WO2009102868A1 - Delivery systems and related methods for convenient preparation of particles for in vivo administration - Google Patents

Delivery systems and related methods for convenient preparation of particles for in vivo administration Download PDF

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Publication number
WO2009102868A1
WO2009102868A1 PCT/US2009/033922 US2009033922W WO2009102868A1 WO 2009102868 A1 WO2009102868 A1 WO 2009102868A1 US 2009033922 W US2009033922 W US 2009033922W WO 2009102868 A1 WO2009102868 A1 WO 2009102868A1
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WIPO (PCT)
Prior art keywords
particles
equilibration
interest
chamber
fluid
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Application number
PCT/US2009/033922
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French (fr)
Inventor
Ulf Fritz
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Celonova Biosciences, Inc.
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Application filed by Celonova Biosciences, Inc. filed Critical Celonova Biosciences, Inc.
Publication of WO2009102868A1 publication Critical patent/WO2009102868A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes

Definitions

  • the present disclosure reiates to various systems and related methods that facilitate in situ equilibration of various particles in liquid or semi-liquid solutions, an ⁇ that can provide a mechanism for rapid and convenient unloading of pre-equilibratecl particles to a recipient in need of particle-mediated diagnostic and/or therapeutic procedures.
  • the disclosed systems and related methods provide one or more enciosable equilibration chambers, as a controllable environment supporting in sit ⁇ equilibration of particles, as a preparation module in part, and as a deployment module as an entire system. After sufficient opportunity for equilibration, the pre-equilibrated particles can be unloaded as a suspension from the enclosed equilibrated chamber.
  • Various embodiments are directed to various configurations suitable for constructing encSosable equilibration chambers partitioned in the interior space to permit the distribution of the particles in a predetermined spatial arrangement.
  • the enciosabie equilibration chambers permit the rapid infusion of a liquid or semi-liquid solution containing reagents of interest so that the pre-arranged particles can rapidly reach an equilibration state when exposed to the reagents.
  • the enciosable equilibration chambers can be manufactured as a stand-alone apparatus that can operate with other readily available standard catheter systems and/or standard syringes.
  • the enciosable equilibration chambers can be manufactured as an interchangeable cartridge that can be conveniently replaced, as necessary, as a replaceable component of a preparatory an ⁇ dispensing system.
  • the disciosed preparatory and dispensing system can be manufactured as a manually operated device,
  • the disclosed preparatory and dispensing system can be manufactured as an automated device,
  • FIG, 1A is a schematic showing an exemplary procedure for manually handling embolic particles provided as a sealed via! product for the preparation of sampie formulations, as commonly practiced.
  • FIG. 1 B is a schematic showing an exemplary procedure for manually handling embolic particles provided as a syringe product for the preparation of sample formulations, as commonly practiced.
  • FIG, 2 is a schematic showing an exemplary equilibration system for enabling the in situ equilibration of particles of interest within an enclosable equilibration chamber, as one embodiment of the present disclosure
  • FIG. 3A is a schematic showing an exemplary enciosabie equilibration chamber in a non-fved state in the absence of particles, from a side perspective, as one embodiment of the present disclosure
  • FIG. 3B is a cross-sectional perspective of the exemplary enclosable equilibration chamber of FIG. 3A, as one embodiment of the present disclosure.
  • FIG. 4A is a schematic showing an exemplary enclosable equilibration chamber, in a pre ⁇ filled state as assembled with pre-arranged particles, from a side perspective, as one embodiment of the present disclosure.
  • FIG. 4B is a cross-sectionai perspective of the exemplary enclosable equilibration chamber of FIG. 4A, as one embodiment of the present disclosure.
  • FIGS. 4C-4E are schematics showing various configurations for forming partitioning members that support the linear alignment of
  • FiG. 5A is a schematic showing an exemplary enciosabie equilibration chamber, in a pre-filled state as assembled with pre-arranged particles, from a side perspective as one embodiment of the present disclosure
  • SJ FSG. 5B is a cross- sectional perspective of the exemplary enciosabie equilibration chamber of FIG. 5A, as one embodiment of the present disclosure.
  • FiG. 6 is a schematic showing an exemplary enciosabie equilibration chamber, in a pre-filled state as assembled with pre-arranged particles, from a side perspective, as one embodiment of the present disclosure
  • FiG. 7 is a schematic showing an exemplary fluid flow pattern through an enciosabie equilibration chamber, as one embodiment of the present disclosure.
  • FiGS, 8A-88 show various embodiments for manufacturing kits and/or systems for the preparation and delivery of pre-eq ⁇ ilibrated particles for various diagnostic and therapeutic applications.
  • particle-mediated procedure refers to any procedure that involves the utilization of particSes ranging in size from approximately
  • Exemplary particle-mediated procedures include various intravascular interventional procedures ("embolization") invoiving in vivo administration of synfheticaiiy made particles of various compositions for reducing or stopping blood flow into the affected tissue/organ, including: for controlling gastrointestinal bleeding of any cause, for controSSing bleeding into the abdomen or pelvis from any physical trauma injuries, for controliing bleeding resulting from long menstrual periods or heavy menstrual bleeding caused by uterine fibroid tumors, for occluding vessels that are supplying blood to tumors, for eliminating arteriovenous malformation (AVM) or arteriovenous fistula (AVF) caused by abnormal connection or connections between arteries and veins, for treating various types of aneurysms, and various other conditions and diseases suitable for such particle-mediated intervention.
  • AMM arteriovenous malformation
  • AVF arteriovenous fistula
  • the contemplated "particle-mediated procedures” include any procedure in which a benefit can be conferred by the delivery of the equilibrated particles of interest for any targeted therapy, including various diagnostic, therapeutic, and cosmetic applications.
  • the particles can be delivered to any tissue or organ of a recipient.
  • the type of optimal particles (size range, color, composition) suitable for a given condition under contempiation would need to be determined by the practitioner.
  • ⁇ article(s) or “particle(s) of interest” can be interchangeably used to refer to any synthetically made particle of any shape or surface contour, with an average diameter size ranging from approximately 10 ⁇ m to approximately 1500 ⁇ m t which are intended to apply to various embolic particles and dermal-filler particles as disclosed.
  • Suitable range in average diameter size of a particle of interest include; from about 10 ⁇ m to about 1500 ⁇ m; from about 10 ⁇ m to about 1 100 ⁇ m; from about 10 ⁇ m to about 1000 ⁇ m; from about 10 ⁇ m to about 900 ⁇ m; from about 10 ⁇ m to about 800 ⁇ m; from about 10 ⁇ m to about 700 ⁇ m; from about 10 ⁇ rn to about 600 ⁇ m; from about 10 ⁇ m to about 500 ⁇ rn; from about 10 ⁇ m to about 400 ⁇ m; from about 10 ⁇ m to about 300 ⁇ m; from about 10 ⁇ m to about 200 ⁇ m; from about 10 ⁇ m to about 175 ⁇ m; from about 10 ⁇ m to about 150 ⁇ m; from about 10 ⁇ m to about 120 ⁇ m; « J 7a i from about 10 ⁇ m to about 80 ⁇ m; and from about 10 ⁇ m to about 40 ⁇ m.
  • Suitable range in average diameter size of a particle of interest include: from about 20 ⁇ m to about 1500 ⁇ m; from about 20 ⁇ m to about 1200 ⁇ m; from about 20 ⁇ m to about 2000 ⁇ m; from about 20 ⁇ m to about 900 ⁇ m; from about 20 ⁇ m to about 800 ⁇ m: from about 20 ⁇ m to about 700 ⁇ m; from about 20 ⁇ m to about 600 ⁇ m; from about 20 ⁇ m to about 500 ⁇ m; from about 20 ⁇ r ⁇ to about 400 ⁇ m: from about 20 ⁇ m to about 300 ⁇ r ⁇ ; from about 20 ⁇ r ⁇ to about 200 ⁇ m; from about 20 ⁇ m to about 175 ⁇ r ⁇ ; from about 20 ⁇ m to about 150 ⁇ m; from about 20 ⁇ m to about 120 ⁇ m; from about 20 ⁇ m to about 80 ⁇ m: and from about 20 ⁇ m to about 40 ⁇ m.
  • Suitable range in average diameter size of a particle of interest include; from about 30 ⁇ m to about 1500 ⁇ m; from about 30 ⁇ m to about 1300 ⁇ m; from about 30 ⁇ m to about 3000 ⁇ m; from about 30 ⁇ m to about 900 ⁇ m; from about 30 ⁇ m to about 800 ⁇ m; from about 30 ⁇ m to about 700 ⁇ m; from about 30 ⁇ r ⁇ to about 600 ⁇ m; from about 30 ⁇ m to about 500 ⁇ r ⁇ ; from about 30 ⁇ m to about 400 ⁇ m; from about 30 ⁇ m to about 300 ⁇ m; from about 30 ⁇ m to about 300 ⁇ m; from about 30 ⁇ m to about 175 ⁇ m; from about 30 ⁇ m to about 150 ⁇ m; from about 30 ⁇ m to about 130 ⁇ m; from about 30 ⁇ m to about 80 ⁇ m; and from about 30 ⁇ m to about 40 ⁇ m.
  • suitable particles can be selected from a relatively broad size range, the set of particles selected to be contained within a given enciosabie equiiibration chamber shouid be substantia!;/ similar in size in order for the particles of this hypothetical set (a) to fit within a partitioned space having substantially uniform cross-sectional dimensions, and (b) to be transported along a defined path, relativeiy unhindered, within the partitioned space prior to exiting from the enciosabie equilibration chamber through one or more output portals.
  • the particles of interest can be composed of one or more of any materia! desired that can be shaped to have physical stability sufficient to retain a particle diameter of interest suitable for diagnostic and/or therapeutic purposes.
  • the particles may be porous or nonporous.
  • the particles may be further modified or surface activated during or after manufacture.
  • the particles may be loaded with bioactive and pharmaceutical agents.
  • the particles may be loaded with fluorescent dyes, radiopaque reagents, or equivalents to permit
  • the particles may be loaded with magnetic elements to impart magnetic properties
  • embolic particles' or 'embolic particles of interest
  • Suitable embolic particles can be composed of any matenal amendable to controlled manufacturing and production specifications according to shaping and sizing requirements.
  • Embolic particles are typically suspended in a transport medium containing various components that stabilize the particles during storage and shipment by manufacturers.
  • dermal-ftller particles 1 refers to any synthetically made particle of any shape or surface contour, with an average diameter size ranging approximately 10 ⁇ m to approximately 1500 ⁇ m, suitable for any cosmetic application procedure.
  • Suitable dermal-filler particles can be composed of any material amendable to controlled manufacturing and production specifications according to shaping and sizing requirements.
  • Dermal-filler particles can be administered to a recipient in nee ⁇ of cosmetic and/or therapeutic enhancement in appearance, including the removal of wrinkles, dermal texture imperfections, dermal blot clots, dermal age-related disease or damage, and other equivalent conditions known by persons skilled tn the art of dermal cosmetic enhancement and dermal diagnostic/ clinical/ therapeutic applications.
  • Exemplary particle-mediated procedures include various intravascular interventional procedures ("embolization") involving in vivo administration of synthetically made particles of various compositions for reducing or stopping blood flow into the affected tissue/organ, including: [00027J
  • the term 'contrast agent refers to various compounds, suspended in contrast medium/media, that enables radiopaque visibility by highlighting specific tsssue/organ of interest during various diagnostic medical imaging examinations and/or treatment procedures that require simultaneous monitoring, by various means including: x-ray exams, computed tomography scans, and magnetic resonance imaging.
  • Exemplary contrast agents include iobitridol, iodixanol, iomeproi.
  • iopamidoi, iopentol, iopromide, ioversol, and other iodine-form ⁇ iatec! compositions which have iodine concentrations between 240 mg/m! - 400 mg/ml, or more. Sn genera!, as the average size of particles increases, a larger volume of contrast medium may be required to sufficiently saturate the particles with an iodine threshold level necessary to provide adequate radiopaque visibility when monitoring particle transport following in vivo administration.
  • driving member refers to any mechanism or a feature, either manually operable or automatically operable, that can generate sufficient force to transport any fluid of interest from a fluid- reservoir member into an enciosabie equilibration chamber, that can generate sufficient force to transport the fluid from the enciosabie equilibration chamber into the transport member, that can generate sufficient force to transport the fluid from the transport member into the vasculature of a recipient.
  • enciosabie equilibration chamber refers to an enciosabie container member comprising a housing that encloses an internal space of any shape, that can be partitioned into sub- compartments, in which the partitioning element can be composed of any materia! having the physical integrity to function as a physical boundary.
