07-06 | Poongunran Muthukumaran | Methods for and compositions of anticancer medicaments |
US20050059613A1 (en) | 2003-07-08 | 2005-03-17 | Bahram Memarzadeh | Compositions and methods for the enhanced uptake of therapeutic agents through the bladder epithelium |
US8021831B2 (en) | 2003-08-25 | 2011-09-20 | Board Of Regents, The University Of Texas System | Taxane chemosensitivity prediction test |
JP2007001865A (en) | 2003-09-16 | 2007-01-11 | Ltt Bio-Pharma Co Ltd | Fine particle enclosing fat-soluble medicine, method for producing the same and preparation containing the same |
JP5645340B2 (en) | 2003-10-15 | 2014-12-24 | メディゲーネ アクチエンゲゼルシャフトMediGene AG | Method for administering cationic liposomes containing active ingredients |
TWI371274B (en) * | 2003-10-23 | 2012-09-01 | Bristol Myers Squibb Co | Process for making sterile aripiprazole of desired mean particle size |
US7208106B2 (en) | 2003-10-24 | 2007-04-24 | Ferro Corporation | Method of forming particles |
US7879360B2 (en) | 2003-11-05 | 2011-02-01 | Elan Pharma International, Ltd. | Nanoparticulate compositions having a peptide as a surface stabilizer |
DE10357091A1 (en) * | 2003-12-06 | 2005-07-07 | Degussa Ag | Device and method for the separation of very fine particles from the gas phase |
GB0402963D0 (en) | 2004-02-11 | 2004-03-17 | Univ Nottingham | Counter current mixing device for two different fluids |
US8043631B2 (en) | 2004-04-02 | 2011-10-25 | Au Jessie L S | Tumor targeting drug-loaded particles |
WO2006046670A1 (en) | 2004-10-29 | 2006-05-04 | Nara Machinery Co., Ltd. | Method of granulating fine particles |
WO2006068890A2 (en) | 2004-12-14 | 2006-06-29 | Transave, Inc. | Lipid particles comprising bioactive agents, methods of preparing and uses thereof |
ES2265262B1 (en) | 2005-01-31 | 2008-03-01 | Activery Biotech, S.L.(Titular Al 50%) | PROCEDURE FOR OBTAINING MICRO- AND NANODISPERSE SYSTEMS. |
US8735394B2 (en) | 2005-02-18 | 2014-05-27 | Abraxis Bioscience, Llc | Combinations and modes of administration of therapeutic agents and combination therapy |
KR20080003322A (en) | 2005-02-24 | 2008-01-07 | 엘란 파마 인터내셔널 리미티드 | Nanoparticulate formulations of docetaxel and analogues thereof |
US7872050B2 (en) | 2005-03-14 | 2011-01-18 | Yaupon Therapeutics Inc. | Stabilized compositions of volatile alkylating agents and methods of using thereof |
US8118795B2 (en) * | 2005-03-22 | 2012-02-21 | Medindica-Pak, Inc | Disposal chain supply systems method and apparatus |
CN101160116B (en) | 2005-03-31 | 2011-12-07 | 利德斯公司 | Method for treating prostate diseases based on local delivery of active substances |
CN1923189A (en) | 2005-08-30 | 2007-03-07 | 孔庆忠 | Taxine kind anti-cancer slow release injection |
WO2007027941A2 (en) | 2005-08-31 | 2007-03-08 | Abraxis Bioscience, Llc. | Compositions and methods for preparation of poorly water soluble drugs with increased stability |
KR20080077680A (en) | 2005-12-11 | 2008-08-25 | 에스씨에프 테크놀로지스 에이/에스 | Production of nanosized materials |
US8906392B2 (en) | 2005-12-16 | 2014-12-09 | University Of Kansas | Nanocluster compositions and methods |
AR054215A1 (en) * | 2006-01-20 | 2007-06-13 | Eriochem Sa | A PHARMACEUTICAL FORMULATION OF A TAXANE, A SOLID COMPOSITION OF A LIOFILIZED TAXAN FROM AN ACETIC ACID SOLUTION, A PROCEDURE FOR THE PREPARATION OF A SOLID COMPOSITION OF A TAXANE, A SOLUBILIZING COMPOSITION OF A LIOFILIZED TAXANE AND AN ELEMENTARY KIT |
CN101336899A (en) | 2006-01-25 | 2009-01-07 | 济南帅华医药科技有限公司 | Anticancer sustained-released injection containing taxane |
DK1996160T3 (en) | 2006-03-14 | 2010-07-05 | Lidds Ab | Controlled release bioresorbable composition |
