CA2560312A1 - Embolization - Google Patents
Embolization Download PDFInfo
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- CA2560312A1 CA2560312A1 CA002560312A CA2560312A CA2560312A1 CA 2560312 A1 CA2560312 A1 CA 2560312A1 CA 002560312 A CA002560312 A CA 002560312A CA 2560312 A CA2560312 A CA 2560312A CA 2560312 A1 CA2560312 A1 CA 2560312A1
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- Prior art keywords
- microns
- substantially spherical
- particles
- composition
- silica particles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/0047—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L24/0073—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix
- A61L24/0089—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix containing inorganic fillers not covered by groups A61L24/0078 or A61L24/0084
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
- A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
- A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
- A61B17/12099—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder
- A61B17/12109—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder in a blood vessel
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
- A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
- A61B17/12131—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device
- A61B17/12181—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device formed by fluidized, gelatinous or cellular remodelable materials, e.g. embolic liquids, foams or extracellular matrices
- A61B17/12186—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device formed by fluidized, gelatinous or cellular remodelable materials, e.g. embolic liquids, foams or extracellular matrices liquid materials adapted to be injected
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/12—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L31/125—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
- A61L31/128—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix containing other specific inorganic fillers not covered by A61L31/126 or A61L31/127
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/18—Materials at least partially X-ray or laser opaque
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- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B33/00—Silicon; Compounds thereof
- C01B33/113—Silicon oxides; Hydrates thereof
- C01B33/12—Silica; Hydrates thereof, e.g. lepidoic silicic acid
- C01B33/124—Preparation of adsorbing porous silica not in gel form and not finely divided, i.e. silicon skeletons, by acidic treatment of siliceous materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/36—Materials or treatment for tissue regeneration for embolization or occlusion, e.g. vaso-occlusive compositions or devices
Abstract
Embolization, as well as related particles, compositions and methods are disclosed. The particles are substantially spherical porous silica particles having a diameter of from about 100 ~m to about 3000 ~m.
Description
EMBOLIZATION
TECHNICAL FIELD
The invention relates to embolization, as well as related particles, compositions and methods.
BACKGROUND
Therapeutic vascular occlusions (embolizations) are used to prevent or treat pathological conditions iya situ. Compositions including embolic particles are used for occluding vessels in a variety of medical applications. Delivery of embolic particles through a catheter is dependent on size uniformity, density and compressibility of the 1 o embolic particles.
SUMMARY
The invention relates to embolization, as well as xelated particles, compositions and methods.
In one aspect, the invention features a substantially spherical porous silica particle having a diameter of from about 100 microns to about 3000 microns.
In another aspect, the invention features a composition that includes a carrier fluid that contains a plurality of substantially spherical porous silica particles.
At least some of the plurality of substantially spherical silica particles have a diameter of from about 100 microns to about 3000 microns; and 2o In a further aspect, the invention features a method that includes administering to a subject a therapeutically effective amount of a composition including a plurality of substantially spherical silica particles in a carrier fluid. ~1t least some of the plurality of substantially spherical silica particles having a diameter of from about 100 microns to about 3000 microns.
Embodiments can include one or more of the following.
In some embodiments, the carrier fluid includes a saline solution.
In certain embodiments, the carrier fluid include s a contrast agent.
In some embodiments, at least some of the substantially spherical porous silica particles have a diameter of at most about 1500 microns.
In certain embodiments, for at least some of the substantially spherical porous silica particles, pores in the substantially spherical porous silica particles have a diameter of from about 20 nanometers to about 90 nanometers.
In some embodiments, for at least some of the substantially spherical porous silica particles, a pore volume of the substantially spherical silica particles is from about 0.4 ml/g to about 1.6 ml/g.
In certain embodiments, the particles can have a pore volume distribution such o that about 70% or more of the pore volume of the particles is made up of pores having pore diameters which have a tolerance of about 10 nm or less on the mean pore diameter.
In some embodiments, the particles exhibit a loss of attrition resistance of about 0.1 °1o by weight or less.
In certain embodiments, at least some of the plurality of substantially spherical ~ 5 porous silica particles include one or more therapeutic agents, one or more ferromagnetic materials, one or more MRI visible materials and/or one or more radiopaque materials.
In some embodiments, the plurality of substantially spherical porous silica particles are sterilized.
In some embodiments, the composition is administered to the subject by 2o percutaneous injection.
W certain embodiments, the composition is administered to the subject by a catheter.
hi some embodiments, the composition is used to treat a cancer condition. The cancer condition can be, for example, ovarian cancer, colorectal cancer, thyroid cancer, 25 gastrointestinal cancer, breast cancer, prostate cancer and/or lung cancer.
Treating the cancer condition can include at least partially occluding a lumen in the subject that provides nutrients to a site of the cancer condition with at least some of the plurality of particles.
In certain embodiments, the method includes at least partially occluding a lumen 3o in the subject with at least some of a plurality of particles.
TECHNICAL FIELD
The invention relates to embolization, as well as related particles, compositions and methods.
BACKGROUND
Therapeutic vascular occlusions (embolizations) are used to prevent or treat pathological conditions iya situ. Compositions including embolic particles are used for occluding vessels in a variety of medical applications. Delivery of embolic particles through a catheter is dependent on size uniformity, density and compressibility of the 1 o embolic particles.
SUMMARY
The invention relates to embolization, as well as xelated particles, compositions and methods.
In one aspect, the invention features a substantially spherical porous silica particle having a diameter of from about 100 microns to about 3000 microns.
In another aspect, the invention features a composition that includes a carrier fluid that contains a plurality of substantially spherical porous silica particles.
At least some of the plurality of substantially spherical silica particles have a diameter of from about 100 microns to about 3000 microns; and 2o In a further aspect, the invention features a method that includes administering to a subject a therapeutically effective amount of a composition including a plurality of substantially spherical silica particles in a carrier fluid. ~1t least some of the plurality of substantially spherical silica particles having a diameter of from about 100 microns to about 3000 microns.
Embodiments can include one or more of the following.
In some embodiments, the carrier fluid includes a saline solution.
In certain embodiments, the carrier fluid include s a contrast agent.
In some embodiments, at least some of the substantially spherical porous silica particles have a diameter of at most about 1500 microns.
In certain embodiments, for at least some of the substantially spherical porous silica particles, pores in the substantially spherical porous silica particles have a diameter of from about 20 nanometers to about 90 nanometers.
In some embodiments, for at least some of the substantially spherical porous silica particles, a pore volume of the substantially spherical silica particles is from about 0.4 ml/g to about 1.6 ml/g.
In certain embodiments, the particles can have a pore volume distribution such o that about 70% or more of the pore volume of the particles is made up of pores having pore diameters which have a tolerance of about 10 nm or less on the mean pore diameter.
In some embodiments, the particles exhibit a loss of attrition resistance of about 0.1 °1o by weight or less.
In certain embodiments, at least some of the plurality of substantially spherical ~ 5 porous silica particles include one or more therapeutic agents, one or more ferromagnetic materials, one or more MRI visible materials and/or one or more radiopaque materials.
In some embodiments, the plurality of substantially spherical porous silica particles are sterilized.
In some embodiments, the composition is administered to the subject by 2o percutaneous injection.
W certain embodiments, the composition is administered to the subject by a catheter.
hi some embodiments, the composition is used to treat a cancer condition. The cancer condition can be, for example, ovarian cancer, colorectal cancer, thyroid cancer, 25 gastrointestinal cancer, breast cancer, prostate cancer and/or lung cancer.
Treating the cancer condition can include at least partially occluding a lumen in the subject that provides nutrients to a site of the cancer condition with at least some of the plurality of particles.
In certain embodiments, the method includes at least partially occluding a lumen 3o in the subject with at least some of a plurality of particles.
Embodiments may include one or more of the following advantages.
In some embodiments, the silica particles can be substantially biologically inert and non-degradable in the body.
Tn certain embodiments, the particles can have, and can maintain after implantation, a highly uniform diameter, geometry, pore volume, and pore size.
In general, the particle diameter, geometry, pore volume and pore diameter can be selected based on a desired application. As an example, in some embodiments (e.g., for embolic applications), the particles may have a spherical geometry with a particle diameter of about 3000 microns or less (e.g., about 1500 microns or less) and a relatively o large pore volume, to enhance the suspendability of the particles in a delivery medium such as a contrast agent, and a relatively small pore size to enhance surface uniformity, robustness and abrasion resistance. As another example, in certain embodiments (e.g., for a therapeutic agent delivery applications), pore volume can be selected to contain a desired therapeutic agent volume, and pore size can be selected to produce a desired time ~5 release, based on diffusion of therapeutic agent from the pores.
In some embodiments, the particles can be made targetable by incorporation of a magnetic material.
In certain embodiments, the particles can be highly incompressible and exhibit a high crushing strength such that they can withstand contact and delivery through a 2o syringe, catheter or the like, as well as, withstand internal body fluid pressure without fracturing.
Features and advantages are in the description, drawings, and claims.
DESCRIPTION OF DRAWINGS
FIG. 1A is a schematic illustrating uterine artery embolization.
25 FIG. 1B is a greatly enlarged view of region A of FIG. 1A.
FIG 2 is a cross-sectional view of a silica embolic particle.
FIG 3 is a flow diagram of a method of malting silica embolic particles.
Life reference symbols in the various drawings indicate like elements.
DETAILED DESCRIPTION
Referring to FIGS. 1A and 1B, an embolic composition, including embolic particles 111 and a Garner fluid, is injected into a vessel through an instrument such as a catheter 150. Catheter 150 is connected to a syringe barrel 110 with a plunger 160.
Catheter 150 is inserted, for example, into a femoral artery 120 of a subject.
Catheter 150 delivers the embolic composition to, for example, occlude a uterine artery 130 leading to a fibroid 140. Fibroid 140 is located in the uterus of a female subject. The embolic composition is initially loaded into syringe 110. Plunger 160 of syringe 110 is then compressed to deliver the embolic composition through catheter 150 into a lumen 165 of 1o uterine artery 130.
FIG. 1B, which is an enlarged view of section 1B of FIG. 1A, shows a uterine artery 130 that is subdivided into smaller uterine vessels 170 (e.g., having a diameter of about two millimeters or less) which feed fibroid 140. The embolic particles 111 in the embolic composition partially or totally fill the lumen of uterine artery 130, either ~ 5 partially or completely occluding the lumen of the uterine artery 130 that feeds uterine fibroid 140.
In general, embolic compositions can be used in, for example, neural, pulmonary, and/or AAA (abdominal aortic aneurysm) applications. The compositions can be used in the treatment of, for example, fibroids, tmnors, internal bleeding, arteriovenous 2o malformations (AVMs), and/or hypervascular tumors. The compositions can be used as, for example, fillers for aneurysm sacs, AAA sac (Type II endolealcs), endoleal~ sealants, arterial sealants, and/or puncture sealmts, and/or can be used to provide occlusion of other lumens such as fallopian tubes. Fibroids can include uterine fibroids which grow within the uterine wall (intramural type), on the outside of the uterus (subserosal type), 2s inside the uterine cavity (submucosal type), between the layers of broad ligament supporting the uterus (interligamentous type), attached to another organ (parasitic type), or on a mushroom-like stall (pedunculated type). Internal bleeding includes gastrointestinal, urinary, renal and varicose bleeding. AVMs are for example, abnormal collections of blood vessels, e.g. in the brain, which shunt blood from a high pressure 3o artery to a low pressure vein, resulting in hypoxia and malnutrition of those regions from which the blood is diverted. 111 some embodiments, a composition containing the particles can be used to prophylactically treat a condition.
The magnitude of a dose of an embolic composition can vary based on the nature, location and severity of the condition to be treated, as well as the route of administration.
A physician treating the condition, disease or disorder can determine an effective amount of embolic composition. An effective amount of embolic composition refers to the amount sufficient to result in amelioration of symptoms or a prolongation of survival of the subject. The embolic compositions can be administered as pharmaceutically acceptable compositions to a subject in any therapeutically acceptable dosage, including 1o those administered to a subject intravenously, subcutaneously, percutaneously, intratrachealy, intramuscularly, intramucosaly, intracutaneously, intra-articularly, orally or parenterally.
An embolic composition can be prepared in calibrated concentrations of the particles for ease of delivery by the physician. Suspensions of the particles in saline solution can be prepared to remain stable (e.g., to not precipitate) over a duration of time.
A suspension of the particles can be stable, for example, for from about one minute to about 20 minutes (e.g. from about one minute to about ten minutes, from about two minutes to about seven minutes, from about three minutes to about six minutes). The concentration of pai.-ticles can be determined by adjusting the weight ratio of the particles 2o to the physiological solution. If the weight ratio of the particles is too small, then too much liquid could be injected into a blood vessel, possibly allowing the particles to stray into lateral vessels. In some embodiments, the physiological solution can contain from about 0.01 weight percent to about 15 weight percent of the particles. A
composition can include a mixture of particles, such as particles including one type of surface preferential material and particles including another, different, type of surface preferential material.
In some embodiments, among the particles delivered to a subject in an embolic composition, the majority (e.g., about 50 percent or more, about 60 percent or more, about 70 percent or more, about 80 percent or more, about 90 percent or more) of the particles have a diameter of about 3,000 microns or less (e.g., about 2,500 microns or less; about 2,000 microns or less; about 1,500 microns or less; about 1,200 microns or less; about 900 microns or less; about 700 microns or less; about 500 microns or less;
about 400 microns or less; about 300 microns or less; about 100 microns or less) and/or about ten microns or more (e.g., about 100 microns or more; about 300 microns or more;
about 400 microns or more; about 500 microns or more; about 700 microns or more;
about 900 microns or more; about 1,200 microns or more; about 1,500 microns or more;
about 2,000 microns or more; about 2,500 microns or more).