  • the partitioned sub-compartments, within the enciosabie equilibration chamber can be designed in various configurations to serve as a stable and continuous pathway to physicaily guide the movement of particles from (a) an initial position within the partitioned sub-compartment space, ⁇ b ⁇ through the pathway, and (c) through one or more output portals positioned anywhere at the distal end of the enciosabie equilibration chamber.
  • 'Vn situ equilibration refers to the process by which particles spatially arranged and filled within an enciosabie equilibration chamber during manufacturing, can be subsequently exposed to a flow of contrast medium containing a contrast agent of interest by a practitioner for a sufficient time to permit the incorporation of the contrast-agent molecules into the pores of individual particles.
  • the « J 7a i pre-equiiibrated particles can be unloaded from the encSosabSe equilibration chamber via one or more output portals into a suitable transport member.
  • transport member refers to any mechanism or a feature, either manually operable or automatically operable, that can be attached to the one or more output portals of an enclosed equilibrium chamber to serve as a conduit for transporting the pre-equilibrated particles of interest to a target tissue/organ of interest
  • Suitable examples of transport articles include macro-catheters, micro-catheters, Injection cannulae, needles of any size or dimension, or various equivalent articles known by persons skilled in the art,
  • FIGS. 1A and 1 B For comparison to the disclosed systems and methods, two standard procedures for combining various contrast agents with embolic particles are shown in FIGS. 1A and 1 B to illustrate the limitations of these methods.
  • FIG. 1A is a schematic showing &n exemplary procedure for manually handling embolic particles provided as a sealed vial product for the preparation of sample formulations, as commonly practiced.
  • a vial of embolic particles suspended in a transport medium 200 is shown, in which the embolic particles, such as 202 and 204, can be transferred from the vial into an open tray 120, in which the embolic particles can be equilibrated in the presence of a contrast agent 120, which can be added to the open tray 120, before or after the transfer of the embolic particles.
  • a contrast agent 120 which can be added to the open tray 120, before or after the transfer of the embolic particles.
  • the resulting pre-equilibrated embolic particle suspension can be transferred to a suitable syringe 120for deployment into a catheter or micro-catheter 140 for subsequent transport to a tissue/organ of interest during an embolization procedure.
  • the disadvantages of this preparatory procedure include additional time required to fill the tray with the contrast medium containing the contrast agent, and to manually mix the embolic « J 7a i beads with the contrast medium. Additional time and further manipulation are required to transfer the embolic particles from the tray into the syringe so that the particles can be exposed to the contrast agent contained in the second syringe,
  • a critical step involves suspending an appropriate amount/volume of the embolic particles in an appropriate amount/volume of the contrast medium to achieve an optima!
  • pre-equilibrated particle suspension that can be transferred to a suitable syringe for deployment into a catheter or micro-catheter for subsequent transport to a tissue/organ of interest during various embolization procedures.
  • the preparation of pre-equi ⁇ brated particles in an optima! suspension state for in vivo administration can be dependent on substantia! skill and experience.
  • RG. 1 B is a schematic showing an exemplary procedure for manually handling embolic particles provided as a syringe product for the preparation of sample formulations, as commonly practiced.
  • a first syringe 160 (“storage syringe") containing embolic particles suspended in a transport medium can be physicaiiy connected by an adaptor 170 to a second syringe 180 (“injection syringe”) containing a contrast agent suspended in a contrast medium.
  • Various adaptors 170 can be used, such as i ⁇ er-lock valves, or other equivalents of three-way valves. The disadvantages of this preparatory procedure inciude additional time required to fii!
  • a second syringe 180 with a contrast medium containing the contrast agent and the necessity of attaching this second syringe 180 to the first syringe 160 containing the emboiic particles. Additional time is required to slowly transfer the emboiic particles from the first syringe 160 into the second syringe 180 so that the embolic particles come into contact with the contrast agent contained in the second syringe 180.
  • the pre-equilibrated embolic particles such as 184 and 186, can be transferred to a suitable syringe for deployment into a catheter, or micro-catheter, 190 for subsequent transport to a tissue/organ of interest during various embolization procedures.
  • the systems and methods of this disclosure provide substantia! advantages not conferred by other devices/systems known to persons skilled in the art in that the disclosed system enables the preparation of ready-to-use sample formulations comprising particies of interest in various suitable and stable suspensions for immediate administration for cosmetic, medical, surgical, and other procedures amenable for various particle-mediated, diagnostic and therapeutic appiications.
  • the disclosed systems and related methods provide an enciosabie equilibration chamber comprising a sealable housing member and an enclosed partitioned space for promoting the equilibration of particles of interest within a suitable volume and composition of a suspension medium for the preparation of a suitable sample formulation ready for in wo administration.
  • the pre-equilibrated particle suspension can be released into one or more transport members without requiring additional preparation steps.
  • the disclosed systems and methods confer a multitude of advantages including: (a) minimizing risks for contaminating preparatory materials during additional handling steps that may be performed in a non- sterile environment; (b) minimizing any risk for physically damaging the deSicate particie-based products during preparatory manipulations; (c) minimizing risks for evaporating highly volatile reagents by directly depositing into the enciosabie equilibration chamber; ⁇ d) minimizing any exposure time to toxic or hazardous reagents by directly depositing info the enciosabie equiiibration chamber; (e) maximizing efficiency by minimizing the number of separate preparatory steps necessary by centralizing the reactive components into a single reaction chamber, in which soluble and particuSate components can interact efficiently; (f)
  • the disciosed systems and related methods can be employed for various embolization procedures by providing an enclosable equilibration chamber comprising a sealable housing member and an enclosable partitioned space for promoting the equilibration of embolic particles of interest within a suitable volume and composition of a suspension medium, containing various ingredients, such as transport medium, contrast agents, saline, and other suitable components, in particular, the enclosable equilibration chamber enables the interaction between the contrast agent of interest and the particles of interest to produce a stable suspension of the particles within a sterile and controlled environment for the preparation of a suitable sample formulation ready, for immediate or delayed, in vivo administration, with minimal or no additional preparation required.
  • the disciosed systems and related methods enable the practitioner to balance the contrast agent with the amount of saline to achieve optimal radiopaque visibility, and to obtain adequate particle suspension in the sample formulation that can be prepared to be administered to a patient in need of embolic particle- mediated therapy.
  • FIG. 2 is a schematic showing an exemplary equiiibration system for enabling in situ equilibration of particles of interest within an enclosable equilibration chamber, as one embodiment of the present disclosure.
  • an exempiary equilibration system 200 is shown, in which a driving member 220 is connected to a fluid-reservoir member 220 in order to mediate the transfer of a fluid of interest stored in fluid-reservoir member 220 into at least one enclosable equilibration chamber 230.
  • Multiple enclosable equiiibration chambers can be optionally assembled as
  • the enciosabie equilibration chamber 220 can be optionally assembled as a cartridge unit that can be reversibly attached to a support frame 260 to facilitate the removal of an exhausted cartridge for replacement with an unused cartridge unit.
  • the support frame 280 can be attached, directly or indirectly, to the fluid-reservoir member 220 and to the transport member 240 in order to stabilize the system during routine use and during cartridge replacement
  • FIG. 3A is a schematic showing an exemplary enciosabie equilibration chamber in a non-f ⁇ led state in the absence of particies, from a side perspective, as one embodiment of the present disclosure.
  • an enciosabie equilibration chamber 300 is shown, comprising a housing member 320 and one or more partition members, such as 320 and 330, arranged in a linear array as a hypothetical spatial arrangement.
  • the enciosabie equilibration chamber 300 inciudes at least one input portal 340, which can be positioned at the proximal end of the enciosabie equilibration chamber as shown.
  • a fluid of interest can enter the enciosabie equilibration chamber 300 via the input porta! 340, which can be hypothetical Iy positioned anywhere with respect to the housing member, as Song as there is a connection, direct or indirect, with a fluid- reservoir member such as 220 of FIG. 2.
  • the enciosabie equilibration chamber 300 includes at least one output portal 350 at the distal end of the enciosabie equilibration chamber as shown.
  • one or more output portals 350 can be hypothetical ⁇ positioned anywhere with respect to the housing member as long as there is a connection, direct or indirect, with a transport member, such as 240 of FIG. 2.
  • the particies should not be permitted to dry out during operation, and the particles should not aggregate together to form dogs when transported, from one position to the next, within the enciosabie equilibration chamber 300.
  • FIG. 3B is a cross-sectiona! perspective of the exemplary encSosabSe equilibration chamber of FIG. 3A, as one embodiment of the present disclosure
  • the enclosable equiiibration chamber 360 is shown, in which the partition members, 370 and 375, are arranged as a rectilinear grid within the housing member 380 as a hypothetical spatia! arrangement.
  • the partition members, 370 and 375 can be arranged in any three-dimensional configuration that can permit the occupation and movement of particles within the partitioned spaces, such as 390 and 395 r within the enclosabie equiiibration chamber 380,
  • FIG. 4A is a schematic showing an exempiary enciosabie equilibration chamber, in a pre-ftlled state as assembled with pre-arranged particles, from a side perspective, as one embodiment of the present disclosure, Sn FSG. 4A, an enclosable equilibration chamber 400 is shown, comprising a housing member 420 and one or more partition members, such as 420 and 430, arranged in a iinear array as a hypothetical spatiai arrangement.
  • the enciosabie equiiibration chamber 400 includes at least one input porta! 440 at the proximal end of the enciosabie equiiibration chamber, and at ieast one output porta!
  • the enciosabie equilibration chamber 400 can be filled with particies of interest, such as 434 and 436, that can be arranged in a pre-determined configuration, supported by partition members, such as 420 and 430, to form a spatiai boundary.
  • a fiuid of interest can be directed into the enciosabie equilibration chamber 400 via the input porta! 440, to contact the prearranged particles, such as 434 and 436.
  • pre- equilibrated particie suspension, including particles such as 434 and 436 can be deployed from the enclosable equiiibration chamber 400 via the output portal 450.
  • partition members, 420 and 430 are shown as a iinear array as a hypothetical spatiai arrangement this disclosure is not limited to any spatiai arrangement, with the condition that when the particles are spatially aiigned, each particie makes direct contact with no more than two other particles so that there is a continuum of
  • FIG. 48 is a cross-sectiona! perspective of the exemplary encSosabSe equilibration chamber of FIG. 4A, as one embodiment of the present disclosure
  • the enclosable equi ⁇ bration chamber 460 is shown, in which the partition members, 470 and 475, are arranged as a rectilinear grid within the housing member 480 as a hypothetical spatia! arrangement.
  • the partition members, 470 and 475 r can be arranged in any three-dimensionai configuration that permits the occupation and movement of particles, such as 478 and 478, within the partitioned spaces of the enciosable equilibration chamber 460.
  • FIGS. 4C-4E are schematics showing various configurations for forming partitioning members that support the iinear alignment of particies within an enclosable equilibration chamber as embodiments of the present disclosure.
  • the partition member is composed of an impermeable materia! 485, and can be formed as a conduit or a tube exhibiting a uniform average diameter that can be fiiied with substantially uniform particies exhibiting uniform average diameters, 486 &n ⁇ 487.
  • the reactants of interest provided in a fluid- reservoir member can be directed into the iumen of the impermeabie conduit in order to react/interact with the particies.
  • the partition member is composed of a semi-pemneable membrane material 490, and formed as a conduit or a tube exhibiting an uniform average diameter that can be filled with substantialiy uniform particles exhibiting uniform average diameters, 491 Bn ⁇ 492.
  • the reactants of interest provided in a fiuid-reservoir member can be directed generally into the enclosable equilibration chamber, since the semi- permeable membrane material includes pores that can allow substantial flow of sate into the iumen 494 of the conduit in order to react/interact with the particles
  • the partition member is composed of a permeable mesh materia! 495, and formed as a conduit or a tube exhibiting an uniform average diameter that can be filled with substantially uniform
  • the reacta ⁇ ts of interest provided in a fluid-reservoir member can be directed generally into the enclosable equilibration chamber, since the permeable mesh materia! includes pores that can aiiow substantial fiow of solvent into the iumen 498 of the conduit in order to react/interact with the particles.
  • the partition member can be manufactured utilizing any materia! known to persons skilled in the art, including any polymers, ceramics, metais, metal alloys, and/or nitinol or other equivalent shape-memory ailoys.