US7964029B2 (en) * | 2006-07-17 | 2011-06-21 | Thar Instrument, Inc. | Process flowstream collection system |
US7744923B2 (en) | 2006-10-11 | 2010-06-29 | Crititech, Inc. | Method for precipitation of small medicament particles into use containers |
WO2008044092A1 (en) | 2006-10-11 | 2008-04-17 | Renault Trucks | Truck provided with a passive keyless access system |
US20100166869A1 (en) | 2007-05-03 | 2010-07-01 | Desai Neil P | Methods and compositions for treating pulmonary hypertension |
WO2009006590A2 (en) | 2007-07-04 | 2009-01-08 | Dr. Reddy's Laboratories Ltd. | Docetaxel process and polymorphs |
CN101129338A (en) * | 2007-08-27 | 2008-02-27 | 四川大学 | Minuteness anti-cancer medicine paclitaxel of novel technique supercritical fluid |
MX2010009670A (en) | 2008-03-06 | 2010-09-22 | Nitto Denko Corp | Polymer paclitaxel conjugates and methods for treating cancer. |
KR101242874B1 (en) * | 2008-03-24 | 2013-03-13 | 산요가세이고교 가부시키가이샤 | Resin particle and method for producing the same |
JP5536654B2 (en) | 2008-09-19 | 2014-07-02 | 株式会社アクティバスファーマ | Medical complex organic compound powder, method for producing the same, and suspension |
CA2745238A1 (en) | 2008-12-02 | 2010-06-10 | Biocompatibles Uk Limited | Pancreatic tumour treatment |
PT104693B (en) | 2009-07-27 | 2011-11-24 | Univ Lisboa | SEMI-SOLID LIPID NANOPARTICLES CONTAINING AN ANTINEOPLASTIC AGENT AND ITS PREPARATION PROCESS |
AU2010289785A1 (en) | 2009-08-24 | 2012-03-15 | Baylor College Of Medicine | Generation of CTL lines with specificity against multiple tumor antigens or multiple viruses |
US20110209578A1 (en) * | 2010-02-26 | 2011-09-01 | Kuniaki Ara | Nanoparticle manufacturing device and nanoparticle manufacturing method and method of manufacturing nanoparticle-dispersed liquid alkali metal |
CN101829061A (en) | 2010-05-14 | 2010-09-15 | 无锡纳生生物科技有限公司 | Taxol nanoparticle composition and preparation method thereof |
EP2575803B1 (en) | 2010-06-02 | 2017-07-26 | Abraxis BioScience, LLC | Methods of treating bladder cancer |
ES2776983T3 (en) | 2010-09-21 | 2020-08-03 | Cristal Delivery B V | Tunable biodegradable linker molecules for transient conjugation of components in drug delivery systems, and drug delivery systems prepared therewith |
US20150093440A1 (en) | 2010-10-15 | 2015-04-02 | Glaxo Group Limited | Aggregate nanoparticulate medicament formulations, manufacture and use thereof |
EP2745921A3 (en) * | 2010-10-29 | 2014-10-01 | Velico Medical, Inc. | System and Method for Spray Drying a Liquid |
WO2012096995A2 (en) * | 2011-01-11 | 2012-07-19 | Boston Scientific Scimed, Inc. | Coated medical devices |
PT2699233T (en) | 2011-04-20 | 2017-07-03 | Univ Sydney | Particulate material and cellular toxin for use in the treatment of a solid tumour |
US20140154269A1 (en) | 2011-04-26 | 2014-06-05 | The Methodist Hospital Research Institute | Targeted nanovectors and their use for treatment of brain tumors |
EA201490047A1 (en) | 2011-06-17 | 2014-08-29 | Берг Ллк | INHALATION PHARMACEUTICAL COMPOSITIONS |
CN103764172A (en) | 2011-06-27 | 2014-04-30 | 科里斯塔鲁传送有限公司 | Controlled release system |
US11766459B2 (en) * | 2011-07-08 | 2023-09-26 | Jointechlabs, Inc. | System and methods for preparation of adipose-derived stem cells |
BR112014004590B1 (en) * | 2011-08-31 | 2019-11-19 | Archer Daniels Midland Co | process to perform an oxidation on a sprayable feed |
FR2980683B1 (en) | 2011-09-30 | 2014-11-21 | Univ Paris Curie | DEVICE FOR GUIDING A MEDICAL INSTRUMENT INSERTED IN A NATURAL PATH OR AN ARTIFICIAL PATH OF A PATIENT |