In certain embodiments, the particles delivered to a subject in an embolic composition have a mean diameter of about 3,000 microns or less (e.g., about 2,500 microns or less; about 2,000 microns or less; about 1,500 microns or less;
about 1,200 o microns or less; about 900 microns or less; about 700 microns or less; about 500 microns or less; about 400 microns or less; about 300 microns or less; about 100 microns or less) and/or about ten microns or more (e.g., about 100 microns or more; about 300 microns or more; about 400 microns or more; about 500 microns or more; about 700 microns or more; about 900 microns or more; about 1,200 microns or more; about 1,500 microns or ~5 more; about 2,000 microns or more; about 2,500 microns or more). Exemplary ranges for the mean diameter of particles delivered to a subject include from about 100 microns to about 500 microns; from about 100 microns to about 300 microns; from about microns to about 500 microns; from about 500 microns to about 700 microns; and from about 900 microns to about 1,200 microns. In general, the particles delivered to a subject 2o in an embolic composition have a mean diameter in approximately the middle of the rmge of the diameters of the individual particles, and a variance of about 20 percent or less (e.g. about 15 percent or less, about ten percent or less).
In some embodiments, the mean size of the particles delivered to a subject in an embolic composition can vary depending upon the particular condition to be treated. As 25 an example, in embodiments in which the particles in an embolic composition are used to treat a liver tumor, the particles delivered to the subject can have a mean diameter of about 500 microns or less (e.g., from about 100 microns to about 300 microns;
from about 300 microns to about 500 microns). As another example, in embodiments in which the particles in an embolic composition are used to treat a uterine fibroid, the particles so delivered to the subject in an embolic composition can have a mean diameter of about 1,200 microns or less (e.g., from about 500 microns to about 700 microns; from about 700 microns to about 900 microns; from about 900 microns to about 1,200 microns).
FIG. 2 shows a cross-section of a silica particle 111 having pores 112.
hi general, particle 111 is substantially spherical. For example, in some embodiments, particle 111 can have a sphericity of about 0.8 or more (e.g., about 0.85 or more, about 0.9 or more, about 0.95 or more, about 0.97 or more). The sphericity of a particle can be determined using a Becl~nan Coulter RapidVZJE Image Analyzer version 2.06 (Beckman Coulter, Miami, FL). Briefly, the RapidWE tales an image of continuous-tone (gray-scale) form and converts it to a digital form through the process of o sampling a~.zd quantization. The system software identifies and measures particles in a~.i image in the form of a fiber, rod or sphere. The sphericity of a particle, which is computed as Da/Dp (where Da = ~(4A/~); Dp = P/~ ; A = pixel area; P = pixel perimeter), is a value from zero to one, with one representing a perfect circle.
In certain embodiments, particle 111 has a diameter of about 3,000 microns or ~5 less (e.g., about 2,500 microns or less; about 2,000 microns or less; about 1,500 microns or less; about 1,200 microns or less; about 900 microns or less; about 700 microns or less; about 500 microns or less; about 400 microns or less; about 300 microns or less;
about 100 microns or less) a~zd/or about ten microns or more (e.g., about 100 microns or more; about 300 microns or more; about 400 microns or more; about 500 microns or 2o snore; about 700 microns or more; about 900 microns or more; about 1,200 microns or more; about 1,500 microns or more; about 2,000 microns or more; about 2,500 microns or more). Exemplary ranges for the diameter of particle 111 include from about microns to about 500 microns; from about 100 microns to about 300 microns;
from about 300 microns to about 500 microns; from about 500 microns to about 700 microns;
and 25 from about 900 microns to about 1,200 microns.
In some embodiments, particle 111 has a substantially uniform pore structure.
In certain embodiments, particle 111 has non-uniform pore structure.
In certain embodiments, pores 112 can intercomzect throughout particle 111. In some embodiments, pores 112 do not interconnect throughout particle 111.
In some embodiments, the diameters of pores 112 in particle 111 are about 20 manometers or more (e.g., about 30 manometers or more, about 40 manometers or more) and/or about 90 manometers or less (e.g., about 80 manometers or less, about manometers or less, about 60 manometers or less).
In general, the density of particle 111 (e.g., as measured in grams of material per unit volume) is such that it can be readily suspended in a carrier fluid (e.g., a pharmaceutically acceptable carrier, such as a saline solution, a contrast solution, or a mixture thereof and remain suspended during delivery (e.g., to form a composition, such as an embolization composition). In some embodiments, the density of particle 111 is o from about 1.1 grams per cubic centimeter to about 1.4 grams per cubic centimeter. As an example, for suspension in a saline-contrast solution, the density of particle 111 can be from about 1.2 grams per cubic centimeter to about 1.3 grams per cubic centimeter.
In some embodiments, particle 111 can have a high pore diameter and/or a high pore volume uniformity. For example, particle 111 can have a pore diameter distribution ~5 such that about 70% or more of the pore volume is made up pores having pore diameters which have a tolerance of not more than 10 manometers on the mean pore diameter. Pore volume and diameter can be measured by mercury porosimetry.
In certain embodiments, particle 111 can exhibit good resistance to abrasion.
For example, a particle can exhibit no detectable loss in attrition resistance. In some 2o embodiments, the loss of attrition of particle 111, as measured using a standard attrition test according to the Peter Spence method, is about 0.1 weight percent or less (e.g., about 0.05 weight percent or less). In some embodiments, particle 111 can exhibit high crush strength.
Characterization of silica particles is disclosed, for example, in U.S. Patent No.
25 4,640,807 and European Patent No. 067459, both of which are hereby incorporated by refer ence.
In some embodiments, particle 111 can include one or more therapeutic agents (e.g., drugs). The therapeutic agent can be in and/or on particle 111. For example, pores 112 of particle 111 can include a therapeutic agent.
Therapeutic agents include agents that are negatively charged, positively charged, amphoteric, or neutral. Therapeutic agents can be, for example, materials that are biologically active to treat physiological conditions; pharmaceutically active compounds;
gene therapies; nucleic acids with and without carrier vectors;
oligonucleotides;
gene/vector systems; DNA chimeras; compacting agents (e.g., DNA compacting agents);
viruses; polymers; hyaluronic acid; proteins (e.g., enzymes such as ribozymes); cells (of human origin, from an animal source, or genetically engineered); stem cells;
immunologic species; nonsteroidal anti-inflammatory medications; oral contraceptives;
progestins; gonadotrophin-releasing hormone agonists; chemotherapeutic agents;
and 1o radioactive species (e.g., radioisotopes, radioactive molecules). Non-limiting exa~.nples of therapeutic agents include anti-thrombogenic agents; antioxidants;
angiogenic and anti-angiogenic agents and factors; anti-proliferative agents (e.g., agents capable of blocl~ing smooth muscle cell proliferation); anti-inflammatory agents; calcium entry bloclcers; antineoplastic/antiproliferative/anti-mitotic agents (e.g., paclitaxel, doxorubicin, ~ 5 cisplatin); antimicrobials; anesthetic agents; anti-coagulants; vascular cell growth promoters; vascular cell growth inhibitors; cholesterol-lowering agents;
vasodilating agents; agents which interfere with endogenous vasoactive mechanisms; and survival genes which protect against cell death. Therapeutic agents are described, for example, in co-pending U. S. Patent Application No. 10/615,276, filed on July 8, 2003, and entitled 20 "Agent Delivery Particle", which is incorporated herein by reference.
Referring to FIG. 3, particles 111 can be prepared by adaptation of processes described in IJ.S. Patent No. 4,640,807 and European Patent No. 067459. In step 300, a silica hydrosol mix is prepared by thorough mixing of an allcali metal silicate and an acid.
Next, in step 310, the silica hydrosol is converted to hydrogel particles by dropping the 25 hydrosol mix through a water-immiscible liquid into an aqueous solution.
Controlling the break-up of the hydrosol stream enables control of size (e.g., diameter) and shape of the resulting particles. Next, in step 320, the hydrogel particles are partially dried in humid air with temperatures, for example, above 100 °C, wherein a controlled amount of water is removed from the particles. The amount of water removed from the particles can 3o be varied, enabling control of the pore volume of the resulting particles.
Further, partial drying can reduce (e.g., prevent) formation of cracl~s resulting in increased crushing strength. A high crushing strength can enable particles 111 to withstand contact and delivery through a syringe, catheter, or the lilce, as well as, withstand internal body fluid pressure without fracturing. Partial drying in the presence of humid air can yield s particles with a narrow distribution of size (i.e., diameter of particles).
Next, in step 330, the particles are subjected to hydrothermal treatment (a treatment at elevated temperatures with liquid water and/or water vapor). The hydrothermal treatment yields particles with a narrow distribution of pore diameter. Next, in step 340, the canon content of the hydrogel particles is lowered by removing all~ali metals.
Finally, in step 0 350, the particles are dried, at temperatures, for example, about 200 °C, and optionally calcined. The particles can be sterilized by e.g., heat or radiation treatment, and suspended in a suitable carrier, e.g., saline and/or a contrast solution such as, Ormzipaque 300 (Nycomed, Buclcinghamshire, LTK. Omnipaque is an aqueous solution of Iohexol, N.N.-Bis (2,3-dihydroxypropyl)-T [N-(2,3-dihydroxypropyl)-acetamide]-2,4,6-trilodo-~s isophthalamide; Omnipaque 300 contains 647 mg of iohexol equivalent to 300 mg of organic iodine per ml).
The particle diameter, pore diameter and volume and/or uniformity caaz be controlled to produce particles optimized for a particular application. For example, for a therapeutic delivery application, particle diameter and pore volume can be selected to 2o contain a desired amount of therapeutic agent. The pore diameter can be selected to elute the therapeutic agent into the body based on diffusion processes at a desired rate. A
composition including a mixture of particles having l~nown percentages of particles with different particle diameters, pore diameter and pore volume can be prepared to produce a desired dosage profile. Particles of different diameters and pore characteristics can also 25 include different therapeutic agent s. The therapeutic agent delivery particles can be implanted into a lumen, e.g., a vascular lumen by catheterization, e.g., as embolic particles, or inj ected into soft tissue adj acent a cancerous tumor or other lesion.
While certain embodiments have been described, the invention is not so limited.
As an example, in some embodiments a particle can be coated (e.g., with a 3o bioabsorbable material, such as sodium alginate). The coating can contain, for example, one or more therapeutic agents. In some cases, the coating can be, for example, a degradable and/or bioabsorbable poly~.ner which erodes when the particle is administered.
The coating can assist in controlling the rate at which therapeutic agent is released from the particle (e.g., from the surface preferential material). For example, the coating can be in the form of a porous membrane. The coating can delay an initial burst of therapeutic agent release. The coating can be applied by dipping or spraying the particle.
The erodible polyner can be a polysaccharide (such as an alginate) or a polysaccharide derivative. In some embodiments, the coating can be an inorganic, ionic salt.
Other erodible coatings include water soluble polymers (such as polyvinyl alcohol, e.g., that has o not been cross-linked), biodegradable poly DL-lactide-poly ethylene glycol (PELA), hydrogels (e.g., polyacrylic acid, haluronic acid, gelatin, carboxymethyl cellulose), polyethylene glycols (PEG), chitosan, polyesters (e.g., polycaprolactones), and poly(lactic-co-glycolic) acids (e.g., poly(d-lactic-co-glycolic) acids). The coating can include therapeutic agent or can be substantially free of therapeutic agent.
The therapeutic agent in the coating ca~.z be the same as or different from an agent on a surface layer of the particle. Apolymer coating, e.g. an erodible coating, can be applied to the particle surface in cases in which a high concentration of therapeutic agent has not been applied to the particle surface. Coatings are described, for example, in U.S.
Patent Application No. 10/615,276, filed on July 8, 2003, and entitled "Agent Delivery 2o Particle", which is incorporated herein by reference.
As an additional example, in some embodiments one or more particles is/are substantially nonspherical. In some embodiments, pa~.-ticles can be shaped (e.g., molded, compressed, punched, and/or agglomerated with other particles) at different points in the particle manufacturing process. Shaped particles are described, for example, in Bourne et al., U. S. Published Patent Application No. US 2003/0203985 Al, which is incorporated herein by reference.
As a further example, in some embodiments the particles can be used for tissue bulling. As an example, the particles can be placed (e.g., injected) into tissue adjacent to a body passageway. The particles can narrow the passageway, thereby providing bulls 3o and allowing the tissue to constrict the passageway more easily The particles can be placed in the tissue according to a number of different methods, for example, percutaneously, laparoscopically, and/or through a catheter. In certain embodiments, a cavity can be formed in the tissue, and the particles can be placed in the cavity Particle tissue bulking can be used to treat, for example, intrinsic sphincteric deficiency (ISD), vesicoureteral reflux, gastroesophageal reflux disease (GERD), and/or vocal cord paralysis (e.g., to restore glottic competence in cases of paralytic dysphonia). In some embodiments, particle tissue bulking can be used to treat urinary incontinence and/or fecal incontinence. The particles can be used as a graft material or a filler to fill and/or to smooth out soft tissue defects, such as for reconstructive or cosmetic applications (e.g., o surgery). Examples of soft tissue defect applications include cleft lips, scars (e.g., depressed scars from chicken pox or acne scars), indentations resulting from liposuction, wriz~lcles (e.g., glabella frown wrinkles), and soft tissue augmentation of thin lips. Tissue bulling is described, for exa~.nple, in Bourne et al., U.S. Published Patent Application No.
US 2003/0233150 A1, which is incorporated herein by reference.
As another example, the particles can include (e.g., encapsulate) diagnostic agents) such as a radiopaque material, an MRI-visible material, a ferromag~.ietic material, and/or an ultrasound contrast agent. For example, a silica particle can encapsulate a ferromagnetic material so that the position of the particle in a lumen can be manipulated with a magnetic field. The mag~zetic field can be created outside the subject or inside the 2o subject (e.g., via a magnetic catheter). In some embodiments, a ferromagnetic material can be incorporated into silica particles by adding the magnetic material to the silica hydrosol mix (step 300, FIG 3) and forming particles as illustrated in FIG 3.
Particles containing diagnostic agents are described in U.S. Patent Application Serial No.
10/651,475, filed on August 29, 2003, and entitled "Embolization", and magnetic devices are described in U.S. Patent Application No. 10/108,874, filed on March 29, 2002, and entitled "Magnetically Enhanced Injection Catheter", both of which are incorporated herein by reference.
As yet another example, in certain embodiments, a particle can include one or more therapeutic agents (e.g., in the pores of the particle) and one or more diagnostic 3o agents (e.g., one or more ferromagnetic materials encapsulated in the silica). In certain embodiments, a therapeutic agent can be conjugated with a diagnostic agent.