  • FIG. 5A is a schematic showing an exemplary enciosabie equilibration chamber, in a pre-filled state as assembled with pre-arranged particles, from a side perspective as one embodiment of the present disclosure, in FSG. 5A, an enclosable equilibration chamber 500 is shown, comprising a housing member 520 and a partition member 520 formed as a continuous tubing 530, arranged as a coii of aligned particles within the housing member 520, as a hypothetical spatia! arrangement.
  • the enciosabie equilibration chamber 500 includes at least one input porta! 540 at the proximal end of the enclosable equilibration chamber, and at least one output porta!
  • the enclosable equilibration chamber 500 can be filled with particles of interest, such as 534 and 536, that can be arranged in a pre-determined configuration, supported by partition members, such as 520 and 530, to form a spatial boundary.
  • a fluid of interest can be directed into the enclosable equilibration chamber 500 via the input portal 540, to come into contact with the pre-arranged particles, such as 534 and 536.
  • pre-equilibrated particle suspension including particles such as 534 and 538 can be deployed from the enclosable equilibration chamber 500 via the output portal 550.
  • the partition members, 520 and 530 are shown as a linear array as a hypothetical spatial arrangement, this disclosure is not limited to any spatial arrangement, with the condition that when the particles are spatially aligned, each particle makes direct contact with no more than two other particles so that there is a continuum of particles arranged in a single-file « J 7a i row, however, the tola! set of particles can be spatially arranged in a nonlinear, convoluted pattern, if desired.
  • a flexible tubing with an uniform diameter can be filled with particles of substantially uniform size so that the pre-filled tubing can be spatially arranged as a coil within the enciosabie equilibration chamber.
  • an orderly coil-like spatial arrangement is not a prerequisite for efficient operation of the enclosed equilibrium chamber.
  • FIG. 5B is a cross-sectional perspective of the exemplary enciosabie equilibration chamber of FIG. 5A, as one embodiment of the present disclosure.
  • the enciosabie equilibration chamber 580 is shown, in which the partition member is formed as a continuous tubing
  • the continuous tubing 570 permits the occupation and movement of particles
  • FIG. 6 is a schematic showing an exemplary enciosabie equilibration chamber, in a pre-filled state as assembled with pre-arranged particles, from a side perspective, as one embodiment of the present disclosure.
  • an enciosabie equilibration chamber 600 is shown, comprising a housing member 620 and a partition member formed as a continuous tubing 630, arranged as a coil of aligned particles within a housing member 620 shaped to follow the contour of the continuous tubing 630, as a hypothetical spatial arrangement
  • the enciosabie equilibration chamber 600 includes at least one input porta!
  • the enciosabie equilibration chamber 600 can be filled with particles of interest, such as 634 and 636, that can be arranged in a predetermined configuration, supported by the walls of the continuous tubing 620that forms a spatial boundary.
  • a fluid of interest can be directed into the enciosabie equilibration chamber 800 via the input portal 840 : to come into contact with the pre-arranged particles, such as 634 and 636, After
  • each particle makes direct contact with no more than two other particies so that there is a continuum of particles arranged in a singie-fil ⁇ row, however, the tota! set of particies can be spatially arranged in a non-linear, convoluted pattern, if desired.
  • FIG. 7 is a schematic showing an exemplary fluid flow pattern through an enclosable equilibration chamber as one embodiment of the present disclosure.
  • an enclosable equilibration chamber 700 is shown, comprising a housing member 720, in broken lines, and a partition member that can be hypothetical Iy formed as a continuous tubing 720, that can be arranged as a coii to contain particles aligned as a single contiguous row as previously shown in FiG, 5.
  • the arrows 720and 740 indicate the hypothetical direction of the fluid flow along the inner lumen of the continuous tubing 720 as the fluid of interest enters from at least one input portal 750 at the proximal end of the enclosable equilibration chamber, and exits from at least one output portal 760 at the dista! end of the enclosable equilibration chamber.
  • the housing member 620 can be shaped as a coil
  • the partition member formed as a continuous tubing 620 can be shaped as a coil with a smaller cross-sectional diameter that can be enclosed within the housing member 620 shaped to follow the outer contour of the continuous tubing 630.
  • FIGS. 8A-8C show various embodiments for manufacturing kits and/or systems for the preparation and delivery of pre-equiiibrated particles for various diagnostic and therapeutic applications, in various kits contemplated, the particies of interest can be provided in a container of any shape or form, suspended in a suitable transport medium. If
  • kits may optionally include one or more contrast agents suspended in contrast media.
  • the kits may include instructions for solution preparation, particle preparation, and/or assembiy of component members into an operabie system.
  • the component members previously described in FiG. 2. can be provided in various combinations as pre-assembSed kits.
  • an enciosable equilibration chamber (“EEC”) is provided as a stand-aione kit component that can be assembled together with other readily available standard catheter systems and/or standard syringes, in FiG. 8A, the enclosabie equilibration chamber 800 can be manufactured as a stand-alone apparatus that can operate with standard catheter systems 820 and/or standard syringes 82O 1 not provided by the kit.
  • any syringe-iike device 820 can function as a driving member and a fluid-reservoir member, by filling the barrel of a syringe with contrast agent/medium and applying the necessary force to transport the contrast agent/medium to an enciosabie equiiibration chamber when assembled together.
  • Any catheter-like device 820 can function as a transport member, by assembling together with the enciosabie equilibration chamber 800.
  • a suitable driving member (“DM”) includes various manually operated devices, such as a two-hole syringe, and various automated devices, such as an electrically powered piston gun capable of transporting the fluid from the fluid-reservoir member into the enciosabie equilibration chamber ("EEC * ).
  • an enciosabie equilibration chamber can be provided in combination with a driving member (“DM”), a fluid-reservoir member (“FRM”), and/or a transport member C'TM”), In this combination, each of these member components can be provided as separate articles that can be assembled together conveniently.
  • the driving member can be manufactured as a manually operated device.
  • the driving member can be manufactured as a manually operated device.
  • DM can be manufactured as an automated device. This configuration
  • J 7a i provides the maximum flexibility by the practitioner, in that any of the member components can be replaced as often as necessary during a procedure depending on the nature of the procedure.
  • the component members shown in FIG.8A can be provided by a pre-assembled kit
  • FIG. 8B is a schematic of an exemplary combination, in which these individual component members can be provided pre-assembled as one complete system, in which the integrated apparatus can be utilised for a single procedure and discarded, in FIG.
  • an ⁇ nciosabSe equilibration chamber (“B") is integrated into a syringe- like apparatus 850 having an external housing member ("P), a syringe-like plunger (“E"), a syringe-like stopper (“D”), and a luer-lock tip ("A”).
  • a fluid of interest can be deposited into compartment ("C") within the syhnge-iike apparatus 850.
  • the endosable equilibration chamber can be manufactured as a replaceable cartridge unit or a moduie that can be conveniently replaced after exhaustion of the prefilled particles.
  • the cartridge unit can be designed to be neversibly attachabie to a support frame to facilitate the removal of an exhausted cartridge for replacement with an unused cartridge unit.
  • the support frame can be attached, directly or indirectly, to the fluid-reservoir member and to the transport member in order to stabilize the system during routine use and during cartridge replacement.
  • the driving member ⁇ "DM can be manufactured as a manually operated device.
  • the driving member (“DM”) can be manufactured as an automated device.
  • polymer-based particles can be engineered to act as carrier devices for releasing various pharmaceutical and/or bioactive agents.
  • the polymer-based particles can be engineered to act as carrier devices for releasing various pharmaceutical and/or bioactive agents.
  • an enciosabie equilibration chamber comprising: a set of particles selected from an average diameter size ranging from 10 ⁇ m to 1500 ⁇ m; a sealabSe housing member including an internal space; at least one partitioning member positioned within the internal space, wherein the partitioning member is formed in a pre- determined configuration to support the contiguous alignment of the set of particles so that each particle is in direct physical contact with no more than two particles; at least one input port for directing the entry of a fluid of interest into the interna!
  • the enciosabie equilibration chamber provides that the average diameter size of a particle ranges: from about 10 ⁇ m to about 1500 ⁇ m; from about 10 ⁇ m to about 1100 ⁇ m; from about 10 ⁇ m to about 1000 ⁇ m; from about 10 ⁇ m to about 900 ⁇ m; from about 10 ⁇ m to about 800 ⁇ m; from about 10 ⁇ m to about 700 ⁇ m; from about 10 ⁇ m to about 800 ⁇ m; from about 10 ⁇ m to about 500 ⁇ m; from about 10 ⁇ m to about 400 ⁇ m; from about 10 ⁇ m to about 300 ⁇ m; from about 10 ⁇ m to about 200 ⁇ m; from about 10 ⁇ m to about 175 ⁇ m; from about 10 ⁇ m to about 150 ⁇ m; from about 10 ⁇ m to about 120 ⁇ m;
  • the enciosabie equilibration chamber provides that the average diameter size of a particle ranges; from about 20 ⁇ m to about 1500 ⁇ m; from about 20 ⁇ m to about 1200 ⁇ m; from about 20 ⁇ m to about 2000 ⁇ m; from about 20 ⁇ m to about 900 ⁇ m; from about 20 ⁇ m to about 800 ⁇ m; from about 20 ⁇ m to about 700 ⁇ m; from about 20 ⁇ m to about 600 ⁇ m; from about 20 ⁇ m to about 500 ⁇ m; from about 20 ⁇ m to about
  • J 7a i chamber provides that the average diameter size of a particle ranges: from about 30 ⁇ m to about 1500 ⁇ m; from about 30 ⁇ m to about 1300 ⁇ m; from about 30 ⁇ m to about 3000 ⁇ m; from about 30 ⁇ m to about 900 ⁇ m; from about 30 ⁇ m to about 800 ⁇ m; from about 30 ⁇ m to about 700 ⁇ m; from about 30 ⁇ m to about 600 ⁇ m: from about 30 ⁇ m to about 500 ⁇ m; from about 30 ⁇ m to about 400 ⁇ m: from about 30 ⁇ m to about 300 ⁇ m; from about 30 ⁇ r ⁇ to about 300 ⁇ m: from about 30 ⁇ m to about 175 ⁇ r ⁇ ; from about 30 ⁇ m to about 150 ⁇ m; from about 30 ⁇ m to about 130 ⁇ m; and from about 30 ⁇ m to about 80 ⁇ m, [00OS8] Sn various embodiments, a system for promoting in situ equilibrium of particles is provided, comprising: an enclon
  • the average diameter size of a particle ranges: from about 10 ⁇ m to about 1500 ⁇ m; from about 10 ⁇ m to about 1 100 ⁇ m; from about 10 ⁇ m to about 1000 ⁇ m; from about 10 ⁇ m to about 900 ⁇ m; from about 10 ⁇ m to about 800 ⁇ m; from about 10 ⁇ m to about 700 ⁇ m; from about 10 ⁇ m to about 600 ⁇ m; from about 10 ⁇ m to about 500 ⁇ m; from about 10 ⁇ m to about 400 ⁇ m; from about 10 ⁇ m to about 300 ⁇ m; from about 10 ⁇ m to about 200 ⁇ m; from about 10 ⁇ m to about 175 ⁇ m; from about 10 ⁇ m to about 150 ⁇ m; from about 10 ⁇ m to about 120 ⁇ m; from about 10 ⁇ m to about 80 ⁇ m; and from about 10 ⁇ m to about 40 ⁇ m.
  • the average diameter size of a particle ranges: from about 20 ⁇ m to about 1500 ⁇ m; from about 20 ⁇ m to about 1200 ⁇ m; from about 20 ⁇ m to about 2000 ⁇ m: from about 20 ⁇ m to about 900 ⁇ m; from about 20 ⁇ m to about 800 ⁇ m; from about 20 ⁇ m to about 700 ⁇ m; from about 20 ⁇ m to about 600 ⁇ m;
  • J 7a i from about 20 ⁇ m to about 500 ⁇ m; from about 20 ⁇ m to about 400 ⁇ m; from about 20 ⁇ m to about 300 ⁇ m; from about 20 ⁇ m to about 200 ⁇ m; from about 20 ⁇ m to about 175 ⁇ m; from about 20 ⁇ m to about 150 ⁇ m; from about 20 ⁇ m to about 120 ⁇ m; from about 20 ⁇ m to about 80 ⁇ m; and from about 20 ⁇ m to about 40 ⁇ m.