CN102319898B (en) * | 2011-10-13 | 2013-05-08 | 西北工业大学 | Spray forming system for preparing alloy and metal-based composite parts |
CN102488682A (en) | 2011-11-22 | 2012-06-13 | 四川九章生物化工科技发展有限公司 | New application of chlorogenic acid in cancer resisting |
JP2013212494A (en) * | 2012-03-05 | 2013-10-17 | Ricoh Co Ltd | Method for producing resin fine particle |
US10555911B2 (en) | 2012-05-04 | 2020-02-11 | Yale University | Highly penetrative nanocarriers for treatment of CNS disease |
CN102728414A (en) | 2012-07-07 | 2012-10-17 | 中山大学 | Preparation method of catalyst for preparing single-walled carbon nanotube and application of catalyst |
TW201408304A (en) | 2012-08-31 | 2014-03-01 | Cathay General Hospital | A combined drug with anti-cancer drug and hormone to treat renal cell carcinoma and its method of fabrication |
CA2884707C (en) | 2012-09-21 | 2019-03-19 | Lewis Bender | Method of treating cancer |
US9132363B2 (en) * | 2012-11-20 | 2015-09-15 | Apeks Llc | Extraction system |
US9511046B2 (en) | 2013-01-11 | 2016-12-06 | Abraxis Bioscience, Llc | Methods of treating pancreatic cancer |
CA2898408C (en) | 2013-02-28 | 2018-01-02 | Pfizer Inc. | Enhanced stability of novel liquid compositions |
US9925512B2 (en) | 2013-03-14 | 2018-03-27 | Crititech, Inc. | Equipment assembly for and method of processing particles |
US20140294967A1 (en) | 2013-03-28 | 2014-10-02 | Bbs Nanotechnology Llc. | Stable nanocomposition comprising paclitaxel, process for the preparation thereof, its use and pharmaceutical compositions containing it |
WO2014169137A1 (en) | 2013-04-10 | 2014-10-16 | Massachusetts Institute Of Technology | Local drug delivery devices and methods for treating cancer |
CN203699094U (en) * | 2013-10-15 | 2014-07-09 | 雷海平 | Novel garbage can and matched inner bucket |
US10188738B2 (en) | 2013-10-16 | 2019-01-29 | Université Libre de Bruxelles | Formulations useful in the treatment of proliferative diseases affecting the respiratory tract |
CA2933883A1 (en) | 2013-12-17 | 2015-06-25 | Genentech, Inc. | Methods of treating her2-positive cancers using pd-1 axis binding antagonists and anti-her2 antibodies |
NZ721908A (en) | 2013-12-20 | 2022-12-23 | Massachusetts Gen Hospital | Combination therapy with neoantigen vaccine |
WO2015103005A1 (en) | 2014-01-03 | 2015-07-09 | Research Institute At Nationwide Children's Hospital | Amphiphilic amine compounds and their use as therapeutic agents and nanocarriers |
CN203737192U (en) * | 2014-01-20 | 2014-07-30 | 四川西汉电子科技有限责任公司 | Granulator |
TWI601542B (en) | 2014-04-18 | 2017-10-11 | 林信湧 | Inhalation-type pharmaceutical composition for lung cancer and preparation method thereof |
US20150342872A1 (en) * | 2014-06-01 | 2015-12-03 | Crititech, Inc. | Use of Paclitaxel Particles |
CN203847940U (en) | 2014-06-04 | 2014-09-24 | 刘希 | Adjusting support for feeding nozzle |
US11033620B2 (en) | 2014-06-09 | 2021-06-15 | Biomed Valley Discoveries, Inc. | Combination therapies targeting tumor-associated stroma or tumor cells and microtubules |
US9533449B2 (en) * | 2014-06-19 | 2017-01-03 | Autodesk, Inc. | Material deposition systems with four or more axes |
US10975442B2 (en) | 2014-12-19 | 2021-04-13 | Massachusetts Institute Of Technology | Molecular biomarkers for cancer immunotherapy |
KR102077518B1 (en) * | 2015-06-04 | 2020-02-14 | 크리티테크, 인크. | Nozzle Assembly and How to Use |
AU2016323770A1 (en) | 2015-09-16 | 2018-03-29 | Dfb Soria, Llc | Delivery of drug nanoparticles and methods of use thereof |
US10517961B2 (en) | 2015-09-25 | 2019-12-31 | ZY Therapeutics, Inc. | Drug formulation based on particulates comprising polysaccharide-vitamin conjugate |