Including both therapeutic agents) and diagnostic agents) in a particle can enhance the ability to deliver the therapeutic agent in a targeted way. , As a further example, in some embodiments a particle contains materials in addition to silica. For example, in some embodiments, the particle can include one or more polymeric materials (e.g., matrix polymeric materials). Examples of polymeric materials include polyvinyl alcohols, polyacrylic acids, polymethacrylic acids, poly vinyl sulfonates, carboxymethyl celluloses, hydroxyethyl celluloses, substituted celluloses, polyacrylamides, polyethylene glycols, polyamides, polyureas, polyurethanes, polyesters, o polyethers, polystyrenes, polysaccharides, polylactic acids, polyethylenes, polymethylmethacrylates, polycaprolactones, polyglycolic acids, poly(lactic-co-glycolic) acids (e.g., poly(d-lactic-co-glycolic) acids), and copolymers or mixtures thereof. In some embodiments, the polymer can be substantially formed of a highly water insoluble, high molecular weight polymer. An example of such a polymer is a high molecular ~ 5 weight polyvinyl alcohol (PVA) that has been acetalized. A polymer can be substantially pure intrachain 1,3-acetalized PVA and substantially free of animal derived residue such as collagen. Examples of particles containing such materials are disclosed in U.S. Patent Application Serial No. 10/637,130, filed August 8, 2003, and entitled "Embolization", which is hereby incorporated by reference.
2o As an additional example, in some embodiments, a particle can be shaped, such as described, for example, in U.S. Patent Application No. 10/700,970, filed on November 4, 2003, and entitled "Embolization", and U.S. Patent Application No. 10/700,403 filed on November 4, 2003, and entitled "Embolization", both of which are incorporated herein by reference.
25 As another example, in some embodiments a particle can be formed with no pores and/or no cavities.
Other embodiments are in the claims.
In some embodiments, the silica particles can be substantially biologically inert and non-degradable in the body.
Tn certain embodiments, the particles can have, and can maintain after implantation, a highly uniform diameter, geometry, pore volume, and pore size.
In general, the particle diameter, geometry, pore volume and pore diameter can be selected based on a desired application. As an example, in some embodiments (e.g., for embolic applications), the particles may have a spherical geometry with a particle diameter of about 3000 microns or less (e.g., about 1500 microns or less) and a relatively o large pore volume, to enhance the suspendability of the particles in a delivery medium such as a contrast agent, and a relatively small pore size to enhance surface uniformity, robustness and abrasion resistance. As another example, in certain embodiments (e.g., for a therapeutic agent delivery applications), pore volume can be selected to contain a desired therapeutic agent volume, and pore size can be selected to produce a desired time ~5 release, based on diffusion of therapeutic agent from the pores.
In some embodiments, the particles can be made targetable by incorporation of a magnetic material.
In certain embodiments, the particles can be highly incompressible and exhibit a high crushing strength such that they can withstand contact and delivery through a 2o syringe, catheter or the like, as well as, withstand internal body fluid pressure without fracturing.
Features and advantages are in the description, drawings, and claims.
DESCRIPTION OF DRAWINGS
FIG. 1A is a schematic illustrating uterine artery embolization.
25 FIG. 1B is a greatly enlarged view of region A of FIG. 1A.
FIG 2 is a cross-sectional view of a silica embolic particle.
FIG 3 is a flow diagram of a method of malting silica embolic particles.
Life reference symbols in the various drawings indicate like elements.
DETAILED DESCRIPTION
Referring to FIGS. 1A and 1B, an embolic composition, including embolic particles 111 and a Garner fluid, is injected into a vessel through an instrument such as a catheter 150. Catheter 150 is connected to a syringe barrel 110 with a plunger 160.
Catheter 150 is inserted, for example, into a femoral artery 120 of a subject.
Catheter 150 delivers the embolic composition to, for example, occlude a uterine artery 130 leading to a fibroid 140. Fibroid 140 is located in the uterus of a female subject. The embolic composition is initially loaded into syringe 110. Plunger 160 of syringe 110 is then compressed to deliver the embolic composition through catheter 150 into a lumen 165 of 1o uterine artery 130.
FIG. 1B, which is an enlarged view of section 1B of FIG. 1A, shows a uterine artery 130 that is subdivided into smaller uterine vessels 170 (e.g., having a diameter of about two millimeters or less) which feed fibroid 140. The embolic particles 111 in the embolic composition partially or totally fill the lumen of uterine artery 130, either ~ 5 partially or completely occluding the lumen of the uterine artery 130 that feeds uterine fibroid 140.
In general, embolic compositions can be used in, for example, neural, pulmonary, and/or AAA (abdominal aortic aneurysm) applications. The compositions can be used in the treatment of, for example, fibroids, tmnors, internal bleeding, arteriovenous 2o malformations (AVMs), and/or hypervascular tumors. The compositions can be used as, for example, fillers for aneurysm sacs, AAA sac (Type II endolealcs), endoleal~ sealants, arterial sealants, and/or puncture sealmts, and/or can be used to provide occlusion of other lumens such as fallopian tubes. Fibroids can include uterine fibroids which grow within the uterine wall (intramural type), on the outside of the uterus (subserosal type), 2s inside the uterine cavity (submucosal type), between the layers of broad ligament supporting the uterus (interligamentous type), attached to another organ (parasitic type), or on a mushroom-like stall (pedunculated type). Internal bleeding includes gastrointestinal, urinary, renal and varicose bleeding. AVMs are for example, abnormal collections of blood vessels, e.g. in the brain, which shunt blood from a high pressure 3o artery to a low pressure vein, resulting in hypoxia and malnutrition of those regions from which the blood is diverted. 111 some embodiments, a composition containing the particles can be used to prophylactically treat a condition.
The magnitude of a dose of an embolic composition can vary based on the nature, location and severity of the condition to be treated, as well as the route of administration.
A physician treating the condition, disease or disorder can determine an effective amount of embolic composition. An effective amount of embolic composition refers to the amount sufficient to result in amelioration of symptoms or a prolongation of survival of the subject. The embolic compositions can be administered as pharmaceutically acceptable compositions to a subject in any therapeutically acceptable dosage, including 1o those administered to a subject intravenously, subcutaneously, percutaneously, intratrachealy, intramuscularly, intramucosaly, intracutaneously, intra-articularly, orally or parenterally.
An embolic composition can be prepared in calibrated concentrations of the particles for ease of delivery by the physician. Suspensions of the particles in saline solution can be prepared to remain stable (e.g., to not precipitate) over a duration of time.
A suspension of the particles can be stable, for example, for from about one minute to about 20 minutes (e.g. from about one minute to about ten minutes, from about two minutes to about seven minutes, from about three minutes to about six minutes). The concentration of pai.-ticles can be determined by adjusting the weight ratio of the particles 2o to the physiological solution. If the weight ratio of the particles is too small, then too much liquid could be injected into a blood vessel, possibly allowing the particles to stray into lateral vessels. In some embodiments, the physiological solution can contain from about 0.01 weight percent to about 15 weight percent of the particles. A
composition can include a mixture of particles, such as particles including one type of surface preferential material and particles including another, different, type of surface preferential material.
In some embodiments, among the particles delivered to a subject in an embolic composition, the majority (e.g., about 50 percent or more, about 60 percent or more, about 70 percent or more, about 80 percent or more, about 90 percent or more) of the particles have a diameter of about 3,000 microns or less (e.g., about 2,500 microns or less; about 2,000 microns or less; about 1,500 microns or less; about 1,200 microns or less; about 900 microns or less; about 700 microns or less; about 500 microns or less;
about 400 microns or less; about 300 microns or less; about 100 microns or less) and/or about ten microns or more (e.g., about 100 microns or more; about 300 microns or more;
about 400 microns or more; about 500 microns or more; about 700 microns or more;
about 900 microns or more; about 1,200 microns or more; about 1,500 microns or more;
about 2,000 microns or more; about 2,500 microns or more).
In certain embodiments, the particles delivered to a subject in an embolic composition have a mean diameter of about 3,000 microns or less (e.g., about 2,500 microns or less; about 2,000 microns or less; about 1,500 microns or less;
about 1,200 o microns or less; about 900 microns or less; about 700 microns or less; about 500 microns or less; about 400 microns or less; about 300 microns or less; about 100 microns or less) and/or about ten microns or more (e.g., about 100 microns or more; about 300 microns or more; about 400 microns or more; about 500 microns or more; about 700 microns or more; about 900 microns or more; about 1,200 microns or more; about 1,500 microns or ~5 more; about 2,000 microns or more; about 2,500 microns or more). Exemplary ranges for the mean diameter of particles delivered to a subject include from about 100 microns to about 500 microns; from about 100 microns to about 300 microns; from about microns to about 500 microns; from about 500 microns to about 700 microns; and from about 900 microns to about 1,200 microns. In general, the particles delivered to a subject 2o in an embolic composition have a mean diameter in approximately the middle of the rmge of the diameters of the individual particles, and a variance of about 20 percent or less (e.g. about 15 percent or less, about ten percent or less).
In some embodiments, the mean size of the particles delivered to a subject in an embolic composition can vary depending upon the particular condition to be treated. As 25 an example, in embodiments in which the particles in an embolic composition are used to treat a liver tumor, the particles delivered to the subject can have a mean diameter of about 500 microns or less (e.g., from about 100 microns to about 300 microns;
from about 300 microns to about 500 microns). As another example, in embodiments in which the particles in an embolic composition are used to treat a uterine fibroid, the particles so delivered to the subject in an embolic composition can have a mean diameter of about 1,200 microns or less (e.g., from about 500 microns to about 700 microns; from about 700 microns to about 900 microns; from about 900 microns to about 1,200 microns).
FIG. 2 shows a cross-section of a silica particle 111 having pores 112.
hi general, particle 111 is substantially spherical. For example, in some embodiments, particle 111 can have a sphericity of about 0.8 or more (e.g., about 0.85 or more, about 0.9 or more, about 0.95 or more, about 0.97 or more). The sphericity of a particle can be determined using a Becl~nan Coulter RapidVZJE Image Analyzer version 2.06 (Beckman Coulter, Miami, FL). Briefly, the RapidWE tales an image of continuous-tone (gray-scale) form and converts it to a digital form through the process of o sampling a~.zd quantization. The system software identifies and measures particles in a~.i image in the form of a fiber, rod or sphere. The sphericity of a particle, which is computed as Da/Dp (where Da = ~(4A/~); Dp = P/~ ; A = pixel area; P = pixel perimeter), is a value from zero to one, with one representing a perfect circle.
In certain embodiments, particle 111 has a diameter of about 3,000 microns or ~5 less (e.g., about 2,500 microns or less; about 2,000 microns or less; about 1,500 microns or less; about 1,200 microns or less; about 900 microns or less; about 700 microns or less; about 500 microns or less; about 400 microns or less; about 300 microns or less;
about 100 microns or less) a~zd/or about ten microns or more (e.g., about 100 microns or more; about 300 microns or more; about 400 microns or more; about 500 microns or 2o snore; about 700 microns or more; about 900 microns or more; about 1,200 microns or more; about 1,500 microns or more; about 2,000 microns or more; about 2,500 microns or more). Exemplary ranges for the diameter of particle 111 include from about microns to about 500 microns; from about 100 microns to about 300 microns;
from about 300 microns to about 500 microns; from about 500 microns to about 700 microns;
and 25 from about 900 microns to about 1,200 microns.
In some embodiments, particle 111 has a substantially uniform pore structure.
In certain embodiments, particle 111 has non-uniform pore structure.
In certain embodiments, pores 112 can intercomzect throughout particle 111. In some embodiments, pores 112 do not interconnect throughout particle 111.
In some embodiments, the diameters of pores 112 in particle 111 are about 20 manometers or more (e.g., about 30 manometers or more, about 40 manometers or more) and/or about 90 manometers or less (e.g., about 80 manometers or less, about manometers or less, about 60 manometers or less).
In general, the density of particle 111 (e.g., as measured in grams of material per unit volume) is such that it can be readily suspended in a carrier fluid (e.g., a pharmaceutically acceptable carrier, such as a saline solution, a contrast solution, or a mixture thereof and remain suspended during delivery (e.g., to form a composition, such as an embolization composition). In some embodiments, the density of particle 111 is o from about 1.1 grams per cubic centimeter to about 1.4 grams per cubic centimeter. As an example, for suspension in a saline-contrast solution, the density of particle 111 can be from about 1.2 grams per cubic centimeter to about 1.3 grams per cubic centimeter.
In some embodiments, particle 111 can have a high pore diameter and/or a high pore volume uniformity. For example, particle 111 can have a pore diameter distribution ~5 such that about 70% or more of the pore volume is made up pores having pore diameters which have a tolerance of not more than 10 manometers on the mean pore diameter. Pore volume and diameter can be measured by mercury porosimetry.
In certain embodiments, particle 111 can exhibit good resistance to abrasion.
For example, a particle can exhibit no detectable loss in attrition resistance. In some 2o embodiments, the loss of attrition of particle 111, as measured using a standard attrition test according to the Peter Spence method, is about 0.1 weight percent or less (e.g., about 0.05 weight percent or less). In some embodiments, particle 111 can exhibit high crush strength.
Characterization of silica particles is disclosed, for example, in U.S. Patent No.
25 4,640,807 and European Patent No. 067459, both of which are hereby incorporated by refer ence.
In some embodiments, particle 111 can include one or more therapeutic agents (e.g., drugs). The therapeutic agent can be in and/or on particle 111. For example, pores 112 of particle 111 can include a therapeutic agent.
Therapeutic agents include agents that are negatively charged, positively charged, amphoteric, or neutral. Therapeutic agents can be, for example, materials that are biologically active to treat physiological conditions; pharmaceutically active compounds;
gene therapies; nucleic acids with and without carrier vectors;
oligonucleotides;
gene/vector systems; DNA chimeras; compacting agents (e.g., DNA compacting agents);
viruses; polymers; hyaluronic acid; proteins (e.g., enzymes such as ribozymes); cells (of human origin, from an animal source, or genetically engineered); stem cells;
immunologic species; nonsteroidal anti-inflammatory medications; oral contraceptives;
progestins; gonadotrophin-releasing hormone agonists; chemotherapeutic agents;
and 1o radioactive species (e.g., radioisotopes, radioactive molecules). Non-limiting exa~.nples of therapeutic agents include anti-thrombogenic agents; antioxidants;
angiogenic and anti-angiogenic agents and factors; anti-proliferative agents (e.g., agents capable of blocl~ing smooth muscle cell proliferation); anti-inflammatory agents; calcium entry bloclcers; antineoplastic/antiproliferative/anti-mitotic agents (e.g., paclitaxel, doxorubicin, ~ 5 cisplatin); antimicrobials; anesthetic agents; anti-coagulants; vascular cell growth promoters; vascular cell growth inhibitors; cholesterol-lowering agents;
vasodilating agents; agents which interfere with endogenous vasoactive mechanisms; and survival genes which protect against cell death. Therapeutic agents are described, for example, in co-pending U. S. Patent Application No. 10/615,276, filed on July 8, 2003, and entitled 20 "Agent Delivery Particle", which is incorporated herein by reference.