  • the average diameter size of a particle ranges; from about 30 ⁇ m to about 1500 ⁇ m; from about 30 ⁇ m to about 1300 ⁇ m; from about 30 ⁇ m to about 3000 ⁇ m; from about 30 ⁇ m Io about 900 ⁇ m; from about 30 ⁇ m to about 800 ⁇ m; from about 30 ⁇ m to about 700 ⁇ m; from about 30 ⁇ m to about 600 ⁇ m; from about 30 ⁇ m to about 500 ⁇ m; from about 30 ⁇ m to about 400 ⁇ m; from about 30 ⁇ m to about 300 ⁇ m; from about 30 ⁇ m to about 300 ⁇ m; from about 30 ⁇ m to about 175 ⁇ m; from about 30 ⁇ m to about 150 ⁇ m; from about 30 ⁇ m to about 130 ⁇ m; and from about 30 ⁇ m to about 80 ⁇ m.
  • the system further comprises a driver member, a fluid-reservoir member, and a transport member.
  • a system for promoting in situ equilibrium of particles comprising: An in situ method for pre- equilibrating particles, the method comprising: providing an enclosabSe equilibration chamber including a set of particles aligned contiguousSy so that each particle is in direct physical contact with no more than two particles; directing a fiuid of interest within the enclosabie equilibration chamber so that the particles are exposed to the fluid of interest for a sufficient time to permit equilibration of the particles; and deploying the pre-equilibrated particles suspended in the fiuid of interest from the encSosabSe equiiibration chamber.
  • the in situ method further comprises adding pharmaceutical and/or bioactive agents.
  • the in situ method further comprises embolic agents.
  • the suitable average diameter size of a particle ranges; from about 10 ⁇ m to about 1500 ⁇ m; from about 10 ⁇ m to about 1100 ⁇ m; from about 10 ⁇ m to about 1000 ⁇ m; from about 10 ⁇ m to about 900 ⁇ m; from about 10 ⁇ m to about 800 ⁇ m; from about 10 ⁇ m to about 700 ⁇ m; from about 10 ⁇ m to about 600 ⁇ m; from about 10 ⁇ m to about 500 ⁇ m; from about 10 ⁇ m to about 400 ⁇ m; from about 10 ⁇ m to about 300 ⁇ m; from about 10 ⁇ m to about 200 ⁇ m; from about 10 ⁇ m to about 175 ⁇ m; from about 10 ⁇ m to about 150 ⁇ m; from about 10 ⁇ m to
  • an in situ method for pre-equilibrating embolic particles and for delivery comprising; providing an enciosabie equilibration chamber including a set of emboiic particles aligned contiguously so that each embolic particle is in direct physical contact with no more than two embolic particies; directing a fluid of interest within the enclosable equilibration chamber so that the emboiic particles are exposed to the fluid of interest for a sufficient time to permit equilibration of the emboiic particles; and deploying the pre-equiiibrated embolic particles suspended in the fluid of interest from the enciosabie equilibration chamber into a transport member.
  • the in situ method of further comprise deploying the pre-equilibrated embolic particles from the transport member to a target vasculature of a recipient.
  • the specific polyphophazene polymers having the general formula (!) can be employed for encapsulating any particles of interest as a coating layer to confer a biocompatible coating to any particles of interest.
  • Various embodiments are directed to particles of interest encapsulated by at least one polymer component having the genera! formula (I):
  • R 1 to R ⁇ are independently selected from: a substituted or unsubstituted alkyl, aikoxy, aryi, aryloxy, silyl, silyioxy, aikylsulfonyL alkyl amino, dialkyl amino, ureido, carboxylic atit ⁇
  • Suitable substituents for R 1 to R 6 can be independently selected from; halide substituents, such as fluorine, chlorine bromine, or iodine; pseudohaiide substituents, such as cyano (-CN) 1 isocyano (-NC), thiocyano (- SCN), isothiocyano (-NCS), cyanato (-OCN), isocyanato (-NCO), azido (-N 3 ) groups; substituents such as nitro- (-HO 2 ) and nitrito (-NO) groups; partially substituted alkyl groups, such as haloalkyl; heteroaryl such as imidazoyl, oxazolyl, thiazoiyi, pyrazolyl derivatives; or purine and pyrimidine bases such as guanidines, amidines and other ureido derivatives of the base structure.
  • halide substituents such as fluorine, chlorine bromine, or iodine
  • cycloalkyl cyclic hydrocarbyl moieties, including alkyl (saturated hydrocarbons) as well as aikeny! &n ⁇ alkynyi moieties, having from 1 to 20 (for example, from 1 to 12, or 1 to 6) carbon atoms.
  • aikenyi and aikynyl moieties provides, among other things, the capability to cross-link the polyphosphaze ⁇ e moieties to any extent desired.
  • Exampies of aikyl groups include, but are not limited to, methyl, ethyi, propyi, isopropyi, n-butyl, t-butyl, isobutyi, sec-butyl, pentyl, isopentyi. neopentyi, hexyl, isohexyi.
  • Cycioaikyi moieties may be monocyclic or muiticyciic, and examples include cyclopropyl, cyclobutyl, cyciopentyl, cyciohexyi, and adamantyl. Additional examples of alky! moieties have Sinear, branched and/or cyclic portions (e.g., 1 -ethy!-4-methyi ⁇ cyciohexyi ⁇ .
  • R (aSkyl) groups include unsubstituted alkyl, substituted aikyl such as halo- substituted alkyl (haSoaikyS), unsubstituted aikenyi, substituted aikenyi such as halo-substituted alkenyl, and unsubstituted alkynyi, and substituted alkynyi such as halo-substituted aikynyl.
  • substituents can be unsubstituted alkoxy ⁇ "aikyloxy"), substituted alkoxy such as halo-substituted alkoxy (haioaikoxy), unsubstituted aikenyioxy, substituted aikenyioxy such as halo-substituted aikenyioxy, unsubstituted alkynyloxy, and substituted alkynyloxy such as halo-substituted alkynyioxy.
  • vinyioxy and aiiyioxy can be useful.
  • a silyl group is a ⁇ 8iR3 group and a silyloxy group is an ⁇ O$iR3 group, where each R moiety is selected independently from the R groups defined supra. That is, R in each occurrence is selected independently from a linear, branched, and/or cyclic ("cycioalkyl") hydrocarbyl moieties, including alkyl (saturated hydrocarbons) as well as alkenyl and alkynyi moieties, having from 1 to 20 (for example, from 1 to 12, or 1 to 8) carbon atoms.
  • a halogen fluorine, chlorine, bromine, or iodine
  • substituted "aikyi” and moieties which encompass substituted aikyl r such as “alkoxy”, include haSoaikyl and haloalkoxy, respectively, including any fluorine-, chlorine-, bromine-, and iodine-substituted alky! and aikoxy.
  • terms haloalkyl and haSoalkoxy refers to alky! and alkoxy groups substituted with one or more haiogen atoms, namely fluorine, chlorine, bromine, or iodine, including any combination thereof,
  • aryl means an aromatic ring or an aromatic or partially aromatic ring system composed of carbon and hydrogen atoms, which may be a single ring moiety, or may contain multiple rings bound or fused together.
  • aryl moieties include, but are not limited to, phenyl, anthracenyS, azulenyl, biphenyl, fSuorenyl, indan, indenyl, naphthyl, phenanthrenyl, 1 ,2,3,4-tetrahydro- ⁇ aphthale ⁇ e, tolyl, and the like, any of which having up to 20 carbon atoms.
  • An aryloxy group refers to an ⁇ O(aryl) moiety.
  • haioaryl and haSoaryioxy refer to aryl and aryloxy groups, respectively, substituted with one or more halogen atoms, namely fluorine, chlorine, bromine, or iodine, including any combination thereof.
  • a heterocyclic aikyl group with at least one nitrogen as a heteroatom refers to a non-aromatic heterocycle and includes a cycloaikyl or a cycloalkenyl moiety in which one or more of the atoms in the ring st ⁇ scture is nitrogen rather than carbon, and which may be monocyclic or muiticyclic, and may include exo-carbony! moieties and the like.
  • heterocyclic aikyl group with nitrogen as a heteroatom examples include, but are not limited to, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydropyrimidinyl, morphoiinyl, aziridinyl, imidazoSidinyl, 1-pyrro!ine, 2-pyrroiine, or 3-pyrroline, pyrrolidinonyl, piperazinonyl, hydantoinyi, piperidin-2-one, pyrroiidin ⁇ 2 ⁇ one, azetidin-2-one, and the like.
  • these groups include heterocyclic exocyc ⁇ c ketones as well.
  • a heteroaryl group with at least one nitrogen as the heteroatom refers to an aryi moiety in which one or more of the atoms in the ring structure is nitrogen rather than carbon, and which may be monocyclic or muiticyclic.
  • heterocyclic alky! group with nitrogen as a heteroatom examples include,
  • J 7a i but are not limited to. acridinyl, benzimidazoiyi, quinazoiinyl, benzoquinazoiinyl imidazoiy!, indolyl, isothiazolyl, isoxazolyL oxazoly! or oxadiazolyl, phthaiazinyi, pyrazinyi, pyrazolyl, pyridaziny!, pyridyl, pyrimidinyl, pyrimidyi, pyrroiyi, quinazolinyl, quinolinyi, tetrazoSyl, thiazolyS, triazinyi, and the like.
  • this disclosure includes or encompasses chemicai moieties found as subunits in a wide range of pharmaceutical agents, natural moieties, natural biomolecuies, and biomacromoSecuies.
  • this disclosure encompasses a number of pharmaceutical agents available with the t ⁇ trazoi ⁇ group (for example, losartan, candesartan, irbesartan, and other Angiotensin receptor antagonists); the triazoie group (for example, fluconazole, isavuconazole, itraconazole, voriconazole, pramiconazole, posaconazoie, and other antifungal agents); diazoles (for example, fungicides such as Miconazole,, Ketoconazole, Clotrimazole , Econazole, Bifonazole, Butoconazoie, Fenticonazole, Isoconazoie, Oxiconazoie, Sertaconazole, Sulconazole, Ti
  • R1 to R6 moieties in the formula I can encompass chemical moieties found as subunits in a wide range of pharmaceutical agents, natural moieties, natural biomolecuies, and biomacromoSecules.
  • a heterocyclic alkyl group with at least one phosphorus, oxygen, sulfur, or selenium as a heteroatom refers to a non-aromatic heterocycie and includes a cycloaikyl or a eycloaSkenyl moiety in which one or more of the atoms in the ring structure is phospho ⁇ is, oxygen, sulfur, or selenium rather than carbon, and which may be monocyclic or muiticyclic, and may include exo ⁇ carbony!
  • heteroaryl group with at least one phosphorus, oxygen, sulfur, or selenium as the heteroafom refers to an aryl moiety in which one or more of the atoms in the ring structure is phosphorus, oxygen, sulfur, or selenium rather than carbon, and which may be monocyclic or muiticyclic.
  • heterocyclic alkyl groups or heteroaryls with phosphorus, oxygen, sulfur, or selenium as a heteroatom include, but are not limited to, substituted or unsubstituted ethylene oxide (epoxides, oxiranes), oxirene, oxetane, tetrahydrofuran (oxolane), dihydrofuran, furan, pyran, tetrahyd ropy ran, dioxane, dioxin, thiirane
  • these groups include a!! isomers, including regioisomers of the recited compounds.
  • these groups include 1 ,2- and 1 ,3- oxazoles, thiazoies, seienazoles, phosphazoles, and the like, which include different heteroatoms from the group 15 or group 16 elements.
  • a nucleotide refers to an organic compound containing a nitrogenous base, a sugar moiety, and one or more phosphate groups.
  • the most common nucleotides contain either a purine or pyrimidine nitrogenous base (for exampie, guanine, adenine, thymine, cytosine and uracil), typically bonded to a pentose (5-carbon) sugar such as a ribose or a deoxyribose sugar, which itself is bonded to one or more phosphate groups.
  • nucleotide is also used to include those materiaSs commonly known for use as monomers for nucleic acids (such as RNA and DNA) as well as cefaclors, moieties, derivatives, and portions thereof including, for exampie Coenzyme A (CoA), FAD (flavin adenine dinucleotide), NAD (nicotinamide adenine dinucieotid ⁇ ), NADP (nicotinamide adenine dinucleotide phosphate), other dinucieotides, and the like.
  • CoA Coenzyme A
  • FAD flavin adenine dinucleotide
  • NAD nicotinamide adenine dinucieotid ⁇
  • NADP nicotinamide adenine dinucleotide phosphate
  • nucleotide residue includes nucleosides, deoxynucleosides, and similar materials, examples of which include but are not limited to, adenosine, guanosine, 5- rm ethyl uridine, uridine, cytidine, deoxyadenosine, deoxyguanosine, deoxythymidine, deoxyuridine, and deoxycytidine, and the like,
  • a purine base is a class of heterocyclic aromatic compounds containing a pyridimine ring fused to an imidazole ring, and including substituted purines and their tautomers.