DE202016006620U1 (en) | 2015-10-28 | 2017-04-12 | Qass Gmbh | Devices for observing a magnetic field of a material volume |
KR20180096707A (en) | 2016-01-20 | 2018-08-29 | 페이트 세러퓨틱스, 인코포레이티드 | Composition and method for immune cell regulation in adoptive immunotherapy |
EP3854381A1 (en) * | 2016-04-04 | 2021-07-28 | Crititech, Inc. | Methods for solid tumor treatment |
CN107281502B (en) | 2016-04-05 | 2021-05-04 | 上海市肿瘤研究所 | Composite developing temperature-sensitive gel suppository, preparation method and application thereof |
WO2017178585A1 (en) | 2016-04-15 | 2017-10-19 | Cellectis | A method of engineering drug-specific hypersensitive t-cells for immunotherapy by gene inactivation |
US10160159B2 (en) * | 2016-05-12 | 2018-12-25 | Hewlett-Packard Development Company, L.P. | Build material container |
US9567399B1 (en) | 2016-06-20 | 2017-02-14 | Kymab Limited | Antibodies and immunocytokines |
WO2018045239A1 (en) | 2016-09-01 | 2018-03-08 | Mayo Foundation For Medical Education And Research | Carrier-pd-l1 binding agent compositions for treating cancers |
CA3056395C (en) | 2017-03-15 | 2022-06-28 | Dfb Soria, Llc | Topical therapy for the treatment of skin malignancies using nanoparticles of taxanes |
WO2018170210A1 (en) | 2017-03-15 | 2018-09-20 | Dfb Soria, Llc | Topical therapy for the treatment of vulvar intraepithelial neoplasia (vin) and genital warts using nanoparticles of taxanes |
WO2018170207A1 (en) | 2017-03-15 | 2018-09-20 | Dfb Soria, Llc | Topical therapy for the treatment of skin keratoses using nanoparticles of taxanes |
CN110730679A (en) | 2017-06-09 | 2020-01-24 | 克里蒂泰克公司 | Intracyst injection anti-tumor particle for treating epithelial cyst |
JP6840869B2 (en) | 2017-06-14 | 2021-03-10 | クリチテック,インコーポレイテッド | How to treat lung disorders |
-
2016
- 2016-06-06 KR KR1020177034414A patent/KR102077518B1/en active IP Right Grant
- 2016-06-06 AU AU2016270558A patent/AU2016270558B2/en active Active
- 2016-06-06 EP EP16734493.6A patent/EP3302423B1/en active Active
- 2016-06-06 WO PCT/US2016/036013 patent/WO2016197101A1/en active Application Filing
- 2016-06-06 US US15/174,505 patent/US9814685B2/en active Active
- 2016-06-06 KR KR1020207004878A patent/KR102317107B1/en active IP Right Grant
- 2016-06-06 KR KR1020177034415A patent/KR102551708B1/en active IP Right Grant
- 2016-06-06 CN CN201680031730.5A patent/CN107743418A/en active Pending
- 2016-06-06 EP EP16731712.2A patent/EP3302780B1/en active Active
- 2016-06-06 KR KR1020207033764A patent/KR20200134347A/en not_active Application Discontinuation
- 2016-06-06 WO PCT/US2016/036012 patent/WO2016197100A1/en active Application Filing
- 2016-06-06 WO PCT/US2016/035993 patent/WO2016197091A1/en active Application Filing
- 2016-06-06 CN CN201680032291.XA patent/CN107683174B/en active Active
- 2016-06-06 DK DK16732387.2T patent/DK3302431T3/en active
- 2016-06-06 US US15/573,091 patent/US10751319B2/en active Active
- 2016-06-06 JP JP2017558537A patent/JP6921759B2/en active Active
- 2016-06-06 ES ES16732387T patent/ES2833749T3/en active Active
- 2016-06-06 JP JP2017560744A patent/JP6758325B2/en active Active
- 2016-06-06 SG SG10201913947RA patent/SG10201913947RA/en unknown
- 2016-06-06 EP EP16732387.2A patent/EP3302431B1/en active Active
- 2016-06-06 US US15/573,157 patent/US11291646B2/en active Active
- 2016-06-06 CN CN201680032549.6A patent/CN107683131B/en active Active
- 2016-06-06 CN CN202111091592.9A patent/CN114010628A/en active Pending
- 2016-06-06 AU AU2016270559A patent/AU2016270559B2/en active Active
- 2016-06-06 CA CA3026452A patent/CA3026452C/en active Active
- 2016-06-06 AU AU2016270549A patent/AU2016270549B2/en active Active