Referring to FIG. 3, particles 111 can be prepared by adaptation of processes described in IJ.S. Patent No. 4,640,807 and European Patent No. 067459. In step 300, a silica hydrosol mix is prepared by thorough mixing of an allcali metal silicate and an acid.
Next, in step 310, the silica hydrosol is converted to hydrogel particles by dropping the 25 hydrosol mix through a water-immiscible liquid into an aqueous solution.
Controlling the break-up of the hydrosol stream enables control of size (e.g., diameter) and shape of the resulting particles. Next, in step 320, the hydrogel particles are partially dried in humid air with temperatures, for example, above 100 °C, wherein a controlled amount of water is removed from the particles. The amount of water removed from the particles can 3o be varied, enabling control of the pore volume of the resulting particles.
Further, partial drying can reduce (e.g., prevent) formation of cracl~s resulting in increased crushing strength. A high crushing strength can enable particles 111 to withstand contact and delivery through a syringe, catheter, or the lilce, as well as, withstand internal body fluid pressure without fracturing. Partial drying in the presence of humid air can yield s particles with a narrow distribution of size (i.e., diameter of particles).
Next, in step 330, the particles are subjected to hydrothermal treatment (a treatment at elevated temperatures with liquid water and/or water vapor). The hydrothermal treatment yields particles with a narrow distribution of pore diameter. Next, in step 340, the canon content of the hydrogel particles is lowered by removing all~ali metals.
Finally, in step 0 350, the particles are dried, at temperatures, for example, about 200 °C, and optionally calcined. The particles can be sterilized by e.g., heat or radiation treatment, and suspended in a suitable carrier, e.g., saline and/or a contrast solution such as, Ormzipaque 300 (Nycomed, Buclcinghamshire, LTK. Omnipaque is an aqueous solution of Iohexol, N.N.-Bis (2,3-dihydroxypropyl)-T [N-(2,3-dihydroxypropyl)-acetamide]-2,4,6-trilodo-~s isophthalamide; Omnipaque 300 contains 647 mg of iohexol equivalent to 300 mg of organic iodine per ml).
The particle diameter, pore diameter and volume and/or uniformity caaz be controlled to produce particles optimized for a particular application. For example, for a therapeutic delivery application, particle diameter and pore volume can be selected to 2o contain a desired amount of therapeutic agent. The pore diameter can be selected to elute the therapeutic agent into the body based on diffusion processes at a desired rate. A
composition including a mixture of particles having l~nown percentages of particles with different particle diameters, pore diameter and pore volume can be prepared to produce a desired dosage profile. Particles of different diameters and pore characteristics can also 25 include different therapeutic agent s. The therapeutic agent delivery particles can be implanted into a lumen, e.g., a vascular lumen by catheterization, e.g., as embolic particles, or inj ected into soft tissue adj acent a cancerous tumor or other lesion.
While certain embodiments have been described, the invention is not so limited.
As an example, in some embodiments a particle can be coated (e.g., with a 3o bioabsorbable material, such as sodium alginate). The coating can contain, for example, one or more therapeutic agents. In some cases, the coating can be, for example, a degradable and/or bioabsorbable poly~.ner which erodes when the particle is administered.
The coating can assist in controlling the rate at which therapeutic agent is released from the particle (e.g., from the surface preferential material). For example, the coating can be in the form of a porous membrane. The coating can delay an initial burst of therapeutic agent release. The coating can be applied by dipping or spraying the particle.
The erodible polyner can be a polysaccharide (such as an alginate) or a polysaccharide derivative. In some embodiments, the coating can be an inorganic, ionic salt.
Other erodible coatings include water soluble polymers (such as polyvinyl alcohol, e.g., that has o not been cross-linked), biodegradable poly DL-lactide-poly ethylene glycol (PELA), hydrogels (e.g., polyacrylic acid, haluronic acid, gelatin, carboxymethyl cellulose), polyethylene glycols (PEG), chitosan, polyesters (e.g., polycaprolactones), and poly(lactic-co-glycolic) acids (e.g., poly(d-lactic-co-glycolic) acids). The coating can include therapeutic agent or can be substantially free of therapeutic agent.
The therapeutic agent in the coating ca~.z be the same as or different from an agent on a surface layer of the particle. Apolymer coating, e.g. an erodible coating, can be applied to the particle surface in cases in which a high concentration of therapeutic agent has not been applied to the particle surface. Coatings are described, for example, in U.S.
Patent Application No. 10/615,276, filed on July 8, 2003, and entitled "Agent Delivery 2o Particle", which is incorporated herein by reference.
As an additional example, in some embodiments one or more particles is/are substantially nonspherical. In some embodiments, pa~.-ticles can be shaped (e.g., molded, compressed, punched, and/or agglomerated with other particles) at different points in the particle manufacturing process. Shaped particles are described, for example, in Bourne et al., U. S. Published Patent Application No. US 2003/0203985 Al, which is incorporated herein by reference.
As a further example, in some embodiments the particles can be used for tissue bulling. As an example, the particles can be placed (e.g., injected) into tissue adjacent to a body passageway. The particles can narrow the passageway, thereby providing bulls 3o and allowing the tissue to constrict the passageway more easily The particles can be placed in the tissue according to a number of different methods, for example, percutaneously, laparoscopically, and/or through a catheter. In certain embodiments, a cavity can be formed in the tissue, and the particles can be placed in the cavity Particle tissue bulking can be used to treat, for example, intrinsic sphincteric deficiency (ISD), vesicoureteral reflux, gastroesophageal reflux disease (GERD), and/or vocal cord paralysis (e.g., to restore glottic competence in cases of paralytic dysphonia). In some embodiments, particle tissue bulking can be used to treat urinary incontinence and/or fecal incontinence. The particles can be used as a graft material or a filler to fill and/or to smooth out soft tissue defects, such as for reconstructive or cosmetic applications (e.g., o surgery). Examples of soft tissue defect applications include cleft lips, scars (e.g., depressed scars from chicken pox or acne scars), indentations resulting from liposuction, wriz~lcles (e.g., glabella frown wrinkles), and soft tissue augmentation of thin lips. Tissue bulling is described, for exa~.nple, in Bourne et al., U.S. Published Patent Application No.
US 2003/0233150 A1, which is incorporated herein by reference.
As another example, the particles can include (e.g., encapsulate) diagnostic agents) such as a radiopaque material, an MRI-visible material, a ferromag~.ietic material, and/or an ultrasound contrast agent. For example, a silica particle can encapsulate a ferromagnetic material so that the position of the particle in a lumen can be manipulated with a magnetic field. The mag~zetic field can be created outside the subject or inside the 2o subject (e.g., via a magnetic catheter). In some embodiments, a ferromagnetic material can be incorporated into silica particles by adding the magnetic material to the silica hydrosol mix (step 300, FIG 3) and forming particles as illustrated in FIG 3.
Particles containing diagnostic agents are described in U.S. Patent Application Serial No.
10/651,475, filed on August 29, 2003, and entitled "Embolization", and magnetic devices are described in U.S. Patent Application No. 10/108,874, filed on March 29, 2002, and entitled "Magnetically Enhanced Injection Catheter", both of which are incorporated herein by reference.
As yet another example, in certain embodiments, a particle can include one or more therapeutic agents (e.g., in the pores of the particle) and one or more diagnostic 3o agents (e.g., one or more ferromagnetic materials encapsulated in the silica). In certain embodiments, a therapeutic agent can be conjugated with a diagnostic agent.
Including both therapeutic agents) and diagnostic agents) in a particle can enhance the ability to deliver the therapeutic agent in a targeted way. , As a further example, in some embodiments a particle contains materials in addition to silica. For example, in some embodiments, the particle can include one or more polymeric materials (e.g., matrix polymeric materials). Examples of polymeric materials include polyvinyl alcohols, polyacrylic acids, polymethacrylic acids, poly vinyl sulfonates, carboxymethyl celluloses, hydroxyethyl celluloses, substituted celluloses, polyacrylamides, polyethylene glycols, polyamides, polyureas, polyurethanes, polyesters, o polyethers, polystyrenes, polysaccharides, polylactic acids, polyethylenes, polymethylmethacrylates, polycaprolactones, polyglycolic acids, poly(lactic-co-glycolic) acids (e.g., poly(d-lactic-co-glycolic) acids), and copolymers or mixtures thereof. In some embodiments, the polymer can be substantially formed of a highly water insoluble, high molecular weight polymer. An example of such a polymer is a high molecular ~ 5 weight polyvinyl alcohol (PVA) that has been acetalized. A polymer can be substantially pure intrachain 1,3-acetalized PVA and substantially free of animal derived residue such as collagen. Examples of particles containing such materials are disclosed in U.S. Patent Application Serial No. 10/637,130, filed August 8, 2003, and entitled "Embolization", which is hereby incorporated by reference.
2o As an additional example, in some embodiments, a particle can be shaped, such as described, for example, in U.S. Patent Application No. 10/700,970, filed on November 4, 2003, and entitled "Embolization", and U.S. Patent Application No. 10/700,403 filed on November 4, 2003, and entitled "Embolization", both of which are incorporated herein by reference.
25 As another example, in some embodiments a particle can be formed with no pores and/or no cavities.
Other embodiments are in the claims.
Claims (20)
1. A substantially spherical porous silica particle having a diameter of from about 100 microns to about 3000 microns.
2. The particle of claim 1, wherein the particle has a diameter of at most about 1500 microns.
3. The particle of claim 1, wherein pores in the particle have a diameter of from about 20 nanometers to about 90 nanometers.
4. A composition, comprising:
a plurality of substantially spherical porous silica particles, at least some of the plurality of substantially spherical silica particles having a diameter of from about 100 microns to about 3000 microns; and a carrier fluid, the plurality of substantially spherical porous particles being in the carrier fluid.
a plurality of substantially spherical porous silica particles, at least some of the plurality of substantially spherical silica particles having a diameter of from about 100 microns to about 3000 microns; and a carrier fluid, the plurality of substantially spherical porous particles being in the carrier fluid.
5. The composition of claim 4, wherein the carrier fluid comprises a saline solution.
6. The composition of claim 4, wherein the carrier fluid comprises a contrast agent.
7. The composition of claim 4, wherein at least some of the plurality of substantially spherical porous silica particles have a diameter of at most about 1500 microns.
8. The composition of claim 4, wherein, for at least some of the plurality of substantially spherical porous silica particles, pores in the substantially spherical porous silica particles have a diameter of from about 20 nanometers to about 90 nanometers.
9. The composition of claim 4, wherein, for at least some of the plurality of substantially spherical porous silica particles, a pore volume of the substantially spherical porous silica particles is from about 0.4 ml/g to about 1.6 ml/g.
10. The composition of claim 4, wherein the plurality of substantially spherical porous silica particles have a pore volume distribution such that about 70% or more of the pore volume of the plurality of substantially spherical porous silica particles is made up of pores having pore diameters which have a tolerance of about 10 nm or less on the mean pore diameter.
11. The composition of claim 4, wherein the substantially spherical porous silica particles exhibit a loss of attrition resistance of about 0.1% by weight or less.
12. The composition of claim 4, wherein at least some of the plurality of substantially spherical porous silica particles include a material selected from the group consisting of therapeutic agents, ferromagnetic materials, MRI visible materials and radiopaque materials.
13. The composition of claim 4, wherein the plurality of substantially spherical porous silica particles are sterilized.
14. A method, comprising:
administering to a subject a therapeutically effective amount of a composition including a plurality of substantially spherical porous silica particles in a carrier fluid, at least some of the plurality of substantially spherical porous silica particles having a diameter of from about 100 microns to about 3000 microns.
administering to a subject a therapeutically effective amount of a composition including a plurality of substantially spherical porous silica particles in a carrier fluid, at least some of the plurality of substantially spherical porous silica particles having a diameter of from about 100 microns to about 3000 microns.
15. The method of claim 14, wherein the composition is administered to the subject by percutaneous injection.
16. The method of claim 14, wherein the composition is administered to the subject by a catheter.
17. The method of claim 14, wherein the composition is used to treat a cancer condition.
18. The method of claim 17, wherein the cancer condition is selected from the group consisting of ovarian cancer, colorectal cancer, thyroid cancer, gastrointestinal cancer, breast cancer, prostate cancer, lung cancer and combinations thereof.
19. The method of claim 18, wherein treating the cancer condition includes at least partially occluding a lumen in the subject that provides nutrients to a site of the cancer condition with at least some of the plurality of particles.
20. The method of claim 14, wherein the method includes at least partially occluding a lumen in the subject with at least some of a plurality of particles.