  • purines include, but are not limited to, purine, adenine, guanine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, isoguanine, and the like.
  • a pyrimidine base include, but are not limited to, pyrimidine, uracil, thymine, and cytosine.
  • R1 to R8 are all trill uoroethoxy (OCH2CF3) groups, and whereinthe n value may vary from at least about 40 to about 100,000 Daltons.
  • n value may vary from at least about 40 to about 100,000 Daltons.
  • one may use derivatives of polymer of formula (I).
  • derivative or “derivatives” is meant to refer to polymers made up of monomers having the structure of formula (I), wherein one or more of the R1 to R6 functionai grou ⁇ (s) is replaced by a different functional group(s), such as an unsubstifufed alkoxide, a halogenated alkoxide, a fluorinated alkoxide, or any combination thereof, or where one or more of the R1 to R6 is repiaced by any of the other functional group(s) disclosed herein, but where the biological inertness of the polymer is not substantially aitered.
  • a different functional group(s) such as an unsubstifufed alkoxide, a halogenated alkoxide, a fluorinated alkoxide, or any combination thereof, or where one or more of the R1 to R6 is repiaced by any of the other functional group(s) disclosed herein, but where the biological inertness of the polymer is not substantially a
  • At least one of the substituents R 1 to R 6 can be an unsubstituted aikoxy substituent : such as methoxy (OCH 3 ), ethoxy (OCH 2 CH 3 ) or n-propoxy (OCH 2 CH 2 CH 3 ).
  • at least one of the substituents R 1 to R 6 is an aikoxy group substituted with at least one fluohne atom.
  • R 1 to R e examples include, but are not limited to OCF 3 , OCH 2 CF 3 , OCH 2 CH 2 CF 3 , OCH 2 CF 2 CF 3 , OCH(CF 3 ) 2 , OCCH 3 (CF 3 ) 2 ,
  • OCH 2 CF 2 CF 2 CF 31 OCH 2 (CF 2 )SCF 3 , OCH 2 (CF 2 J 4 CF 3 , OCH 2 (CF 2 ) 5 CF 3 ⁇ OCH 2 (CF 2 ) 6 CF 3 , OCH 2 (CF 2 ) 7 CF 3 , OCH 2 CF 2 CHF 2 , OCH 2 CF 2 CF 2 CHF 2 , OCH 2 (CF 2 ) 3 CHF 2 , OCH 2 (CF 2 J 4 CHF 2 , OCH ⁇ (CF ⁇ ) 5 CHF 2 , OCH 2 (CF 2 ) 6 CHF 2 , OCH 2 (CF 2 )TCHF 2 , and the iike.
  • t ⁇ fluoroethoxy (OCH 2 CF 3 ) groups are preferred, these further exemplary functional groups also may be used alone, in combination with trifiuoro ⁇ thoxy, or in combination with each other.
  • especially useful fluorinated aikoxide functional groups include, but are not limited to, 2,2,3,3,3-pentafluoropropyioxy (OCH 2 CF 2 CF 3 ), 2 ( 2,2,2 ⁇ 2 : ,2' ⁇ hexafluoroisopropyloxy (OCH(CFs) 2 ) r 2,2,3,3,4 A4 ⁇ heptafluorobuty!oxy (OCH 2 CF 2 CF 2 CF 3 ), 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyioxy
  • R 1 to R 6 groups may be alkenoxy groups, a feature that can promote crosslinking to produce a phosphazene polymer exhibiting more
  • residues R 1 to R 6 are each independently variabie, and therefore can be the same or different.
  • the polymers of formula (I) include polyphosphazene polymers that can have an average molecular weight of up to about 75 million Daltons.
  • the polymers of formula (i) include poiyphosphazene polymers having an average molecular weight ranging from about 40 to about 100,000 Daltons
  • the polymers of formula (!) include polyphosphazene polymers having an average molecular weight ranging from about 1 ,000 to about 70,000 Daltons; from about 4,000 to about 50,000 Daltons; from about 7,000 to about 40,000 Daltons; or from about 13,000 to about 30,000 Daltons.
  • the degree of polymerization (n) of the biocompatible polymer according to FormuSa (!) is typically in a range from about 20 to about 200,000 Daltons, and generally from about 40 to about 100,000 Daltons.
  • the polyphosphazene used to prepare the disclosed particles of interest, can have a molecular weight based on the above formula, which can be a molecular weight of at least about 70,000 g/moS, a molecular weight of at least about 1 ,000,000 g/mol, or a molecular weight from at least about 3x10 e g/mol to about 20x10 ⁇ g/mol.
  • the polyphosphazenes have a molecular weight of at least about 10,000,000 g/moS.
  • the typical molecular weights can range up to about 25,000,000 g/moi, up to about 20,000,000 g/moi, or up to about 15,000,000 g/moi.
  • At least one of the groups R 1 to R 6 in the polymer is preferably an alkoxy group substituted with at least one fluorine atom,
  • the aSkyl group in the aik ⁇ xy, aikyisuSfonyl and clialkyl amino groups include straight or branched chain alky! groups with 1 to 20 carbon atoms, wherein the alkyl groups may be substituted with at least one halogen atom, such as a fluorine atom.
  • aikoxy groups include methoxy, eth ⁇ xy, propoxy andutzoxy groups, which preferably can be substituted with at ieast one fluorine atom. Particularly preferred is the 2,2,2-trifluoroethoxy group.
  • alkylsulfonyl groups are methyl, ethyl, propyl and butylsulfony! groups.
  • dialkyl amino groups are the dimethyl, diethyl, dipropyl, and dibutyiamino groups.
  • the ary! group in the aryloxy group is, for example, a compound with one or more aromatic ring systems, wherein the ary! group can be substituted with at least one of the previously defined aikyl groups, for example.
  • aryioxy groups are phenoxy and naphthoxy groups and derivatives thereof,
  • the heterocyclic alky I group is for example a 3 or 7 membered ring system wherein at least one ring atom is a nitrogen atom.
  • the heterocyclic alkyl group can, for example, be substituted by at least one of the previously defined alkyl groups.
  • heterocyclic alkyl groups include piperidinyi, piperazinyl, pyrrolidinyl and morpholinyl groups and derivatives thereof.
  • the heteroaryi group can be a compound with one or more aromatic ring systems, wherein at least one ring atom is a nitrogen atom.
  • the heteroaryS group can be substituted with at least one of the previously defined alkyl groups, for example.
  • Examples of heteroary! groups include pyrrolyl, pyridinyl, pyridinoyl, isoquinolinyl, and quinoiinyi groups and derivatives thereof.

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Abstract

Various embodiments are directed to various systems and related methods that facilitate in situ equilibration of various particles in liquid or semi- liquid solutions of interest, and that can provide a mechanism for rapid and convenient unloading of the pre-equilibrated particles from at least one enclosable equilibration chamber into another transport device for targeted delivery to a recipient in need of diagnostic analysis and/or particle-mediated therapy. The disclosed systems and methods can minimize sample preparation time and related risks involved in various particle-mediated diagnostic and therapeutic applications.

Description

DELIVERY SYSTEMS AMD RELATED METHODS FOR
CONVENIENT PREPARATION OF PARTICLES FOR
W VIVO ADMINISTRATION
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C. §119{β) of U.S. Provisional Patent Application No. 61/028,010, filed Febαsary 12,
2008, incorporated herein by reference in its entirety.
TECHNiCAL FIELD
[0002] The present disclosure reiates to various systems and related methods that facilitate in situ equilibration of various particles in liquid or semi-liquid solutions, anά that can provide a mechanism for rapid and convenient unloading of pre-equilibratecl particles to a recipient in need of particle-mediated diagnostic and/or therapeutic procedures.
BACKGROUND
[0003] Various cosmetic, clinical, and surgical procedures involve in vivo administration of synthetic particles, manufactured in various sizes and compositions. For example, various blends of polymeric embolic particles can be introduced into the lumen of blood vessels to intentionally impede blood flow through various tissues/organs affected with physical trauma, tumor, or any condition in which blood-flow intervention can provide an effective and noninvasive form of temporary or permanent mode of therapy ("embolization"). [0004] In general, the manufactured products containing such synthetic particles require further manipulation by the practitioner prior to in vivo administration. The particle-based products provided by a manufacturer neeύ to be combined with other reagents in order to make a final sample preparation suitable for in vivo administration. Substantial human errors can be inadvertently introduced during the preparatory procedures that may increase the overall risk associated with performing a given
1
82« J 7a i treatment. Practitioners need improved systems and related methods for minimizing the various types of risks that can be introduced during sample preparations for various particle-mediated diagnostic and therapeutic applications.
SUMMARY OF THE INVENTION
[0005] In various embodiments, the disclosed systems and related methods provide one or more enciosable equilibration chambers, as a controllable environment supporting in sitυ equilibration of particles, as a preparation module in part, and as a deployment module as an entire system. After sufficient opportunity for equilibration, the pre-equilibrated particles can be unloaded as a suspension from the enclosed equilibrated chamber. Various embodiments are directed to various configurations suitable for constructing encSosable equilibration chambers partitioned in the interior space to permit the distribution of the particles in a predetermined spatial arrangement. The enciosabie equilibration chambers permit the rapid infusion of a liquid or semi-liquid solution containing reagents of interest so that the pre-arranged particles can rapidly reach an equilibration state when exposed to the reagents. t0°06] Sn some embodiments, the enciosable equilibration chambers can be manufactured as a stand-alone apparatus that can operate with other readily available standard catheter systems and/or standard syringes. In some embodiments, the enciosable equilibration chambers can be manufactured as an interchangeable cartridge that can be conveniently replaced, as necessary, as a replaceable component of a preparatory anά dispensing system. In some embodiments, the disciosed preparatory and dispensing system can be manufactured as a manually operated device, In some embodiments, the disclosed preparatory and dispensing system can be manufactured as an automated device,
82« J 7a i BRiEF DESCRIPTION OF THE DRAWINGS
[0007] FIG, 1A is a schematic showing an exemplary procedure for manually handling embolic particles provided as a sealed via! product for the preparation of sampie formulations, as commonly practiced.
[0008] FIG. 1 B is a schematic showing an exemplary procedure for manually handling embolic particles provided as a syringe product for the preparation of sample formulations, as commonly practiced.
[0009] FIG, 2 is a schematic showing an exemplary equilibration system for enabling the in situ equilibration of particles of interest within an enclosable equilibration chamber, as one embodiment of the present disclosure,
[00010] FIG. 3A is a schematic showing an exemplary enciosabie equilibration chamber in a non-fiiled state in the absence of particles, from a side perspective, as one embodiment of the present disclosure,
[00011] FIG. 3B is a cross-sectional perspective of the exemplary enclosable equilibration chamber of FIG. 3A, as one embodiment of the present disclosure.
[00012] FIG. 4A is a schematic showing an exemplary enclosable equilibration chamber, in a pre~filled state as assembled with pre-arranged particles, from a side perspective, as one embodiment of the present disclosure.
[00013] FIG. 4B is a cross-sectionai perspective of the exemplary enclosable equilibration chamber of FIG. 4A, as one embodiment of the present disclosure.
[00014] FIGS. 4C-4E are schematics showing various configurations for forming partitioning members that support the linear alignment of
82« J 7a i particles within an enciosabie equilibration chamber as embodiments of the present disclosure,
[00015] FiG. 5A is a schematic showing an exemplary enciosabie equilibration chamber, in a pre-filled state as assembled with pre-arranged particles, from a side perspective as one embodiment of the present disclosure,
[0001 SJ FSG. 5B is a cross- sectional perspective of the exemplary enciosabie equilibration chamber of FIG. 5A, as one embodiment of the present disclosure.
[00017] FiG. 6 is a schematic showing an exemplary enciosabie equilibration chamber, in a pre-filled state as assembled with pre-arranged particles, from a side perspective, as one embodiment of the present disclosure,
[00018] FiG. 7 is a schematic showing an exemplary fluid flow pattern through an enciosabie equilibration chamber, as one embodiment of the present disclosure.
[00019] FiGS, 8A-88 show various embodiments for manufacturing kits and/or systems for the preparation and delivery of pre-eqυilibrated particles for various diagnostic and therapeutic applications.
DETAILED DESCRIPTION OF THE INVENTION
[00020] DEFiNITIONS
[00021] Throughout this disciosure, the articie "a" that precedes a noun/pronoun refers to one or more of the modified noun/pronoun. The terms "approximately" and "about" are interchangeabie in meaning in this disclosure.