- 2016-06-06 RU RU2017140678A patent/RU2750163C2/en active
- 2016-06-06 EP EP20206804.5A patent/EP3838264A1/en active Pending
- 2016-06-06 KR KR1020177033970A patent/KR102337080B1/en active IP Right Grant
- 2016-06-06 CA CA3026454A patent/CA3026454C/en active Active
- 2016-06-06 CA CA2988132A patent/CA2988132C/en active Active
- 2016-06-06 JP JP2017558020A patent/JP6892394B2/en active Active
- 2016-06-06 SG SG10201913945QA patent/SG10201913945QA/en unknown
- 2016-06-06 PT PT167323872T patent/PT3302431T/en unknown
- 2016-09-09 US US15/261,108 patent/US20160374953A1/en not_active Abandoned
-
2017
- 2017-04-27 US US15/499,397 patent/US9918957B2/en active Active
-
2018
- 2018-02-13 US US15/895,197 patent/US10507195B2/en active Active
- 2018-09-27 HK HK18112397.4A patent/HK1253020A1/en unknown
- 2018-09-27 HK HK18112394.7A patent/HK1253018A1/en unknown
- 2018-09-27 HK HK18112398.3A patent/HK1253021B/en unknown
-
2019
- 2019-10-30 US US16/669,310 patent/US11123322B2/en active Active
-
2020
- 2020-01-30 US US16/776,919 patent/US10729673B2/en active Active
- 2020-09-01 JP JP2020146459A patent/JP7096299B2/en active Active
- 2020-09-16 US US17/023,098 patent/US20200405684A1/en not_active Abandoned
- 2020-09-17 US US17/023,635 patent/US10993927B2/en active Active
-
2021
- 2021-09-07 US US17/467,655 patent/US20210393569A1/en active Pending
-
2022
- 2022-06-23 JP JP2022101327A patent/JP2022121532A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000072827A2 (en) * | 1999-05-27 | 2000-12-07 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
WO2003032906A2 (en) * | 2001-10-15 | 2003-04-24 | Crititech, Inc. | Delivery of poorly soluble drugs |
US20060078619A1 (en) * | 2002-11-13 | 2006-04-13 | Hanmi Pharm Co., Ltd. | Method for the preparatin of paclitaxel solid dispersion by using the supercritical fluid process and paclitaxel solid dispersion prepared thereby |
US20120237768A1 (en) * | 2007-04-06 | 2012-09-20 | Activus Pharma Co., Ltd. | Method for producing pulverized organic compound particle |
US8778181B1 (en) * | 2013-03-14 | 2014-07-15 | Crititech, Inc. | Equipment assembly for and method of processing particles |
Non-Patent Citations (3)
Title |
---|
BEIGE S.M ET AL.: "Phannaceutical Salts", J. PHARM. SCI., vol. 66, 1977, pages 1 - 19 |
KAKRAN MITALI ET AL: "Modified supercritical antisolvent method with enhanced mass transfer to fabricate drug nanoparticles", MATERIALS SCIENCE AND ENGINEERING C, ELSEVIER SCIENCE S.A, CH, vol. 33, no. 5, 14 March 2013 (2013-03-14), pages 2864 - 2870, XP028584709, ISSN: 0928-4931, DOI: 10.1016/J.MSEC.2013.03.002 * |
LEE ET AL: "Supercritical antisolvent production of biodegradable micro- and nanoparticles for controlled delivery of paclitaxel", JOURNAL OF CONTROLLED RELEASE, ELSEVIER, AMSTERDAM, NL, vol. 125, no. 2, 13 October 2007 (2007-10-13), pages 96 - 106, XP022402137, ISSN: 0168-3659 * |
Cited By (48)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11123322B2 (en) | 2015-06-04 | 2021-09-21 | Crititech, Inc. | Taxane particles and their use |
US10993927B2 (en) | 2015-06-04 | 2021-05-04 | Crititech, Inc. | Taxane particles and their use |
US10729673B2 (en) | 2015-06-04 | 2020-08-04 | Crititech, Inc. | Taxane particles and their use |
US10507195B2 (en) | 2015-06-04 | 2019-12-17 | Crititech, Inc. | Taxane particles and their use |
US10449162B2 (en) | 2015-09-16 | 2019-10-22 | Dfb Soria Llc | Delivery of drug nanoparticles and methods of use thereof |
US11331278B2 (en) | 2015-09-16 | 2022-05-17 | Dfb Soria, Llc | Delivery of drug nanoparticles and methods of use thereof |