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Families Citing this family (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7842377B2 (en) * | 2003-08-08 | 2010-11-30 | Boston Scientific Scimed, Inc. | Porous polymeric particle comprising polyvinyl alcohol and having interior to surface porosity-gradient |
US7449236B2 (en) * | 2002-08-09 | 2008-11-11 | Boston Scientific Scimed, Inc. | Porous polymeric particle comprising polyvinyl alcohol and having interior to surface porosity-gradient |
US7976823B2 (en) | 2003-08-29 | 2011-07-12 | Boston Scientific Scimed, Inc. | Ferromagnetic particles and methods |
US7311861B2 (en) | 2004-06-01 | 2007-12-25 | Boston Scientific Scimed, Inc. | Embolization |
US20060020246A1 (en) * | 2004-07-22 | 2006-01-26 | Mclucas Bruce | Angiographic catheter for uterine artery embolization |
US8425550B2 (en) | 2004-12-01 | 2013-04-23 | Boston Scientific Scimed, Inc. | Embolic coils |
US7727555B2 (en) | 2005-03-02 | 2010-06-01 | Boston Scientific Scimed, Inc. | Particles |
US7858183B2 (en) | 2005-03-02 | 2010-12-28 | Boston Scientific Scimed, Inc. | Particles |
US7963287B2 (en) | 2005-04-28 | 2011-06-21 | Boston Scientific Scimed, Inc. | Tissue-treatment methods |
US9463426B2 (en) | 2005-06-24 | 2016-10-11 | Boston Scientific Scimed, Inc. | Methods and systems for coating particles |
US8007509B2 (en) | 2005-10-12 | 2011-08-30 | Boston Scientific Scimed, Inc. | Coil assemblies, components and methods |
US8101197B2 (en) | 2005-12-19 | 2012-01-24 | Stryker Corporation | Forming coils |
US8152839B2 (en) | 2005-12-19 | 2012-04-10 | Boston Scientific Scimed, Inc. | Embolic coils |
US7947368B2 (en) | 2005-12-21 | 2011-05-24 | Boston Scientific Scimed, Inc. | Block copolymer particles |
KR101443926B1 (en) | 2006-06-15 | 2014-10-02 | 마이크로벤션, 인코포레이티드 | Embolization device constructed from expansible polymer |
US8414927B2 (en) | 2006-11-03 | 2013-04-09 | Boston Scientific Scimed, Inc. | Cross-linked polymer particles |
EP2266639B1 (en) | 2007-12-21 | 2016-10-05 | MicroVention, Inc. | Methods for preparing hydrogel filaments for biomedical use |
WO2010028047A1 (en) * | 2008-09-02 | 2010-03-11 | Cook Incorporated | Erodible embolization material |
US9216188B2 (en) | 2008-09-04 | 2015-12-22 | The General Hospital Corporation | Hydrogels for vocal cord and soft tissue augmentation and repair |
EP2451488A2 (en) * | 2009-07-07 | 2012-05-16 | Bartling, Sönke | Multimodal visible polymer embolization material |
WO2011014722A2 (en) * | 2009-07-30 | 2011-02-03 | Cook Incorporated | Erodible embolization material |
JP5722333B2 (en) | 2009-10-26 | 2015-05-20 | マイクロベンション インコーポレイテッド | Embolization device composed of expandable polymer |
WO2011109730A2 (en) | 2010-03-04 | 2011-09-09 | The General Hospital Corporation | Methods and systems of matching voice deficits with a tunable mucosal implant to restore and enhance individualized human sound and voice production |
WO2012145431A2 (en) | 2011-04-18 | 2012-10-26 | Microvention, Inc. | Embolic devices |
US9011884B2 (en) | 2012-04-18 | 2015-04-21 | Microvention, Inc. | Embolic devices |
US8906003B2 (en) | 2012-06-05 | 2014-12-09 | Cook Medical Technologies Llc | Erodible embolization material for targeted tumor cryoablation |
CA2876474C (en) | 2012-06-14 | 2021-06-22 | Microvention, Inc. | Polymeric treatment compositions |
CN104717983B (en) | 2012-10-15 | 2018-09-18 | 微仙美国有限公司 | It polymerize therapeutic combination |
US10124090B2 (en) | 2014-04-03 | 2018-11-13 | Terumo Corporation | Embolic devices |
WO2015167751A1 (en) | 2014-04-29 | 2015-11-05 | Microvention, Inc. | Polymers |
WO2015167752A1 (en) | 2014-04-29 | 2015-11-05 | Microvention, Inc. | Polymers including active agents |
EP3173074A4 (en) | 2014-07-22 | 2018-03-07 | Lemonex Inc. | Composition for delivering bioactive material or protein, and use thereof |
WO2016201250A1 (en) | 2015-06-11 | 2016-12-15 | Microvention, Inc. | Expansile device for implantation |
JP2019529354A (en) * | 2016-08-10 | 2019-10-17 | ユナイテッド キングダム リサーチ アンド イノベーション | Compositions comprising nanosilica particles and their use in methods of activating T lymphocytes for therapy |
US10368874B2 (en) | 2016-08-26 | 2019-08-06 | Microvention, Inc. | Embolic compositions |
CN110475546A (en) | 2017-02-06 | 2019-11-19 | 雷莫内克斯生物制药有限公司 | Physiological activator carrier |
WO2019022521A2 (en) * | 2017-07-25 | 2019-01-31 | 주식회사 레모넥스 | Composition for delivering physiologically active ingredients into blood vessel |
JP6865491B2 (en) * | 2017-07-25 | 2021-04-28 | レモネックス インコーポレイテッドLemonex Inc. | Composition for delivery of bioactive substances in blood vessels |
KR102152348B1 (en) | 2017-09-05 | 2020-09-08 | 주식회사 레모넥스 | Composition for modulating cell fate |
EP3694422A4 (en) | 2017-10-09 | 2021-06-30 | Microvention, Inc. | Radioactive liquid embolic |
CA3138548A1 (en) * | 2019-05-10 | 2020-11-19 | Incept, Llc | Embolization with transient materials |
WO2021020945A1 (en) * | 2019-07-31 | 2021-02-04 | 주식회사 레모넥스 | Anticancer agent and method for preparation of porous silica particle |
Family Cites Families (336)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2275154A (en) | 1940-07-10 | 1942-03-03 | United Drug Company | Method for making capsules |
US2609347A (en) | 1948-05-27 | 1952-09-02 | Wilson Christopher Lumley | Method of making expanded polyvinyl alcohol-formaldehyde reaction product and product resulting therefrom |
JPS4820019B1 (en) | 1969-06-05 | 1973-06-18 | ||
US3737398A (en) | 1969-11-13 | 1973-06-05 | D Yamaguchi | Method of making a polyvinyl acetal sponge buff |
CS179075B1 (en) | 1974-11-26 | 1977-10-31 | Stoy Vladimir | Mode of manufacture of spherical particles from polymer |
US4076640A (en) | 1975-02-24 | 1978-02-28 | Xerox Corporation | Preparation of spheroidized particles |
US3957933A (en) | 1975-03-05 | 1976-05-18 | General Atomic Company | Apparatus for producing microspherical particles and method for operating such apparatus |
JPS51135958A (en) | 1975-05-20 | 1976-11-25 | Fuji Photo Film Co Ltd | Method of making fine powder polymer having pores |
US4025686A (en) | 1975-06-26 | 1977-05-24 | Owens-Corning Fiberglas Corporation | Molded composite article and method for making the article |
US4034759A (en) | 1975-08-27 | 1977-07-12 | Xomed, Inc. | Moisture-expandable prosthesis |
JPS5260876A (en) * | 1975-11-14 | 1977-05-19 | Bridgestone Tire Co Ltd | Apparatus for making tube for tire |
US4098728A (en) | 1976-01-02 | 1978-07-04 | Solomon Rosenblatt | Medical surgical sponge and method of making same |
US4055377A (en) | 1976-08-03 | 1977-10-25 | Minnesota Mining And Manufacturing Company | Magnetically orientable retroreflectorization particles |
GB1591924A (en) | 1976-10-25 | 1981-07-01 | Berger Jenson & Nicholson Ltd | Polymer aggregates |
US4159719A (en) | 1977-05-09 | 1979-07-03 | Xomed, Inc. | Moisture-expandable ear wick |
EP0004587B1 (en) | 1978-03-23 | 1983-02-09 | Hoechst Aktiengesellschaft | Polyvinyl alcohol pellets containing a plasticizer, and method for their preparation |
DE2834539A1 (en) | 1978-08-07 | 1980-02-21 | Basf Ag | MACROPOROUS POLYMERS AS CARRIER MATERIAL FOR THE COVALENT BINDING OF PROTEINS |
US4793980A (en) | 1978-09-21 | 1988-12-27 | Torobin Leonard B | Hollow porous microspheres as substrates and containers for catalyst |
US4243794A (en) | 1978-10-10 | 1981-01-06 | Minnesota Mining And Manufacturing Company | Mixture of rough and spheroidized resin particles |
US4198318A (en) | 1978-11-24 | 1980-04-15 | Conoco, Inc. | Production of high strength alumina spheres by hydrogelling corresponding slurries |
US4268495A (en) | 1979-01-08 | 1981-05-19 | Ethicon, Inc. | Injectable embolization and occlusion solution |
US4246208A (en) | 1979-03-22 | 1981-01-20 | Xerox Corporation | Dust-free plasma spheroidization |
US4346712A (en) | 1979-04-06 | 1982-08-31 | Kuraray Company, Ltd. | Releasable balloon catheter |
HU184722B (en) | 1980-02-18 | 1984-10-29 | Laszlo Lazar | Therapeutically suitable silicone rubber mixture and therapeuticaid |
US4271281A (en) | 1980-05-29 | 1981-06-02 | American Hoechst Corporation | Process for preparing styrenic polymer particles |
DE3031737A1 (en) | 1980-08-22 | 1982-04-01 | Bayer Ag, 5090 Leverkusen | METHOD FOR PRODUCING PEARL POLYMERISATS OF UNIFORM PARTICLE SIZE |
CA1166413A (en) | 1980-10-30 | 1984-05-01 | Edward E. Timm | Process and apparatus for preparing uniform size polymer beads |
US4442843A (en) | 1980-11-17 | 1984-04-17 | Schering, Ag | Microbubble precursors and methods for their production and use |
US4657756A (en) | 1980-11-17 | 1987-04-14 | Schering Aktiengesellschaft | Microbubble precursors and apparatus for their production and use |
US4681119A (en) | 1980-11-17 | 1987-07-21 | Schering Aktiengesellschaft | Method of production and use of microbubble precursors |
NZ199916A (en) | 1981-03-11 | 1985-07-12 | Unilever Plc | Low density polymeric block material for use as carrier for included liquids |
US4413070A (en) | 1981-03-30 | 1983-11-01 | California Institute Of Technology | Polyacrolein microspheres |
US4622362A (en) | 1981-03-30 | 1986-11-11 | California Institute Of Technology | Polyacrolein microspheres |
US4678814A (en) | 1981-03-30 | 1987-07-07 | California Institute Of Technology | Polyacrolein microspheres |
CA1177811A (en) | 1981-04-13 | 1984-11-13 | Theo G. Spek | Process for the preparation of silica particles; silica particles with a narrow pore diameter distribution, catalysts made therefrom and use of these catalysts |
US4428869A (en) | 1981-08-20 | 1984-01-31 | International Flavors & Fragrances Inc. | Cologne consisting of microcapsule suspension |
US4456693A (en) | 1982-03-08 | 1984-06-26 | W. R. Grace & Co. | Hydrocracking catalyst |
US4452773A (en) | 1982-04-05 | 1984-06-05 | Canadian Patents And Development Limited | Magnetic iron-dextran microspheres |
US4472552A (en) | 1982-09-27 | 1984-09-18 | W. R. Grace & Co. | Continuous process for making solid, free-flowing water dispersible PVA-aldehyde reaction product |
US4459145A (en) | 1982-09-30 | 1984-07-10 | The United States Of America As Represented By The United States Department Of Energy | Fabrication of glass microspheres with conducting surfaces |
JPS59131355A (en) | 1983-01-17 | 1984-07-28 | 森下仁丹株式会社 | Multiple soft capsule |
US4515906A (en) | 1983-02-28 | 1985-05-07 | Bend Research, Inc. | Anisotropic microporous supports impregnated with polymeric ion-exchange materials |
DE3313946A1 (en) | 1983-04-15 | 1984-10-18 | Schering AG, 1000 Berlin und 4709 Bergkamen | MICROPARTICLES AND GAS BUBBLES CONTAINING ULTRASONIC CONTRASTING AGENTS |
DE3313947A1 (en) | 1983-04-15 | 1984-10-18 | Schering AG, 1000 Berlin und 4709 Bergkamen | MICROPARTICLES AND GAS BUBBLES CONTAINING ULTRASONIC CONTRASTING AGENTS |
DE3834705A1 (en) | 1988-10-07 | 1990-04-12 | Schering Ag | ULTRASONIC CONTRASTING AGENTS FROM GAS BUBBLES AND MICROPARTICLES CONTAINING FATTY ACID |
CA1225585A (en) | 1983-06-30 | 1987-08-18 | Maria T. Litvinova | Composition for embolization of blood vessels |
US4492720A (en) | 1983-11-15 | 1985-01-08 | Benjamin Mosier | Method of preparing microspheres for intravascular delivery |
US4573967A (en) | 1983-12-06 | 1986-03-04 | Eli Lilly And Company | Vacuum vial infusion system |
US4671954A (en) | 1983-12-13 | 1987-06-09 | University Of Florida | Microspheres for incorporation of therapeutic substances and methods of preparation thereof |
US4551436A (en) | 1984-04-11 | 1985-11-05 | General Electric Company | Fabrication of small dense silicon carbide spheres |
DE3414924A1 (en) | 1984-04-19 | 1985-10-31 | Klaus Dr.med. Dr.med.habil. 8000 München Draenert | COATED ANCHORAGE PART FOR IMPLANTS |
US4674480A (en) | 1984-05-25 | 1987-06-23 | Lemelson Jerome H | Drug compositions and methods of applying same |
FR2566384B1 (en) | 1984-06-21 | 1986-09-05 | Saint Gobain Vitrage | IMPROVEMENTS IN TECHNIQUES FOR THE PRODUCTION OF GLASS MICROSPHERES |
DE3527482A1 (en) | 1984-07-31 | 1986-02-06 | Fuji Spinning Co., Ltd., Tokio/Tokyo | METHOD FOR PRODUCING GRAINY POROUS CHITOSAN |
GB8419708D0 (en) | 1984-08-02 | 1984-09-05 | Shell Int Research | Preparation of silica spheres |