[00022] The term "particle-mediated procedure" refers to any procedure that involves the utilization of particSes ranging in size from approximately
82« J 7a i 10 μm to approximately 1500 μm in order to facilitate a diagnostic purpose and/or a therapeutic purpose. Exemplary particle-mediated procedures include various intravascular interventional procedures ("embolization") invoiving in vivo administration of synfheticaiiy made particles of various compositions for reducing or stopping blood flow into the affected tissue/organ, including: for controlling gastrointestinal bleeding of any cause, for controSSing bleeding into the abdomen or pelvis from any physical trauma injuries, for controliing bleeding resulting from long menstrual periods or heavy menstrual bleeding caused by uterine fibroid tumors, for occluding vessels that are supplying blood to tumors, for eliminating arteriovenous malformation (AVM) or arteriovenous fistula (AVF) caused by abnormal connection or connections between arteries and veins, for treating various types of aneurysms, and various other conditions and diseases suitable for such particle-mediated intervention. The contemplated "particle-mediated procedures" include any procedure in which a benefit can be conferred by the delivery of the equilibrated particles of interest for any targeted therapy, including various diagnostic, therapeutic, and cosmetic applications. The particles can be delivered to any tissue or organ of a recipient. The type of optimal particles (size range, color, composition) suitable for a given condition under contempiation would need to be determined by the practitioner. [00023J The terms "ρarticle(s)" or "particle(s) of interest" can be interchangeably used to refer to any synthetically made particle of any shape or surface contour, with an average diameter size ranging from approximately 10 μm to approximately 1500 μmt which are intended to apply to various embolic particles and dermal-filler particles as disclosed. Suitable range in average diameter size of a particle of interest include; from about 10 μm to about 1500 μm; from about 10 μm to about 1 100 μm; from about 10 μm to about 1000 μm; from about 10 μm to about 900 μm; from about 10 μm to about 800 μm; from about 10 μm to about 700 μm; from about 10 μrn to about 600 μm; from about 10 μm to about 500 μrn; from about 10 μm to about 400 μm; from about 10 μm to about 300 μm; from about 10 μm to about 200 μm; from about 10 μm to about 175 μm; from about 10 μm to about 150 μm; from about 10 μm to about 120 μm; « J 7a i from about 10 μm to about 80 μm; and from about 10 μm to about 40 μm. Suitable range in average diameter size of a particle of interest include: from about 20 μm to about 1500 μm; from about 20 μm to about 1200 μm; from about 20 μm to about 2000 μm; from about 20 μm to about 900 μm; from about 20 μm to about 800 μm: from about 20 μm to about 700 μm; from about 20 μm to about 600 μm; from about 20 μm to about 500 μm; from about 20 μrπ to about 400 μm: from about 20 μm to about 300 μrπ; from about 20 μrπ to about 200 μm; from about 20 μm to about 175 μrπ; from about 20 μm to about 150 μm; from about 20 μm to about 120 μm; from about 20 μm to about 80 μm: and from about 20 μm to about 40 μm.
Suitable range in average diameter size of a particle of interest include; from about 30 μm to about 1500 μm; from about 30 μm to about 1300 μm; from about 30 μm to about 3000 μm; from about 30 μm to about 900 μm; from about 30 μm to about 800 μm; from about 30 μm to about 700 μm; from about 30 μrπ to about 600 μm; from about 30 μm to about 500 μrπ; from about 30 μm to about 400 μm; from about 30 μm to about 300 μm; from about 30 μm to about 300 μm; from about 30 μm to about 175 μm; from about 30 μm to about 150 μm; from about 30 μm to about 130 μm; from about 30 μm to about 80 μm; and from about 30 μm to about 40 μm. Although suitable particles can be selected from a relatively broad size range, the set of particles selected to be contained within a given enciosabie equiiibration chamber shouid be substantia!!;/ similar in size in order for the particles of this hypothetical set (a) to fit within a partitioned space having substantially uniform cross-sectional dimensions, and (b) to be transported along a defined path, relativeiy unhindered, within the partitioned space prior to exiting from the enciosabie equilibration chamber through one or more output portals. The particles of interest can be composed of one or more of any materia! desired that can be shaped to have physical stability sufficient to retain a particle diameter of interest suitable for diagnostic and/or therapeutic purposes. The particles may be porous or nonporous. The particles may be further modified or surface activated during or after manufacture. The particles may be loaded with bioactive and pharmaceutical agents. The particles may be loaded with fluorescent dyes, radiopaque reagents, or equivalents to permit
6 « J 7a i contemporaneous monitoring. The particles may be loaded with magnetic elements to impart magnetic properties,
[00024] The terms "embolic particles'" or 'embolic particles of interest" can be interchangeably used to refer to any synthetically made particle of any shape or surface contour, with an average diameter ssze ranging approximately 10 μm to approximately 1500 μm, suitable for any embolization procedure. Suitable embolic particles can be composed of any matenal amendable to controlled manufacturing and production specifications according to shaping and sizing requirements. Embolic particles are typically suspended in a transport medium containing various components that stabilize the particles during storage and shipment by manufacturers.
J0002SJ The term "dermal-ftller particles1' refers to any synthetically made particle of any shape or surface contour, with an average diameter size ranging approximately 10 μm to approximately 1500 μm, suitable for any cosmetic application procedure. Suitable dermal-filler particles can be composed of any material amendable to controlled manufacturing and production specifications according to shaping and sizing requirements. Dermal-filler particles can be administered to a recipient in neeύ of cosmetic and/or therapeutic enhancement in appearance, including the removal of wrinkles, dermal texture imperfections, dermal blot clots, dermal age-related disease or damage, and other equivalent conditions known by persons skilled tn the art of dermal cosmetic enhancement and dermal diagnostic/ clinical/ therapeutic applications. J00026J Exemplary particle-mediated procedures include various intravascular interventional procedures ("embolization") involving in vivo administration of synthetically made particles of various compositions for reducing or stopping blood flow into the affected tissue/organ, including: [00027J The term 'contrast agent" refers to various compounds, suspended in contrast medium/media, that enables radiopaque visibility by highlighting specific tsssue/organ of interest during various diagnostic medical imaging examinations and/or treatment procedures that require simultaneous monitoring, by various means including: x-ray exams, computed tomography scans, and magnetic resonance imaging. ,HM79 t Exemplary contrast agents include iobitridol, iodixanol, iomeproi. iopamidoi, iopentol, iopromide, ioversol, and other iodine-formυiatec! compositions, which have iodine concentrations between 240 mg/m! - 400 mg/ml, or more. Sn genera!, as the average size of particles increases, a larger volume of contrast medium may be required to sufficiently saturate the particles with an iodine threshold level necessary to provide adequate radiopaque visibility when monitoring particle transport following in vivo administration. [00028] The term "driving member" refers to any mechanism or a feature, either manually operable or automatically operable, that can generate sufficient force to transport any fluid of interest from a fluid- reservoir member into an enciosabie equilibration chamber, that can generate sufficient force to transport the fluid from the enciosabie equilibration chamber into the transport member, that can generate sufficient force to transport the fluid from the transport member into the vasculature of a recipient.
[00029] The term "enciosabie equilibration chamber" refers to an enciosabie container member comprising a housing that encloses an internal space of any shape, that can be partitioned into sub- compartments, in which the partitioning element can be composed of any materia! having the physical integrity to function as a physical boundary. The partitioned sub-compartments, within the enciosabie equilibration chamber, can be designed in various configurations to serve as a stable and continuous pathway to physicaily guide the movement of particles from (a) an initial position within the partitioned sub-compartment space, {b} through the pathway, and (c) through one or more output portals positioned anywhere at the distal end of the enciosabie equilibration chamber. [0O030J The term 'Vn situ equilibration" refers to the process by which particles spatially arranged and filled within an enciosabie equilibration chamber during manufacturing, can be subsequently exposed to a flow of contrast medium containing a contrast agent of interest by a practitioner for a sufficient time to permit the incorporation of the contrast-agent molecules into the pores of individual particles. After sufficient time, the « J 7a i pre-equiiibrated particles can be unloaded from the encSosabSe equilibration chamber via one or more output portals into a suitable transport member.
[00031] The term "transport member" refers to any mechanism or a feature, either manually operable or automatically operable, that can be attached to the one or more output portals of an enclosed equilibrium chamber to serve as a conduit for transporting the pre-equilibrated particles of interest to a target tissue/organ of interest Suitable examples of transport articles include macro-catheters, micro-catheters, Injection cannulae, needles of any size or dimension, or various equivalent articles known by persons skilled in the art,
Rβcofinjtjpi)..pi. ϋmjtaM
[00032] For comparison to the disclosed systems and methods, two standard procedures for combining various contrast agents with embolic particles are shown in FIGS. 1A and 1 B to illustrate the limitations of these methods.
[00033] FIG. 1A is a schematic showing &n exemplary procedure for manually handling embolic particles provided as a sealed vial product for the preparation of sample formulations, as commonly practiced, In FIG. 1A, a vial of embolic particles suspended in a transport medium 200 is shown, in which the embolic particles, such as 202 and 204, can be transferred from the vial into an open tray 120, in which the embolic particles can be equilibrated in the presence of a contrast agent 120, which can be added to the open tray 120, before or after the transfer of the embolic particles. 202 and 204. After several minutes of gentle swirling, the resulting pre-equilibrated embolic particle suspension can be transferred to a suitable syringe 120for deployment into a catheter or micro-catheter 140 for subsequent transport to a tissue/organ of interest during an embolization procedure. The disadvantages of this preparatory procedure include additional time required to fill the tray with the contrast medium containing the contrast agent, and to manually mix the embolic « J 7a i beads with the contrast medium. Additional time and further manipulation are required to transfer the embolic particles from the tray into the syringe so that the particles can be exposed to the contrast agent contained in the second syringe, A critical step involves suspending an appropriate amount/volume of the embolic particles in an appropriate amount/volume of the contrast medium to achieve an optima! pre-equilibrated particle suspension that can be transferred to a suitable syringe for deployment into a catheter or micro-catheter for subsequent transport to a tissue/organ of interest during various embolization procedures. The preparation of pre-equiϋbrated particles in an optima! suspension state for in vivo administration can be dependent on substantia! skill and experience.
J00034J Alternatively, RG. 1 B is a schematic showing an exemplary procedure for manually handling embolic particles provided as a syringe product for the preparation of sample formulations, as commonly practiced. In FIG. 1 B1 a first syringe 160 ("storage syringe") containing embolic particles suspended in a transport medium can be physicaiiy connected by an adaptor 170 to a second syringe 180 ("injection syringe") containing a contrast agent suspended in a contrast medium. Various adaptors 170 can be used, such as iυer-lock valves, or other equivalents of three-way valves. The disadvantages of this preparatory procedure inciude additional time required to fii! a second syringe 180 with a contrast medium containing the contrast agent, and the necessity of attaching this second syringe 180 to the first syringe 160 containing the emboiic particles. Additional time is required to slowly transfer the emboiic particles from the first syringe 160 into the second syringe 180 so that the embolic particles come into contact with the contrast agent contained in the second syringe 180. When the appropriate volume of the embolic particles have been suspended in the appropriate volume of the contrast medium, then the pre-equilibrated embolic particles, such as 184 and 186, can be transferred to a suitable syringe for deployment into a catheter, or micro-catheter, 190 for subsequent transport to a tissue/organ of interest during various embolization procedures. The preparation of pre- equilibrated particles in an optima! suspension state for in vivo
10 « J 7a i administration can be dependent on substantia! skili and experience for the same reasons described in FSG. 1A.
Various Embodiments to Enable . Convenient, Rapid, and Safe
[00035] in various embodiments, the systems and methods of this disclosure provide substantia! advantages not conferred by other devices/systems known to persons skilled in the art in that the disclosed system enables the preparation of ready-to-use sample formulations comprising particies of interest in various suitable and stable suspensions for immediate administration for cosmetic, medical, surgical, and other procedures amenable for various particle-mediated, diagnostic and therapeutic appiications. [00036] In various embodiments, the disclosed systems and related methods provide an enciosabie equilibration chamber comprising a sealable housing member and an enclosed partitioned space for promoting the equilibration of particles of interest within a suitable volume and composition of a suspension medium for the preparation of a suitable sample formulation ready for in wo administration. The pre-equilibrated particle suspension can be released into one or more transport members without requiring additional preparation steps.