US10918606B2 (en) | 2015-09-16 | 2021-02-16 | Dfb Soria, Llc | Delivery of drug nanoparticles and methods of use thereof |
US11458133B2 (en) | 2016-04-04 | 2022-10-04 | Crititech, Inc. | Methods for solid tumor treatment |
EP3854381A1 (en) | 2016-04-04 | 2021-07-28 | Crititech, Inc. | Methods for solid tumor treatment |
US11033542B2 (en) | 2016-04-04 | 2021-06-15 | Crititech, Inc. | Methods for solid tumor treatment |
US10894045B2 (en) | 2016-04-04 | 2021-01-19 | Crititech, Inc. | Methods for solid tumor treatment |
US10874660B2 (en) | 2016-04-04 | 2020-12-29 | CritlTech, Inc. | Methods for solid tumor treatment |
US10842736B2 (en) | 2017-03-15 | 2020-11-24 | Dfb Soria, Llc | Topical therapy for the treatment of skin malignancies using nanoparticles of taxanes |
US11633349B2 (en) | 2017-03-15 | 2023-04-25 | Dfb Soria, Llc | Topical therapy for the treatment of skin malignancies using nanoparticles of taxanes |
WO2018170207A1 (en) | 2017-03-15 | 2018-09-20 | Dfb Soria, Llc | Topical therapy for the treatment of skin keratoses using nanoparticles of taxanes |
WO2018170210A1 (en) | 2017-03-15 | 2018-09-20 | Dfb Soria, Llc | Topical therapy for the treatment of vulvar intraepithelial neoplasia (vin) and genital warts using nanoparticles of taxanes |
US11191717B2 (en) | 2017-03-15 | 2021-12-07 | Dfb Soria, Llc | Topical therapy for the treatment of skin malignancies using nanoparticles of taxanes |
WO2018170196A1 (en) | 2017-03-15 | 2018-09-20 | Dfb Soria, Llc | Topical therapy for the treatment of skin malignancies using nanoparticles of taxanes |
US10555898B2 (en) | 2017-03-15 | 2020-02-11 | Dfb Soria, Llc | Topical therapy for the treatment of skin malignancies using nanoparticles of taxanes |
US11523983B2 (en) | 2017-06-09 | 2022-12-13 | Crititech, Inc. | Treatment of epithelial cysts by intracystic injection of antineoplastic particles |
WO2018227037A1 (en) | 2017-06-09 | 2018-12-13 | Crititech, Inc. | Treatment of epithelial cysts by intracystic injection of antineoplastic particles |
US11737972B2 (en) | 2017-06-09 | 2023-08-29 | Crititech, Inc. | Treatment of epithelial cysts by intracystic injection of antineoplastic particles |
US10507181B2 (en) | 2017-06-14 | 2019-12-17 | Crititech, Inc. | Methods for treating lung disorders |
JP2020523286A (en) * | 2017-06-14 | 2020-08-06 | クリチテック,インコーポレイテッド | How to treat lung disorders |
US11160754B2 (en) | 2017-06-14 | 2021-11-02 | Crititech, Inc. | Methods for treating lung disorders |
WO2018231908A1 (en) | 2017-06-14 | 2018-12-20 | Crititech, Inc. | Methods for treating lung disorders |
WO2019067851A1 (en) | 2017-09-29 | 2019-04-04 | Crititech, Inc. | Ciprofloxacin polymorph and its use |
WO2019070850A1 (en) | 2017-10-03 | 2019-04-11 | Crititech, Inc. | Local delivery of antineoplastic particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer |
US11058639B2 (en) | 2017-10-03 | 2021-07-13 | Crititech, Inc. | Local delivery of antineoplastic particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer |
CN111278436A (en) * | 2017-10-03 | 2020-06-12 | 克里蒂泰克公司 | Local delivery of anti-tumor particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer |
US11583499B2 (en) | 2017-10-03 | 2023-02-21 | Crititech, Inc. | Local delivery of antineoplastic particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer |
US11918691B2 (en) | 2017-10-03 | 2024-03-05 | Crititech, Inc. | Local delivery of antineoplastic particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer |
JP2020536052A (en) * | 2017-10-03 | 2020-12-10 | クリティテック・インコーポレイテッド | Topical delivery of antitumor particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer |
WO2019136188A1 (en) | 2018-01-05 | 2019-07-11 | Crititech, Inc. | Treatment of bladder cancer by intratumoral injection of taxane particles |
WO2019136187A1 (en) | 2018-01-05 | 2019-07-11 | Crititech, Inc. | Treatment of bladder cancer by local administration of taxane particles |
US11497726B2 (en) | 2018-03-16 | 2022-11-15 | Dfb Soria, Ll. | Topical therapy for the treatment of cervical intraepithelial neoplasia (CIN) and cervical cancer using nanoparticles of taxanes |
JP2021526354A (en) * | 2018-05-31 | 2021-10-07 | クリティテック・インコーポレイテッド | Methods for Isolating Tumor-Specific Immune Cells for Adoptive Cell Therapy and Cancer Vaccines From Subjects |
WO2019231499A1 (en) | 2018-05-31 | 2019-12-05 | Crititech, Inc. | Use of antineoplastic agents to stimulate the immune system for treatment of cancer |
WO2019231567A1 (en) | 2018-05-31 | 2019-12-05 | Crititech, Inc. | Methods for isolating tumor-specific immune cells from a subject for adoptive cell therapy and cancer vaccines |
WO2019231498A1 (en) | 2018-05-31 | 2019-12-05 | Crititech, Inc. | Treatment of kidney tumors by intratumoral injection of taxane particles |
JP7423544B2 (en) | 2018-05-31 | 2024-01-29 | クリティテック・インコーポレイテッド | Methods for isolating tumor-specific immune cells from a subject for adoptive cell therapy and cancer vaccines |
WO2020072090A1 (en) | 2018-10-03 | 2020-04-09 | Crititech, Inc. | Use of antineoplastic agents to stimulate the immune system for production of tertiary lymphoid structures (tls) |
WO2022020449A1 (en) | 2020-07-23 | 2022-01-27 | Crititech, Inc. | Sorafenib particles and uses thereof |
WO2022020455A1 (en) | 2020-07-23 | 2022-01-27 | Crititech, Inc. | Lapatinib particles and uses thereof |
WO2023086784A1 (en) | 2021-11-10 | 2023-05-19 | Crititech, Inc. | Rucaparib particles and uses thereof |
US11738014B2 (en) | 2021-11-10 | 2023-08-29 | Crititech, Inc. | Niraparib particles and uses thereof |
US11738029B2 (en) | 2021-11-10 | 2023-08-29 | Crititech, Inc. | Rucaparib particles and uses thereof |
WO2023086779A1 (en) | 2021-11-10 | 2023-05-19 | Crititech, Inc. | Niraparib particles and uses thereof |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10993927B2 (en) | Taxane particles and their use | |
AU2021311602A1 (en) | Sorafenib particles and uses thereof | |
US11738029B2 (en) | Rucaparib particles and uses thereof | |
US20230364021A1 (en) | Sorafenib particles and uses thereof | |
BR112017025815B1 (en) | TAXANE PARTICLES, COMPOSITIONS COMPRISING TAXANE PARTICLES, USE OF THE COMPOSITION COMPRISING TAXANE PARTICLES AND METHODS OF MANUFACTURING THE TAXANE PARTICLES | |
US20230142591A1 (en) | Niraparib particles and uses thereof | |
EP4329778A1 (en) | Cisplatin particles and uses thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 16732387 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2016270549 Country of ref document: AU Date of ref document: 20160606 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2017560744 Country of ref document: JP Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 20177033970 Country of ref document: KR Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2988132 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 11201709975Q Country of ref document: SG |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2016732387 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2017140678 Country of ref document: RU |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112017025815 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 112017025815 Country of ref document: BR Kind code of ref document: A2 Effective date: 20171130 |