US4623706A (en) | 1984-08-23 | 1986-11-18 | The Dow Chemical Company | Process for preparing uniformly sized polymer particles by suspension polymerization of vibratorily excited monomers in a gaseous or liquid stream |
JPS61101242A (en) | 1984-10-22 | 1986-05-20 | Showa Denko Kk | Production of coated substance |
US4789501A (en) | 1984-11-19 | 1988-12-06 | The Curators Of The University Of Missouri | Glass microspheres |
US4675113A (en) | 1984-11-28 | 1987-06-23 | University Patents, Inc. | Affinity chromatography using dried calcium alginate-magnetite separation media in a magnetically stabilized fluidized bed |
EP0184198B1 (en) | 1984-12-06 | 1989-03-01 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | A method of preparation of droplets |
US5106903A (en) | 1984-12-17 | 1992-04-21 | Lehigh University | Preparation of large particle size monodisperse latexes |
US4897255A (en) | 1985-01-14 | 1990-01-30 | Neorx Corporation | Metal radionuclide labeled proteins for diagnosis and therapy |
JPH0678460B2 (en) | 1985-05-01 | 1994-10-05 | 株式会社バイオマテリアル・ユニバース | Porous transparent polyvinyl alcohol gel |
JPS61293911A (en) | 1985-06-24 | 1986-12-24 | Teisan Seiyaku Kk | Sustained release preparation |
SE459005B (en) | 1985-07-12 | 1989-05-29 | Aake Rikard Lindahl | SET TO MANUFACTURE SPHERICAL POLYMER PARTICLES |
USH915H (en) | 1985-07-22 | 1991-05-07 | Gibbs Marylu B | Controlled macroporous copolymer properties by removal of impurities in the diluent |
US4742086A (en) | 1985-11-02 | 1988-05-03 | Lion Corporation | Process for manufacturing porous polymer |
DE3543348A1 (en) | 1985-12-07 | 1987-06-11 | Bayer Ag | PEARL-SHAPED CROSS-NETWORKED MIXED POLYMERS WITH EPOXY AND BASIC AMINO GROUPS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE |
JPS62169723A (en) | 1986-01-22 | 1987-07-25 | Teisan Seiyaku Kk | Sustained release preparation |
GB8610024D0 (en) | 1986-04-24 | 1986-05-29 | Unilever Plc | Porous structures |
US4929400A (en) | 1986-04-28 | 1990-05-29 | California Institute Of Technology | Production of monodisperse, polymeric microspheres |
US5262176A (en) | 1986-07-03 | 1993-11-16 | Advanced Magnetics, Inc. | Synthesis of polysaccharide covered superparamagnetic oxide colloids |
JPS6317904A (en) | 1986-07-09 | 1988-01-25 | Mitsubishi Chem Ind Ltd | Production of crosslinked porous polyvinyl alcohol particle |
US4743507A (en) | 1986-09-12 | 1988-05-10 | Franses Elias I | Nonspherical microparticles and method therefor |
US5114421A (en) | 1986-09-22 | 1992-05-19 | Polak Robert B | Medicament container/dispenser assembly |
CA1287459C (en) | 1986-10-01 | 1991-08-13 | Mukesh Jain | Process for the preparation of hollow microspheres |
US4859711A (en) | 1986-10-01 | 1989-08-22 | Alcan International Limited | Hollow microspheres |
US5263992A (en) | 1986-10-17 | 1993-11-23 | Bio-Metric Systems, Inc. | Biocompatible device with covalently bonded biocompatible agent |
DE3787700T3 (en) | 1986-10-29 | 1998-12-24 | Kanegafuchi Chemical Ind | Uniform polymer particles. |
US5292814A (en) | 1987-04-29 | 1994-03-08 | Ernst Bayer | Process for the preparation of monodispersed polymer beads |
US4795741A (en) | 1987-05-06 | 1989-01-03 | Biomatrix, Inc. | Compositions for therapeutic percutaneous embolization and the use thereof |
GB8713263D0 (en) | 1987-06-05 | 1987-07-08 | Unilever Plc | Spheroidal silica |
JPH0612993B2 (en) | 1987-08-10 | 1994-02-23 | 株式会社クラレ | Method for producing spherical microbe-immobilized moldings |
US4819637A (en) | 1987-09-01 | 1989-04-11 | Interventional Therapeutics Corporation | System for artificial vessel embolization and devices for use therewith |
JPH0762054B2 (en) | 1987-10-13 | 1995-07-05 | 倉敷紡績株式会社 | Crosslinked polymer particles |
US4804366A (en) | 1987-10-29 | 1989-02-14 | Baxter International Inc. | Cartridge and adapter for introducing a beneficial agent into an intravenous delivery system |
US4850978A (en) | 1987-10-29 | 1989-07-25 | Baxter International Inc. | Drug delivery cartridge with protective cover |
US4981625A (en) | 1988-03-14 | 1991-01-01 | California Institute Of Technology | Monodisperse, polymeric microspheres produced by irradiation of slowly thawing frozen drops |
FR2634376B1 (en) | 1988-07-21 | 1992-04-17 | Farmalyoc | NOVEL SOLID AND POROUS UNIT FORM COMPRISING MICROPARTICLES AND / OR NANOPARTICLES, AS WELL AS ITS PREPARATION |
JP2836878B2 (en) | 1988-08-24 | 1998-12-14 | スリピアン,マービン,ジェイ | Intraluminal sealing with biodegradable polymer material |
DE3829938A1 (en) | 1988-09-02 | 1990-03-29 | Hermann Hofmann | ORGANO-MINERAL DUENGER AND METHOD FOR THE PRODUCTION THEREOF |
US5047438A (en) | 1988-09-26 | 1991-09-10 | Supelco, Inc. | Porous rigid resins and process of preparation |
US4933372A (en) | 1988-09-26 | 1990-06-12 | Supelco, Inc. | Porous rigid resins and process of preparation |
US5681576A (en) | 1988-11-16 | 1997-10-28 | Mdv Technologies, Inc. | Method and composition for post surgical adhesion reduction |
DE3841401A1 (en) | 1988-12-08 | 1990-06-13 | Martin Lemperle | ALLOPLASTIC IMPLANT |
US5258028A (en) | 1988-12-12 | 1993-11-02 | Ersek Robert A | Textured micro implants |
US4946899A (en) | 1988-12-16 | 1990-08-07 | The University Of Akron | Thermoplastic elastomers of isobutylene and process of preparation |
GB8900376D0 (en) | 1989-01-09 | 1989-03-08 | Nycomed As | Iodinated esters |
US5091205A (en) | 1989-01-17 | 1992-02-25 | Union Carbide Chemicals & Plastics Technology Corporation | Hydrophilic lubricious coatings |
FR2641692A1 (en) | 1989-01-17 | 1990-07-20 | Nippon Zeon Co | Plug for closing an opening for a medical application, and device for the closure plug making use thereof |
US5032117A (en) | 1989-01-30 | 1991-07-16 | Motta Louis J | Tandem syringe |
GB8905934D0 (en) | 1989-03-15 | 1989-04-26 | Dow Europ Sa | A process for preparing adsorptive porous resin beads |
US5888930A (en) | 1989-03-27 | 1999-03-30 | Bend Research, Inc. | Asymmetric microporous beads for controlled release |
US5354290A (en) | 1989-05-31 | 1994-10-11 | Kimberly-Clark Corporation | Porous structure of an absorbent polymer |
CA2017570C (en) | 1989-05-31 | 2000-12-19 | James R. Gross | Porous structure of an absorbent polymer |
US5007940A (en) | 1989-06-09 | 1991-04-16 | American Medical Systems, Inc. | Injectable polymeric bodies |
US5158573A (en) | 1989-06-09 | 1992-10-27 | American Medical Systems, Inc. | Injectable polymeric bodies |
US5116387A (en) | 1989-06-09 | 1992-05-26 | American Medical Systems, Inc. | Preparation of injectable polymeric bodies |
US5190760A (en) | 1989-07-08 | 1993-03-02 | Coopers Animal Health Limited | Solid pharmaceutical composition |
US5698271A (en) | 1989-08-22 | 1997-12-16 | Immunivest Corporation | Methods for the manufacture of magnetically responsive particles |
US5253991A (en) | 1989-11-20 | 1993-10-19 | Sumitomo Cement Co., Ltd. | Apparatus for producing spheroidal inorganic particulate material |
US5922304A (en) | 1989-12-22 | 1999-07-13 | Imarx Pharmaceutical Corp. | Gaseous precursor filled microspheres as magnetic resonance imaging contrast agents |
US5469854A (en) | 1989-12-22 | 1995-11-28 | Imarx Pharmaceutical Corp. | Methods of preparing gas-filled liposomes |
US5580575A (en) | 1989-12-22 | 1996-12-03 | Imarx Pharmaceutical Corp. | Therapeutic drug delivery systems |
US5585112A (en) | 1989-12-22 | 1996-12-17 | Imarx Pharmaceutical Corp. | Method of preparing gas and gaseous precursor-filled microspheres |
US5542935A (en) | 1989-12-22 | 1996-08-06 | Imarx Pharmaceutical Corp. | Therapeutic delivery systems related applications |
US6306427B1 (en) | 1989-12-28 | 2001-10-23 | Rhone-Poulenc Nutrition Animale | Pellets containing active ingredients protected against degradation in the rumen of ruminants |
US5435645A (en) | 1989-12-29 | 1995-07-25 | Tecres Spa | Process and apparatus for the mixing and direct emplacement of a two-component bone cement |
US5147937A (en) | 1990-03-22 | 1992-09-15 | Rohm And Haas Company | Process for making controlled, uniform-sized particles in the 1 to 50 micrometer range |
US5556610A (en) | 1992-01-24 | 1996-09-17 | Bracco Research S.A. | Gas mixtures useful as ultrasound contrast media, contrast agents containing the media and method |
JPH03297475A (en) | 1990-04-16 | 1991-12-27 | Ken Ishihara | Controlling method for emission of medicine by means of resonance sound wave |
US5514090A (en) | 1990-04-24 | 1996-05-07 | Science Incorporated | Closed drug delivery system |
US5137928A (en) | 1990-04-26 | 1992-08-11 | Hoechst Aktiengesellschaft | Ultrasonic contrast agents, processes for their preparation and the use thereof as diagnostic and therapeutic agents |
CA2016870C (en) | 1990-05-15 | 1994-03-29 | Arnie Drudik | Dispenser for storing and mixing several components |
AU636481B2 (en) | 1990-05-18 | 1993-04-29 | Bracco International B.V. | Polymeric gas or air filled microballoons usable as suspensions in liquid carriers for ultrasonic echography |
JP2514087Y2 (en) | 1990-05-25 | 1996-10-16 | 幸三 牧田 | Balloon with detachable double-sided check valve |
US6291605B1 (en) | 1990-06-06 | 2001-09-18 | Clarence S. Freeman | Polymerization process with spraying step |
EP0533799B1 (en) | 1990-06-20 | 1995-10-18 | Advanced Polymer Systems, Inc. | Compositions and methods for the controlled release of soluble active substances |
US5202352A (en) | 1990-08-08 | 1993-04-13 | Takeda Chemical Industries, Ltd. | Intravascular embolizing agent containing angiogenesis-inhibiting substance |
US5484584A (en) | 1990-10-02 | 1996-01-16 | Board Of Regents, The University Of Texas System | Therapeutic and diagnostic use of modified polymeric microcapsules |
US5149543A (en) | 1990-10-05 | 1992-09-22 | Massachusetts Institute Of Technology | Ionically cross-linked polymeric microcapsules |
US5120349A (en) | 1990-12-07 | 1992-06-09 | Landec Labs, Inc. | Microcapsule having temperature-dependent permeability profile |
US5171214A (en) | 1990-12-26 | 1992-12-15 | Abbott Laboratories | Drug storage and delivery system |
US5171217A (en) | 1991-02-28 | 1992-12-15 | Indiana University Foundation | Method for delivery of smooth muscle cell inhibitors |
US5147631A (en) | 1991-04-30 | 1992-09-15 | Du Pont Merck Pharmaceutical Company | Porous inorganic ultrasound contrast agents |
FR2676927B1 (en) | 1991-05-29 | 1995-06-23 | Ibf | MICROSPHERES FOR USE IN THERAPEUTIC VASCULAR OCCLUSIONS AND INJECTABLE SOLUTIONS CONTAINING THEM. |
WO1992021382A1 (en) | 1991-06-03 | 1992-12-10 | Holmes, Michael, John | Improvements in or relating to contrast agents |
GB9116610D0 (en) | 1991-08-01 | 1991-09-18 | Danbiosyst Uk | Preparation of microparticles |
US5216096A (en) | 1991-09-24 | 1993-06-01 | Japan Synthetic Rubber Co., Ltd. | Process for the preparation of cross-linked polymer particles |
US5811447A (en) | 1993-01-28 | 1998-09-22 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
DE69220317T2 (en) | 1991-10-01 | 1997-10-16 | Takeda Chemical Industries Ltd | Microparticle summary for extended release and manufacture of the same |
JP3356447B2 (en) | 1991-10-16 | 2002-12-16 | テルモ株式会社 | Vascular lesion embolic material composed of dried polymer gel |
US5258042A (en) | 1991-12-16 | 1993-11-02 | Henry Ford Health System | Intravascular hydrogel implant |
DE69226203T2 (en) | 1991-12-20 | 1998-12-10 | Allied Signal Inc | MATERIALS WITH LOW DENSITY AND HIGH SPECIFIC SURFACE AND ARTICLES MOLDED THEREOF FOR USE IN METAL RECOVERY |
US5260002A (en) | 1991-12-23 | 1993-11-09 | Vanderbilt University | Method and apparatus for producing uniform polymeric spheres |
WO1993013111A1 (en) | 1991-12-24 | 1993-07-08 | E.I. Du Pont De Nemours And Company | Dual stabilized microparticles |
GB9200391D0 (en) | 1992-01-09 | 1992-02-26 | Nycomed As | Improvements in or relating to contrast agents |
GB9200388D0 (en) | 1992-01-09 | 1992-02-26 | Nycomed As | Improvements in or relating to contrast agents |
US6537574B1 (en) | 1992-02-11 | 2003-03-25 | Bioform, Inc. | Soft tissue augmentation material |
US5480644A (en) | 1992-02-28 | 1996-01-02 | Jsf Consultants Ltd. | Use of injectable biomaterials for the repair and augmentation of the anal sphincters |
BR9306044A (en) | 1992-03-06 | 1997-11-18 | Nycomed Imaging | Contrast agent use the same processes to generate enhanced images of a human or non-human animal body and to prepare a contrast agent |