[00037] The disclosed systems and methods confer a multitude of advantages including: (a) minimizing risks for contaminating preparatory materials during additional handling steps that may be performed in a non- sterile environment; (b) minimizing any risk for physically damaging the deSicate particie-based products during preparatory manipulations; (c) minimizing risks for evaporating highly volatile reagents by directly depositing into the enciosabie equilibration chamber; <d) minimizing any exposure time to toxic or hazardous reagents by directly depositing info the enciosabie equiiibration chamber; (e) maximizing efficiency by minimizing the number of separate preparatory steps necessary by centralizing the reactive components into a single reaction chamber, in which soluble and particuSate components can interact efficiently; (f)
1 1 « J 7a i maximizing efficiency by concentrating reactants in a smaller total volume; (g) minimizing the need to manually achieve an optimal pre-equiiibratecS particle suspension; and (h) maximizing efficiency by enabling the fast removal of a cartridge unit of the enclosable equilibration chamber pre- filiecl with a given set of particles, and amenable for fast replacement with another cartridge unit of the same type, or for another cartridge unit containing pre-fsSled particles of a different size and/or composition. [00038] in various embodiments, the disciosed systems and related methods can be employed for various embolization procedures by providing an enclosable equilibration chamber comprising a sealable housing member and an enclosable partitioned space for promoting the equilibration of embolic particles of interest within a suitable volume and composition of a suspension medium, containing various ingredients, such as transport medium, contrast agents, saline, and other suitable components, in particular, the enclosable equilibration chamber enables the interaction between the contrast agent of interest and the particles of interest to produce a stable suspension of the particles within a sterile and controlled environment for the preparation of a suitable sample formulation ready, for immediate or delayed, in vivo administration, with minimal or no additional preparation required. The disciosed systems and related methods enable the practitioner to balance the contrast agent with the amount of saline to achieve optimal radiopaque visibility, and to obtain adequate particle suspension in the sample formulation that can be prepared to be administered to a patient in need of embolic particle- mediated therapy.
[00039] FIG. 2 is a schematic showing an exemplary equiiibration system for enabling in situ equilibration of particles of interest within an enclosable equilibration chamber, as one embodiment of the present disclosure. In FIG. 2, an exempiary equilibration system 200 is shown, in which a driving member 220 is connected to a fluid-reservoir member 220 in order to mediate the transfer of a fluid of interest stored in fluid-reservoir member 220 into at least one enclosable equilibration chamber 230. Multiple enclosable equiiibration chambers can be optionally assembled as
12 « J 7a i various serial or parallel configurations, if desired. After sufficient time in the eπclosabie equilibration chamber 230r the pre-equilibrated particies suspended in the given fluid can be transported into a transport member 240 for further transport to a targeted vasculature 250 of a recipient. The enciosabie equilibration chamber 220can be optionally assembled as a cartridge unit that can be reversibly attached to a support frame 260 to facilitate the removal of an exhausted cartridge for replacement with an unused cartridge unit. The support frame 280 can be attached, directly or indirectly, to the fluid-reservoir member 220 and to the transport member 240 in order to stabilize the system during routine use and during cartridge replacement
J00040J FIG. 3A is a schematic showing an exemplary enciosabie equilibration chamber in a non-fϋled state in the absence of particies, from a side perspective, as one embodiment of the present disclosure. In FIG. 3A, an enciosabie equilibration chamber 300 is shown, comprising a housing member 320 and one or more partition members, such as 320 and 330, arranged in a linear array as a hypothetical spatial arrangement. The enciosabie equilibration chamber 300 inciudes at least one input portal 340, which can be positioned at the proximal end of the enciosabie equilibration chamber as shown. A fluid of interest can enter the enciosabie equilibration chamber 300 via the input porta! 340, which can be hypothetical Iy positioned anywhere with respect to the housing member, as Song as there is a connection, direct or indirect, with a fluid- reservoir member such as 220 of FIG. 2. The enciosabie equilibration chamber 300 includes at least one output portal 350 at the distal end of the enciosabie equilibration chamber as shown. However one or more output portals 350 can be hypothetical^ positioned anywhere with respect to the housing member as long as there is a connection, direct or indirect, with a transport member, such as 240 of FIG. 2. For optimal performance, the particies should not be permitted to dry out during operation, and the particles should not aggregate together to form dogs when transported, from one position to the next, within the enciosabie equilibration chamber 300.
13 « J 7a i [00041J FIG. 3B is a cross-sectiona! perspective of the exemplary encSosabSe equilibration chamber of FIG. 3A, as one embodiment of the present disclosure, In FiG.3B, the enclosable equiiibration chamber 360 is shown, in which the partition members, 370 and 375, are arranged as a rectilinear grid within the housing member 380 as a hypothetical spatia! arrangement. The partition members, 370 and 375, can be arranged in any three-dimensional configuration that can permit the occupation and movement of particles within the partitioned spaces, such as 390 and 395r within the enclosabie equiiibration chamber 380,
[00042] FIG. 4A is a schematic showing an exempiary enciosabie equilibration chamber, in a pre-ftlled state as assembled with pre-arranged particles, from a side perspective, as one embodiment of the present disclosure, Sn FSG. 4A, an enclosable equilibration chamber 400 is shown, comprising a housing member 420 and one or more partition members, such as 420 and 430, arranged in a iinear array as a hypothetical spatiai arrangement. The enciosabie equiiibration chamber 400 includes at least one input porta! 440 at the proximal end of the enciosabie equiiibration chamber, and at ieast one output porta! 450 at the dista! end of the enciosabie equiϋbration chamber. During manufacturing, the enciosabie equilibration chamber 400 can be filled with particies of interest, such as 434 and 436, that can be arranged in a pre-determined configuration, supported by partition members, such as 420 and 430, to form a spatiai boundary. A fiuid of interest can be directed into the enciosabie equilibration chamber 400 via the input porta! 440, to contact the prearranged particles, such as 434 and 436. After sufficient time, pre- equilibrated particie suspension, including particles such as 434 and 436 can be deployed from the enclosable equiiibration chamber 400 via the output portal 450. Although, the partition members, 420 and 430, are shown as a iinear array as a hypothetical spatiai arrangement this disclosure is not limited to any spatiai arrangement, with the condition that when the particles are spatially aiigned, each particie makes direct contact with no more than two other particles so that there is a continuum of
14 « J 7a i particles arranged in a singie-fiie row, however, the total set of particles can be spatially arranged in a non-linear, convoluted pattern, if desired.
[00043] FIG. 48 is a cross-sectiona! perspective of the exemplary encSosabSe equilibration chamber of FIG. 4A, as one embodiment of the present disclosure, in FIG. 4B, the enclosable equiϋbration chamber 460 is shown, in which the partition members, 470 and 475, are arranged as a rectilinear grid within the housing member 480 as a hypothetical spatia! arrangement. The partition members, 470 and 475r can be arranged in any three-dimensionai configuration that permits the occupation and movement of particles, such as 478 and 478, within the partitioned spaces of the enciosable equilibration chamber 460.
[00044] FIGS. 4C-4E are schematics showing various configurations for forming partitioning members that support the iinear alignment of particies within an enclosable equilibration chamber as embodiments of the present disclosure. In FIG 4C, the partition member is composed of an impermeable materia! 485, and can be formed as a conduit or a tube exhibiting a uniform average diameter that can be fiiied with substantially uniform particies exhibiting uniform average diameters, 486 &nά 487. For this type of partition member, the reactants of interest provided in a fluid- reservoir member can be directed into the iumen of the impermeabie conduit in order to react/interact with the particies. In FiG 4D, the partition member is composed of a semi-pemneable membrane material 490, and formed as a conduit or a tube exhibiting an uniform average diameter that can be filled with substantialiy uniform particles exhibiting uniform average diameters, 491 Bnά 492. For this type of partition member, the reactants of interest provided in a fiuid-reservoir member can be directed generally into the enclosable equilibration chamber, since the semi- permeable membrane material includes pores that can allow substantial flow of soivent into the iumen 494 of the conduit in order to react/interact with the particles, in FiG 4Er the partition member is composed of a permeable mesh materia! 495, and formed as a conduit or a tube exhibiting an uniform average diameter that can be filled with substantially uniform
15 « J 7a i particles exhibiting uniform average diameters, 496 and 497. For this type of partition member the reactaπts of interest provided in a fluid-reservoir member can be directed generally into the enclosable equilibration chamber, since the permeable mesh materia! includes pores that can aiiow substantial fiow of solvent into the iumen 498 of the conduit in order to react/interact with the particles. The partition member can be manufactured utilizing any materia! known to persons skilled in the art, including any polymers, ceramics, metais, metal alloys, and/or nitinol or other equivalent shape-memory ailoys.
[00046] FIG. 5A is a schematic showing an exemplary enciosabie equilibration chamber, in a pre-filled state as assembled with pre-arranged particles, from a side perspective as one embodiment of the present disclosure, in FSG. 5A, an enclosable equilibration chamber 500 is shown, comprising a housing member 520 and a partition member 520 formed as a continuous tubing 530, arranged as a coii of aligned particles within the housing member 520, as a hypothetical spatia! arrangement. The enciosabie equilibration chamber 500 includes at least one input porta! 540 at the proximal end of the enclosable equilibration chamber, and at least one output porta! 550 at the dista! end of the enc!osab!e equilibration chamber. During manufacturing, the enclosable equilibration chamber 500 can be filled with particles of interest, such as 534 and 536, that can be arranged in a pre-determined configuration, supported by partition members, such as 520 and 530, to form a spatial boundary. A fluid of interest can be directed into the enclosable equilibration chamber 500 via the input portal 540, to come into contact with the pre-arranged particles, such as 534 and 536. After sufficient time, pre-equilibrated particle suspension, including particles such as 534 and 538 can be deployed from the enclosable equilibration chamber 500 via the output portal 550. Although, the partition members, 520 and 530, are shown as a linear array as a hypothetical spatial arrangement, this disclosure is not limited to any spatial arrangement, with the condition that when the particles are spatially aligned, each particle makes direct contact with no more than two other particles so that there is a continuum of particles arranged in a single-file « J 7a i row, however, the tola! set of particles can be spatially arranged in a nonlinear, convoluted pattern, if desired. In this example, a flexible tubing with an uniform diameter can be filled with particles of substantially uniform size so that the pre-filled tubing can be spatially arranged as a coil within the enciosabie equilibration chamber. A person skilled in the art can appreciate that an orderly coil-like spatial arrangement is not a prerequisite for efficient operation of the enclosed equilibrium chamber.
[00046J FIG. 5B is a cross-sectional perspective of the exemplary enciosabie equilibration chamber of FIG. 5A, as one embodiment of the present disclosure. In FIG, 5B, the enciosabie equilibration chamber 580 is shown, in which the partition member is formed as a continuous tubing
570, arranged as a coil of aligned particles, such as 576 and 578, within the housing member 580 as a hypothetical spatial arrangement The continuous tubing 570 permits the occupation and movement of particles,
578 and 578, within the enciosabie equilibration chamber 460.
J00047J FIG. 6 is a schematic showing an exemplary enciosabie equilibration chamber, in a pre-filled state as assembled with pre-arranged particles, from a side perspective, as one embodiment of the present disclosure. In FiG, 8A, an enciosabie equilibration chamber 600 is shown, comprising a housing member 620 and a partition member formed as a continuous tubing 630, arranged as a coil of aligned particles within a housing member 620 shaped to follow the contour of the continuous tubing 630, as a hypothetical spatial arrangement The enciosabie equilibration chamber 600 includes at least one input porta! 640 at the proximal end of the enciosabie equilibration chamber, Bnά at least one output portal 650 at the distal end of the enciosabie equilibration chamber. During manufacturing, the enciosabie equilibration chamber 600 can be filled with particles of interest, such as 634 and 636, that can be arranged in a predetermined configuration, supported by the walls of the continuous tubing 620that forms a spatial boundary. A fluid of interest can be directed into the enciosabie equilibration chamber 800 via the input portal 840: to come into contact with the pre-arranged particles, such as 634 and 636, After
1 7 « J 7a i sufficient time, pre-equilibrated particle suspension, inducting particles such as 834 and 638 can be deployed from the enclosable equilibration chamber 800 via the output portal 850. In this hypothetical spatiai arrangement, each particle makes direct contact with no more than two other particies so that there is a continuum of particles arranged in a singie-filβ row, however, the tota! set of particies can be spatially arranged in a non-linear, convoluted pattern, if desired.