EP0636014B1 (en) | 1992-04-06 | 1998-05-27 | Uroplasty, Inc. | Treatment of reflux disorder by microparticles injection |
DE69306844T2 (en) | 1992-04-10 | 1997-07-10 | Mitsubishi Chem Corp | Process for the preparation of spherical cross-linked acrylonitrile copolymers |
US6235313B1 (en) | 1992-04-24 | 2001-05-22 | Brown University Research Foundation | Bioadhesive microspheres and their use as drug delivery and imaging systems |
AU4198793A (en) | 1992-07-24 | 1994-01-27 | Takeda Chemical Industries Ltd. | Microparticle preparation and production thereof |
US5807323A (en) | 1992-08-13 | 1998-09-15 | Science Incorporated | Mixing and delivery syringe assembly |
US6592859B1 (en) | 1992-08-20 | 2003-07-15 | Ethicon, Inc. | Controlled expansion sphincter augmentation media |
US5512604A (en) | 1992-08-28 | 1996-04-30 | The Dow Chemical Company | Porous copolymers having a cellular polymeric structure suitable for preparing ion-exchange resins and adsorbents |
WO1994006477A1 (en) | 1992-09-16 | 1994-03-31 | Holmes, Michael, John | Improvements in or relating to contrast agents |
WO1994006460A1 (en) | 1992-09-21 | 1994-03-31 | Vitaphore Corporation | Embolization plugs for blood vessels |
KR960001417B1 (en) | 1992-09-26 | 1996-01-27 | 한국과학기술원 | Method for preparing an improved porous polymer bead |
DE4232755A1 (en) | 1992-09-26 | 1994-03-31 | Schering Ag | Microparticle preparations made from biodegradable copolymers |
GB9221329D0 (en) | 1992-10-10 | 1992-11-25 | Delta Biotechnology Ltd | Preparation of further diagnostic agents |
US5382260A (en) | 1992-10-30 | 1995-01-17 | Interventional Therapeutics Corp. | Embolization device and apparatus including an introducer cartridge and method for delivering the same |
US5369163A (en) | 1992-11-13 | 1994-11-29 | Rohm And Haas Company | Process for preparing large dimension emulsion polymer particles, polymer product and uses thereof |
US5690666A (en) | 1992-11-18 | 1997-11-25 | Target Therapeutics, Inc. | Ultrasoft embolism coils and process for using them |
US5349957A (en) | 1992-12-02 | 1994-09-27 | Sterling Winthrop Inc. | Preparation and magnetic properties of very small magnetite-dextran particles |
JP3256583B2 (en) | 1992-12-10 | 2002-02-12 | 株式会社リコー | Electrophotographic toner and method for producing the same |
US5288763A (en) | 1992-12-23 | 1994-02-22 | The Johns Hopkins University School Of Medicine | Porous, polymer beads and process of their preparation |
US6482436B1 (en) | 1993-01-29 | 2002-11-19 | Ferx Incorporated | Magnetically responsive composition |
US5328936A (en) | 1993-02-01 | 1994-07-12 | Rohm And Haas Company | Polymerization process for making porous polymeric particles |
JPH06254413A (en) | 1993-03-01 | 1994-09-13 | Ngk Insulators Ltd | Honeycomb with turbulence holes |
US6090925A (en) | 1993-03-09 | 2000-07-18 | Epic Therapeutics, Inc. | Macromolecular microparticles and methods of production and use |
US5320639A (en) | 1993-03-12 | 1994-06-14 | Meadox Medicals, Inc. | Vascular plug delivery system |
US5701899A (en) | 1993-05-12 | 1997-12-30 | The Board Of Regents Of The University Of Nebraska | Perfluorobutane ultrasound contrast agent and methods for its manufacture and use |
US5567415A (en) | 1993-05-12 | 1996-10-22 | The Board Of Regents Of The University Of Nebraska | Ultrasound contrast agents and methods for their manufacture and use |
US5695740A (en) | 1993-05-12 | 1997-12-09 | The Board Of Regents Of The University Of Nebraska | Perfluorocarbon ultrasound contrast agent comprising microbubbles containing a filmogenic protein and a saccharide |
US5344867A (en) | 1993-06-14 | 1994-09-06 | The Bfgoodrich Company | Vinylidene chloride emulsion interpolymer composition |
US5886026A (en) | 1993-07-19 | 1999-03-23 | Angiotech Pharmaceuticals Inc. | Anti-angiogenic compositions and methods of use |
WO1995003036A1 (en) | 1993-07-19 | 1995-02-02 | Angiogenesis Technologies, Inc. | Anti-angiogenic compositions and methods of use |
US5397303A (en) | 1993-08-06 | 1995-03-14 | River Medical, Inc. | Liquid delivery device having a vial attachment or adapter incorporated therein |
US5398851A (en) | 1993-08-06 | 1995-03-21 | River Medical, Inc. | Liquid delivery device |
US5443495A (en) | 1993-09-17 | 1995-08-22 | Scimed Lifesystems Inc. | Polymerization angioplasty balloon implant device |
US5531716A (en) | 1993-09-29 | 1996-07-02 | Hercules Incorporated | Medical devices subject to triggered disintegration |
US5556391A (en) | 1993-10-01 | 1996-09-17 | Merocel Corporation | Surgical sponge device |
EP1258262A3 (en) | 1993-10-28 | 2002-12-18 | Medrad, Inc. | Total system for contrast delivery |
PT682530E (en) | 1993-12-15 | 2003-06-30 | Bracco Research Sa | UTEIS GAS MIXTURES AS CONTRAST MEANS FOR ULTRASSONS |
ATE281886T1 (en) | 1994-01-21 | 2004-11-15 | Sirtex Medical Ltd | YTTRIA PARTICULATE GOOD |
US5417982A (en) | 1994-02-17 | 1995-05-23 | Modi; Pankaj | Controlled release of drugs or hormones in biodegradable polymer microspheres |
US5569468A (en) | 1994-02-17 | 1996-10-29 | Modi; Pankaj | Vaccine delivery system for immunization, using biodegradable polymer microspheres |
ATE173160T1 (en) | 1994-02-17 | 1998-11-15 | Pankaj Modi | DRUGS, VACCINES AND HORMONES IN POLYLACTIDE-COATED MICROPARTICLES |
AU705305B2 (en) | 1994-03-18 | 1999-05-20 | Cook Medical Technologies Llc | Helical embolization coil |
US5431174A (en) | 1994-04-04 | 1995-07-11 | Via Medical Corporation | Method of fluid delivery and collection |
EP0757553B1 (en) | 1994-04-28 | 2000-08-02 | Primed Halberstadt Medizintechnik Gmbh | One-piece dispensing device for the contamination-free administration of medicaments (cytostatica) |
US5534589A (en) | 1994-05-04 | 1996-07-09 | Minnesota Mining And Manufacturing Company | Repulpable plastic films |
DE69521997T2 (en) | 1994-05-15 | 2002-04-04 | Apbiotech Ab Uppsala | METHOD FOR PRODUCING PARTICLES AND PARTICLES THAT CAN BE MANUFACTURED BY THIS PROCESS |
JP2535785B2 (en) | 1994-06-03 | 1996-09-18 | 工業技術院長 | Vascular embolic agent |
US5583162A (en) | 1994-06-06 | 1996-12-10 | Biopore Corporation | Polymeric microbeads and method of preparation |
US5639710A (en) | 1994-07-06 | 1997-06-17 | Zeneca Limited | Solid microspheres for agriculturally active compounds and process for their production |
ES2096521B1 (en) | 1994-08-10 | 1997-11-16 | Univ La Laguna | BIODEGRADABLE SYNTHETIC POLYMER MICROSPHERES IN THE MANUFACTURE AND ELABORATION OF REACTIVE EQUIPMENT FOR THE PREPARATION OF RADIOPHARMACEUTICAL MEDICINES. |
WO1996004954A1 (en) | 1994-08-17 | 1996-02-22 | Boston Scientific Corporation | Implant, and method and device for inserting the implant |
US5827531A (en) | 1994-12-02 | 1998-10-27 | The United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration | Microcapsules and methods for making |
US6099864A (en) | 1994-12-02 | 2000-08-08 | The United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration | In situ activation of microcapsules |
DK175166B1 (en) | 1995-01-03 | 2004-06-21 | Cook William Europ | Method of manufacturing an assembly for placing an embolization coil in the vascular system and such assembly as well as an apparatus for advancing the assembly |
WO1996022736A1 (en) | 1995-01-27 | 1996-08-01 | Scimed Life Systems, Inc. | Embolizing system |
US6179817B1 (en) | 1995-02-22 | 2001-01-30 | Boston Scientific Corporation | Hybrid coating for medical devices |
ES2161825T3 (en) | 1995-03-07 | 2001-12-16 | Ethicon Inc | MEANS TO INCREASE THE FUNCTION OF THE CONTROLLED EXPANSION SPHINTER. |
US5637087A (en) | 1995-03-22 | 1997-06-10 | Abbott Laboratories | Prefilled, two-constituent syringe |
US5785682A (en) | 1995-03-22 | 1998-07-28 | Abbott Laboratories | Pre-filled syringe drug delivery system |
US5876372A (en) | 1995-03-22 | 1999-03-02 | Abbott Laboratories | Syringe system accomodating seperate prefilled barrels for two constituents |
US5569193A (en) | 1995-03-22 | 1996-10-29 | Abbott Laboratories | Syringe system accommodating separately storable prefilled containers for two constituents |
CA2216919C (en) | 1995-03-28 | 2007-09-18 | Fidia Advanced Biopolymers Srl | Nanospheres comprising a biocompatible polysaccharide |
US5779668A (en) | 1995-03-29 | 1998-07-14 | Abbott Laboratories | Syringe barrel for lyophilization, reconstitution and administration |
US6428771B1 (en) | 1995-05-15 | 2002-08-06 | Pharmaceutical Discovery Corporation | Method for drug delivery to the pulmonary system |
US6312407B1 (en) | 1995-06-05 | 2001-11-06 | Medtronic Percusurge, Inc. | Occlusion of a vessel |
US6214331B1 (en) | 1995-06-06 | 2001-04-10 | C. R. Bard, Inc. | Process for the preparation of aqueous dispersions of particles of water-soluble polymers and the particles obtained |
US5766147A (en) | 1995-06-07 | 1998-06-16 | Winfield Medical | Vial adaptor for a liquid delivery device |
US5657756A (en) | 1995-06-07 | 1997-08-19 | Ctf Systems Inc. | Method and systems for obtaining higher order gradiometer measurements with lower order gradiometers |
US6143211A (en) | 1995-07-21 | 2000-11-07 | Brown University Foundation | Process for preparing microparticles through phase inversion phenomena |
US5877224A (en) | 1995-07-28 | 1999-03-02 | Rutgers, The State University Of New Jersey | Polymeric drug formulations |
US5840387A (en) | 1995-07-28 | 1998-11-24 | Aegis Biosciences L.L.C. | Sulfonated multiblock copolymer and uses therefor |
US6096344A (en) | 1995-07-28 | 2000-08-01 | Advanced Polymer Systems, Inc. | Bioerodible porous compositions |
US5558822A (en) | 1995-08-16 | 1996-09-24 | Gas Research Institute | Method for production of spheroidized particles |
US5888546A (en) | 1995-08-28 | 1999-03-30 | The Regents Of The University Of California | Embolic material for endovascular occlusion of abnormal vasculature and method for using the same |
US5833361A (en) | 1995-09-07 | 1998-11-10 | Funk; James E. | Apparatus for the production of small spherical granules |
CA2161863A1 (en) | 1995-10-31 | 1997-05-01 | Michael Vivian Sefton | Angiogenic material and uses thereof |
US5752974A (en) | 1995-12-18 | 1998-05-19 | Collagen Corporation | Injectable or implantable biomaterials for filling or blocking lumens and voids of the body |
WO1997025015A1 (en) | 1996-01-11 | 1997-07-17 | Duoject Medical Systems Inc. | Delivery system for pharmaceuticals packed in pharmaceutical vials |
US5702361A (en) | 1996-01-31 | 1997-12-30 | Micro Therapeutics, Inc. | Method for embolizing blood vessels |
US5895398A (en) | 1996-02-02 | 1999-04-20 | The Regents Of The University Of California | Method of using a clot capture coil |
US6051247A (en) | 1996-05-30 | 2000-04-18 | University Of Florida Research Foundation, Inc. | Moldable bioactive compositions |
US5855615A (en) | 1996-06-07 | 1999-01-05 | Menlo Care, Inc. | Controller expansion sphincter augmentation media |
US5792478A (en) | 1996-07-08 | 1998-08-11 | Advanced Uro Science | Tissue injectable composition and method of use |
US5830178A (en) | 1996-10-11 | 1998-11-03 | Micro Therapeutics, Inc. | Methods for embolizing vascular sites with an emboilizing composition comprising dimethylsulfoxide |
US5695480A (en) | 1996-07-29 | 1997-12-09 | Micro Therapeutics, Inc. | Embolizing compositions |
US5741331A (en) | 1996-07-29 | 1998-04-21 | Corvita Corporation | Biostable elastomeric polymers having quaternary carbons |
US5823198A (en) | 1996-07-31 | 1998-10-20 | Micro Therapeutics, Inc. | Method and apparatus for intravasculer embolization |
TW421658B (en) | 1996-07-31 | 2001-02-11 | Kanebo Ltd | Porious spherical particles and the preparation process for preparing thereof |
US5902832A (en) | 1996-08-20 | 1999-05-11 | Menlo Care, Inc. | Method of synthesizing swollen hydrogel for sphincter augmentation |
US5813411A (en) | 1996-08-20 | 1998-09-29 | Menlo Care, Inc. | Method of deforming tissue with a swollen hydrogel |
US5785642A (en) | 1996-10-18 | 1998-07-28 | Micro Therapeutics, Inc. | Methods for treating urinary incontinence in mammals |
US5756127A (en) | 1996-10-29 | 1998-05-26 | Wright Medical Technology, Inc. | Implantable bioresorbable string of calcium sulfate beads |
US6139963A (en) | 1996-11-28 | 2000-10-31 | Kuraray Co., Ltd. | Polyvinyl alcohol hydrogel and process for producing the same |
DE29724255U1 (en) | 1996-12-18 | 2000-10-05 | Alpha Bioverfahrenstechnik Gmb | Microcapsules |
US6090800A (en) | 1997-05-06 | 2000-07-18 | Imarx Pharmaceutical Corp. | Lipid soluble steroid prodrugs |
AU6893898A (en) | 1997-04-10 | 1998-10-30 | Johns Hopkins University, The | Gaz syringe and package therefor |
JP4102459B2 (en) | 1997-05-14 | 2008-06-18 | 森下仁丹株式会社 | Seamless capsule for synthesizing biopolymer and method for producing the same |
FR2763581B1 (en) * | 1997-05-26 | 1999-07-23 | Rhodia Chimie Sa | PRECIPITATED SILICA FOR USE AS A REINFORCING FILLER FOR ELASTOMERS |
US6056844A (en) | 1997-06-06 | 2000-05-02 | Triton Systems, Inc. | Temperature-controlled induction heating of polymeric materials |
JP2002503991A (en) | 1997-06-13 | 2002-02-05 | マイクロ・テラピューティクス・インコーポレーテッド | Syringe and luer hub having novel shape and method of forming embolus |
US6048908A (en) | 1997-06-27 | 2000-04-11 | Biopore Corporation | Hydrophilic polymeric material |
US5959073A (en) | 1997-07-07 | 1999-09-28 | Southwest Research Institute | Method for preparing polymeric beads |
US6056721A (en) | 1997-08-08 | 2000-05-02 | Sunscope International, Inc. | Balloon catheter and method |
EP1009317A4 (en) | 1997-08-28 | 2001-01-24 | Boston Scient Corp | System for implanting a cross-linked polysaccharide fiber and methods of forming and inserting the fiber |
US6476069B2 (en) | 1997-09-11 | 2002-11-05 | Provasis Therapeutics Inc. | Compositions for creating embolic agents and uses thereof |
US6538026B1 (en) | 1997-09-11 | 2003-03-25 | Provasis Therapeutics, Inc. | Compositions useful for remodeling body spaces |
AU739610B2 (en) | 1997-11-07 | 2001-10-18 | Salviac Limited | Implantable occluder devices for medical use |
US5951160A (en) | 1997-11-20 | 1999-09-14 | Biomet, Inc. | Method and apparatus for packaging, mixing and delivering bone cement |
DE19752585B4 (en) | 1997-11-27 | 2007-06-28 | Inotech Ag | Device and method for encapsulating microbial, plant and animal cells or of biological and chemical substances |
US6159192A (en) | 1997-12-04 | 2000-12-12 | Fowles; Thomas A. | Sliding reconstitution device with seal |
JP3732404B2 (en) | 1998-02-23 | 2006-01-05 | ニーモサイエンス ゲーエムベーハー | Shape memory polymer composition, method of forming a shape memory product, and method of forming a composition that stores a shape |
IL137299A0 (en) | 1998-02-23 | 2001-07-24 | Massachusetts Inst Technology | Biodegradable shape memory polymers |
US6003566A (en) | 1998-02-26 | 1999-12-21 | Becton Dickinson And Company | Vial transferset and method |
US6059766A (en) | 1998-02-27 | 2000-05-09 | Micro Therapeutics, Inc. | Gynecologic embolotherapy methods |
US6660301B1 (en) | 1998-03-06 | 2003-12-09 | Biosphere Medical, Inc. | Injectable microspheres for dermal augmentation and tissue bulking |
US6458296B1 (en) | 1998-03-07 | 2002-10-01 | Inotech Ag | Method and device for capsulating microbial, plant and animal cells or biological and chemical substances |
US6047861A (en) | 1998-04-15 | 2000-04-11 | Vir Engineering, Inc. | Two component fluid dispenser |
US6224794B1 (en) | 1998-05-06 | 2001-05-01 | Angiotech Pharmaceuticals, Inc. | Methods for microsphere production |
US6224630B1 (en) | 1998-05-29 | 2001-05-01 | Advanced Bio Surfaces, Inc. | Implantable tissue repair device |
EP1082072B8 (en) | 1998-06-04 | 2014-03-05 | New York University | Endovascular thin film devices for treating and preventing stroke |
US6267154B1 (en) | 1998-06-05 | 2001-07-31 | Abbott Laboratories | System for storing mixing and administering a drug |
US6165193A (en) | 1998-07-06 | 2000-12-26 | Microvention, Inc. | Vascular embolization with an expansible implant |
US6099064A (en) | 1998-07-10 | 2000-08-08 | Lund Industries, Inc. | Windshield visor for motor vehicles |
US6264861B1 (en) | 1998-08-05 | 2001-07-24 | Xeikon Nv | Method for producing rounded polymeric particles |
US6315709B1 (en) | 1998-08-07 | 2001-11-13 | Stereotaxis, Inc. | Magnetic vascular defect treatment system |
US6152943A (en) | 1998-08-14 | 2000-11-28 | Incept Llc | Methods and apparatus for intraluminal deposition of hydrogels |
US6296622B1 (en) | 1998-12-21 | 2001-10-02 | Micrus Corporation | Endoluminal device delivery system using axially recovering shape memory material |
CA2248592A1 (en) | 1998-08-31 | 2000-02-29 | Christopher D. Batich | Microspheres for use in the treatment of cancer |
FR2784580B1 (en) | 1998-10-16 | 2004-06-25 | Biosepra Inc | POLYVINYL-ALCOHOL MICROSPHERES AND METHODS OF MAKING THE SAME |
US6238335B1 (en) | 1998-12-11 | 2001-05-29 | Enteric Medical Technologies, Inc. | Method for treating gastroesophageal reflux disease and apparatus for use therewith |
JP2000189511A (en) | 1998-12-25 | 2000-07-11 | Kaneka Medeikkusu:Kk | Embolization material |
US6162377A (en) | 1999-02-23 | 2000-12-19 | Alberta Research Council Inc. | Apparatus and method for the formation of uniform spherical particles |
US6296604B1 (en) | 1999-03-17 | 2001-10-02 | Stereotaxis, Inc. | Methods of and compositions for treating vascular defects |
US6306425B1 (en) | 1999-04-09 | 2001-10-23 | Southern Research Institute | Injectable naltrexone microsphere compositions and their use in reducing consumption of heroin and alcohol |
US6368658B1 (en) | 1999-04-19 | 2002-04-09 | Scimed Life Systems, Inc. | Coating medical devices using air suspension |
US6280457B1 (en) | 1999-06-04 | 2001-08-28 | Scimed Life Systems, Inc. | Polymer covered vaso-occlusive devices and methods of producing such devices |
ATE506021T1 (en) | 1999-06-09 | 2011-05-15 | Ethicon Inc | DEVICE FOR ADJUSTING POLYMER IMPLANTS TO SOFT SURFACES |
CN1248689C (en) | 1999-08-27 | 2006-04-05 | 南方研究所 | Injectable bupernorphine microparticle compositions and their use |
FR2797769B1 (en) | 1999-09-01 | 2003-07-25 | Cis Bio Int | RADIOPHARMACEUTICAL PRODUCTS AND THEIR PREPARATION PROCESS |
JP2001079011A (en) | 1999-09-14 | 2001-03-27 | Akira Morimoto | Embolization coil and its manufacture |
US6277392B1 (en) | 1999-09-16 | 2001-08-21 | Carbon Medical Technologies, Inc. | Tissue injectable composition |
US6602261B2 (en) | 1999-10-04 | 2003-08-05 | Microvention, Inc. | Filamentous embolic device with expansile elements |
US6238403B1 (en) | 1999-10-04 | 2001-05-29 | Microvention, Inc. | Filamentous embolic device with expansible elements |
GB2355711B (en) * | 1999-10-27 | 2003-12-24 | Agilent Technologies Inc | Porous silica microsphere scavengers |
KR100335866B1 (en) | 2000-01-06 | 2002-05-10 | 박호군 | Microspheric Embolic Materials Having Duel Structure of Poly(Vinyl Acetate) Core/Poly(Vinyl Alcohol) Shell, and Method for Preparing The Same |
US6306419B1 (en) | 2000-02-23 | 2001-10-23 | Aegis Biosciences, Llc | Medical uses of styrene sulfonate polymers |
CA2401879A1 (en) * | 2000-03-06 | 2001-09-13 | Stephan Mangin | Embolic agents visible under ultrasound |
US6652883B2 (en) | 2000-03-13 | 2003-11-25 | Biocure, Inc. | Tissue bulking and coating compositions |
US6676971B2 (en) | 2000-03-13 | 2004-01-13 | Biocure, Inc. | Embolic compositions |
AUPQ677200A0 (en) | 2000-04-07 | 2000-05-11 | Dunstan, David Edwin | Production method |
US6423332B1 (en) | 2000-05-26 | 2002-07-23 | Ethicon, Inc. | Method and composition for deforming soft tissues |
US6355275B1 (en) | 2000-06-23 | 2002-03-12 | Carbon Medical Technologies, Inc. | Embolization using carbon coated microparticles |
JP2002017848A (en) | 2000-07-12 | 2002-01-22 | Terumo Corp | Intravitally injectable particulate and method for preparing the same |
WO2002011696A2 (en) | 2000-08-08 | 2002-02-14 | Ev & M | Active tissue augmentation materials and method |
US6394965B1 (en) | 2000-08-15 | 2002-05-28 | Carbon Medical Technologies, Inc. | Tissue marking using biocompatible microparticles |
EP1355630B1 (en) | 2000-08-15 | 2009-11-25 | The Board Of Trustees Of The University Of Illinois | Method of forming microparticles |
AU2001294772A1 (en) | 2000-09-27 | 2002-04-08 | Microtek Laboratories, Inc. | Macrocapsules containing microencapsulated phase change materials |
AUPR098200A0 (en) | 2000-10-25 | 2000-11-16 | Sirtex Medical Limited | Production of low density radionuclide containing microspheres |
AUPR098300A0 (en) | 2000-10-25 | 2000-11-16 | Sirtex Medical Limited | Polymer based radionuclide containing microspheres |
ES2326209T3 (en) | 2000-10-27 | 2009-10-05 | Baxter Healthcare S.A. | MICRO SPHERES PRODUCTION. |
US6545097B2 (en) | 2000-12-12 | 2003-04-08 | Scimed Life Systems, Inc. | Drug delivery compositions and medical devices containing block copolymer |
AU2001298061A1 (en) | 2000-12-13 | 2003-07-09 | Purdue Research Foundation | Microencapsulation of drugs by solvent exchange |
US6632531B2 (en) | 2001-02-15 | 2003-10-14 | Rohm And Haas Company | Porous particles, their aqueous dispersions, and method of preparation |
US6887857B2 (en) | 2001-04-27 | 2005-05-03 | Scimed Life Systems, Inc. | Microparticle protection of therapeutic agents |
US20030032935A1 (en) | 2001-08-10 | 2003-02-13 | Scimed Life Systems, Inc. | Packages facilitating convenient mixing and delivery of liquids |
US7687053B2 (en) | 2001-08-20 | 2010-03-30 | Boston Scientific Scimed, Inc. | Embolic compositions with non-cyanoacrylate rheology modifying agents |
GB0130608D0 (en) | 2001-12-21 | 2002-02-06 | Psimedica Ltd | Medical fibres and fabrics |
US7094369B2 (en) | 2002-03-29 | 2006-08-22 | Scimed Life Systems, Inc. | Processes for manufacturing polymeric microspheres |
US7218962B2 (en) | 2002-03-29 | 2007-05-15 | Boston Scientific Scimed, Inc. | Magnetically enhanced injection catheter |
CA2480630A1 (en) | 2002-03-29 | 2003-10-09 | Boston Scientific Limited | Tissue treatment |
US7131997B2 (en) | 2002-03-29 | 2006-11-07 | Scimed Life Systems, Inc. | Tissue treatment |
US7462366B2 (en) | 2002-03-29 | 2008-12-09 | Boston Scientific Scimed, Inc. | Drug delivery particle |
US7053134B2 (en) | 2002-04-04 | 2006-05-30 | Scimed Life Systems, Inc. | Forming a chemically cross-linked particle of a desired shape and diameter |
US7838699B2 (en) | 2002-05-08 | 2010-11-23 | Biosphere Medical | Embolization using degradable crosslinked hydrogels |
US20040076582A1 (en) | 2002-08-30 | 2004-04-22 | Dimatteo Kristian | Agent delivery particle |
US7449236B2 (en) | 2002-08-09 | 2008-11-11 | Boston Scientific Scimed, Inc. | Porous polymeric particle comprising polyvinyl alcohol and having interior to surface porosity-gradient |
US8012454B2 (en) | 2002-08-30 | 2011-09-06 | Boston Scientific Scimed, Inc. | Embolization |
US7883490B2 (en) | 2002-10-23 | 2011-02-08 | Boston Scientific Scimed, Inc. | Mixing and delivery of therapeutic compositions |
US7588825B2 (en) | 2002-10-23 | 2009-09-15 | Boston Scientific Scimed, Inc. | Embolic compositions |
ATE403469T1 (en) | 2003-02-26 | 2008-08-15 | Micro Therapeutics Inc | EMBOLIC COMPOSITIONS CONTAINING PYROGENIC SILICON |
US7792568B2 (en) | 2003-03-17 | 2010-09-07 | Boston Scientific Scimed, Inc. | MRI-visible medical devices |
US7906148B2 (en) | 2003-07-31 | 2011-03-15 | Boston Scientific Scimed, Inc. | Latex medical articles for release of antimicrobial agents |
US20050037047A1 (en) | 2003-08-11 | 2005-02-17 | Young-Ho Song | Medical devices comprising spray dried microparticles |
US7976823B2 (en) | 2003-08-29 | 2011-07-12 | Boston Scientific Scimed, Inc. | Ferromagnetic particles and methods |
US7901770B2 (en) | 2003-11-04 | 2011-03-08 | Boston Scientific Scimed, Inc. | Embolic compositions |
US7736671B2 (en) | 2004-03-02 | 2010-06-15 | Boston Scientific Scimed, Inc. | Embolization |
-
2004
- 2004-03-30 US US10/814,079 patent/US8173176B2/en active Active
-
2005
- 2005-03-24 WO PCT/US2005/009851 patent/WO2005097677A1/en not_active Application Discontinuation
- 2005-03-24 EP EP05729240.1A patent/EP1730077B1/en active Active
- 2005-03-24 CA CA002560312A patent/CA2560312A1/en not_active Abandoned
- 2005-03-24 ES ES05729240T patent/ES2432366T3/en active Active
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US20050226935A1 (en) | 2005-10-13 |
EP1730077B1 (en) | 2013-07-24 |
US8173176B2 (en) | 2012-05-08 |
WO2005097677A1 (en) | 2005-10-20 |
EP1730077A1 (en) | 2006-12-13 |
ES2432366T3 (en) | 2013-12-03 |
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