[00048] FIG. 7 is a schematic showing an exemplary fluid flow pattern through an enclosable equilibration chamber as one embodiment of the present disclosure. In FIG. 7, an enclosable equilibration chamber 700 is shown, comprising a housing member 720, in broken lines, and a partition member that can be hypothetical Iy formed as a continuous tubing 720, that can be arranged as a coii to contain particles aligned as a single contiguous row as previously shown in FiG, 5. The arrows 720and 740 indicate the hypothetical direction of the fluid flow along the inner lumen of the continuous tubing 720 as the fluid of interest enters from at least one input portal 750 at the proximal end of the enclosable equilibration chamber, and exits from at least one output portal 760 at the dista! end of the enclosable equilibration chamber. Alternatively, the arrows 720and
740 can indicate the hypothetical direction of the fluid flow along the inner lumen of the continuous tubing 620as the fluid of interest is transported through the enclosable equilibration chamber as previously shown in FIG. 6, in which the housing member 620 can be shaped as a coil, and the partition member formed as a continuous tubing 620can be shaped as a coil with a smaller cross-sectional diameter that can be enclosed within the housing member 620 shaped to follow the outer contour of the continuous tubing 630.
[00049] FIGS. 8A-8C show various embodiments for manufacturing kits and/or systems for the preparation and delivery of pre-equiiibrated particles for various diagnostic and therapeutic applications, in various kits contemplated, the particies of interest can be provided in a container of any shape or form, suspended in a suitable transport medium. If
18 « J 7a i provided as dry particles, then a suitable transport medium may be provided in a separate container. The kits may optionally include one or more contrast agents suspended in contrast media. The kits may include instructions for solution preparation, particle preparation, and/or assembiy of component members into an operabie system. The component members previously described in FiG. 2. can be provided in various combinations as pre-assembSed kits.
[00050J in one embodiment, an enciosable equilibration chamber ("EEC") is provided as a stand-aione kit component that can be assembled together with other readily available standard catheter systems and/or standard syringes, in FiG. 8A, the enclosabie equilibration chamber 800 can be manufactured as a stand-alone apparatus that can operate with standard catheter systems 820 and/or standard syringes 82O1 not provided by the kit. For example, any syringe-iike device 820 can function as a driving member and a fluid-reservoir member, by filling the barrel of a syringe with contrast agent/medium and applying the necessary force to transport the contrast agent/medium to an enciosabie equiiibration chamber when assembled together. Any catheter-like device 820 can function as a transport member, by assembling together with the enciosabie equilibration chamber 800. A suitable driving member ("DM") includes various manually operated devices, such as a two-hole syringe, and various automated devices, such as an electrically powered piston gun capable of transporting the fluid from the fluid-reservoir member into the enciosabie equilibration chamber ("EEC*).
[00051] In another embodiment an enciosabie equilibration chamber ("EEC") can be provided in combination with a driving member ("DM"), a fluid-reservoir member ("FRM"), and/or a transport member C'TM"), In this combination, each of these member components can be provided as separate articles that can be assembled together conveniently. In related embodiments, the driving member ("DM") can be manufactured as a manually operated device. In related embodiments, the driving member
("DM") can be manufactured as an automated device. This configuration
H) « J 7a i provides the maximum flexibility by the practitioner, in that any of the member components can be replaced as often as necessary during a procedure depending on the nature of the procedure. The component members shown in FIG.8A can be provided by a pre-assembled kit
J0O0S2J Sn another embodiment, an enclosabie equilibration chamber ("EEC") is provided in combination with a driving member ("DM"), a fluid- reservoir member ("FRfVI"), and a transport member ("TM"), as a single integrated apparatus. FIG. 8B is a schematic of an exemplary combination, in which these individual component members can be provided pre-assembled as one complete system, in which the integrated apparatus can be utilised for a single procedure and discarded, in FIG. 8B, an βnciosabSe equilibration chamber ("B") is integrated into a syringe- like apparatus 850 having an external housing member ("P), a syringe-like plunger ("E"), a syringe-like stopper ("D"), and a luer-lock tip ("A"). A fluid of interest can be deposited into compartment ("C") within the syhnge-iike apparatus 850.
[00053] In other embodiments, the endosable equilibration chamber ("EEC") can be manufactured as a replaceable cartridge unit or a moduie that can be conveniently replaced after exhaustion of the prefilled particles. In this case, the cartridge unit can be designed to be neversibly attachabie to a support frame to facilitate the removal of an exhausted cartridge for replacement with an unused cartridge unit. The support frame can be attached, directly or indirectly, to the fluid-reservoir member and to the transport member in order to stabilize the system during routine use and during cartridge replacement. In related embodiments, the driving member {"DM") can be manufactured as a manually operated device. In related embodiments, the driving member ("DM") can be manufactured as an automated device.
[00054J For many particle-mediated interventions, such polymer-based particles can be engineered to act as carrier devices for releasing various pharmaceutical and/or bioactive agents, In various embodiments, the
20 « J 7a i pharmaceutical and/or bioactive agents can be incorporated into particies of interest within the enclosable equilibration chamber if such agents can be introduced via one of the input portais, Suitabie pharmaceutics! and/or bioactive agents are known by persons skilled in the art, [00055] in various embodiments, an enciosabie equilibration chamber is provided, comprising: a set of particles selected from an average diameter size ranging from 10 μm to 1500 μm; a sealabSe housing member including an internal space; at least one partitioning member positioned within the internal space, wherein the partitioning member is formed in a pre- determined configuration to support the contiguous alignment of the set of particles so that each particle is in direct physical contact with no more than two particles; at least one input port for directing the entry of a fluid of interest into the interna! space to permit equilibration of the particles; and at least one output port for directing the exit of the pre-eqυilibrated particles suspended in the fluid of interest from the internal space. The enciosabie equilibration chamber provides that the average diameter size of a particle ranges: from about 10 μm to about 1500 μm; from about 10 μm to about 1100 μm; from about 10 μm to about 1000 μm; from about 10 μm to about 900 μm; from about 10 μm to about 800 μm; from about 10 μm to about 700 μm; from about 10 μm to about 800 μm; from about 10 μm to about 500 μm; from about 10 μm to about 400 μm; from about 10 μm to about 300 μm; from about 10 μm to about 200 μm; from about 10 μm to about 175 μm; from about 10 μm to about 150 μm; from about 10 μm to about 120 μm; from about 10 μm to about 80 μm; and from about 10 μm to about 40 μm. The enciosabie equilibration chamber provides that the average diameter size of a particle ranges; from about 20 μm to about 1500 μm; from about 20 μm to about 1200 μm; from about 20 μm to about 2000 μm; from about 20 μm to about 900 μm; from about 20 μm to about 800 μm; from about 20 μm to about 700 μm; from about 20 μm to about 600 μm; from about 20 μm to about 500 μm; from about 20 μm to about
400 μm; from about 20 μm to about 300 μm; from about 20 μm to about 200 μm; from about 20 μm to about 175 μm; from about 20 μm to about 150 μm; from about 20 μm to about 120 μm; from about 20 μm to about 80 μm; and from about 20 μm to about 40 μm. The enclosabSe equilibration
21 « J 7a i chamber provides that the average diameter size of a particle ranges: from about 30 μm to about 1500 μm; from about 30 μm to about 1300 μm; from about 30 μm to about 3000 μm; from about 30 μm to about 900 μm; from about 30 μm to about 800 μm; from about 30 μm to about 700 μm; from about 30 μm to about 600 μm: from about 30 μm to about 500 μm; from about 30 μm to about 400 μm: from about 30 μm to about 300 μm; from about 30 μrπ to about 300 μm: from about 30 μm to about 175 μrπ; from about 30 μm to about 150 μm; from about 30 μm to about 130 μm; and from about 30 μm to about 80 μm, [00OS8] Sn various embodiments, a system for promoting in situ equilibrium of particles is provided, comprising: an enclosable equilibration chamber that includes: a set of particles selected from an average diameter size ranging from 10 μm to 1500 μm; a sealabie housing member including an interna! space; at ieast one partitioning member positioned within the internal space, wherein the partitioning member is formed in a pre-determined configuration to support the contiguous aiignment of the set of particles so that each particle is in direct physical contact with no more than two particles; at least one input port for directing the entry of a fluid of interest into the internal space to permit equilibration of the particles; and at least one output port for directing the exit of the pre- equilibrated particles suspended in the fluid of interest from the internal space. The average diameter size of a particle ranges: from about 10 μm to about 1500 μm; from about 10 μm to about 1 100 μm; from about 10 μm to about 1000 μm; from about 10 μm to about 900 μm; from about 10 μm to about 800 μm; from about 10 μm to about 700 μm; from about 10 μm to about 600 μm; from about 10 μm to about 500 μm; from about 10 μm to about 400 μm; from about 10 μm to about 300 μm; from about 10 μm to about 200 μm; from about 10 μm to about 175 μm; from about 10 μm to about 150 μm; from about 10 μm to about 120 μm; from about 10 μm to about 80 μm; and from about 10 μm to about 40 μm. The average diameter size of a particle ranges: from about 20 μm to about 1500 μm; from about 20 μm to about 1200 μm; from about 20 μm to about 2000 μm: from about 20 μm to about 900 μm; from about 20 μm to about 800 μm; from about 20 μm to about 700 μm; from about 20 μm to about 600 μm;
22 « J 7a i from about 20 μm to about 500 μm; from about 20 μm to about 400 μm; from about 20 μm to about 300 μm; from about 20 μm to about 200 μm; from about 20 μm to about 175 μm; from about 20 μm to about 150 μm; from about 20 μm to about 120 μm; from about 20 μm to about 80 μm; and from about 20 μm to about 40 μm. The average diameter size of a particle ranges; from about 30 μm to about 1500 μm; from about 30 μm to about 1300 μm; from about 30 μm to about 3000 μm; from about 30 μm Io about 900 μm; from about 30 μm to about 800 μm; from about 30 μm to about 700 μm; from about 30 μm to about 600 μm; from about 30 μm to about 500 μm; from about 30 μm to about 400 μm; from about 30 μm to about 300 μm; from about 30 μm to about 300 μm; from about 30 μm to about 175 μm; from about 30 μm to about 150 μm; from about 30 μm to about 130 μm; and from about 30 μm to about 80 μm. The system further comprises a driver member, a fluid-reservoir member, and a transport member.
[000S7] in various embodiments, a system for promoting in situ equilibrium of particles is provided, comprising: An in situ method for pre- equilibrating particles, the method comprising: providing an enclosabSe equilibration chamber including a set of particles aligned contiguousSy so that each particle is in direct physical contact with no more than two particles; directing a fiuid of interest within the enclosabie equilibration chamber so that the particles are exposed to the fluid of interest for a sufficient time to permit equilibration of the particles; and deploying the pre-equilibrated particles suspended in the fiuid of interest from the encSosabSe equiiibration chamber. The in situ method further comprises adding pharmaceutical and/or bioactive agents. The in situ method further comprises embolic agents. The suitable average diameter size of a particle ranges; from about 10 μm to about 1500 μm; from about 10 μm to about 1100 μm; from about 10 μm to about 1000 μm; from about 10 μm to about 900 μm; from about 10 μm to about 800 μm; from about 10 μm to about 700 μm; from about 10 μm to about 600 μm; from about 10 μm to about 500 μm; from about 10 μm to about 400 μm; from about 10 μm to about 300 μm; from about 10 μm to about 200 μm; from about 10 μm to about 175 μm; from about 10 μm to about 150 μm; from about 10 μm to
23 « J 7a i about 120 μm; from about 10 μm to about 80 μm; and from about 10 μm to about 40 μm.
[0QOS8] Sn various embodiments, an in situ method for pre-equilibrating embolic particles and for delivery is provided, the method comprising; providing an enciosabie equilibration chamber including a set of emboiic particles aligned contiguously so that each embolic particle is in direct physical contact with no more than two embolic particies; directing a fluid of interest within the enclosable equilibration chamber so that the emboiic particles are exposed to the fluid of interest for a sufficient time to permit equilibration of the emboiic particles; and deploying the pre-equiiibrated embolic particles suspended in the fluid of interest from the enciosabie equilibration chamber into a transport member. The in situ method of further comprise deploying the pre-equilibrated embolic particles from the transport member to a target vasculature of a recipient.
Exempiary Particles of Interest Suitable for Filling and Equilibrating within Disclosed Deiivery Systems
[00059] In various embodiments, the specific polyphophazene polymers having the general formula (!) can be employed for encapsulating any particles of interest as a coating layer to confer a biocompatible coating to any particles of interest. Various embodiments are directed to particles of interest encapsulated by at least one polymer component having the genera! formula (I):
Figure imgf000026_0001
in which the n value is an integer from 2 to °°; R1 to Rδ are independently selected from: a substituted or unsubstituted alkyl, aikoxy, aryi, aryloxy, silyl, silyioxy, aikylsulfonyL alkyl amino, dialkyl amino, ureido, carboxylic atitύ
24 « J 7a i ester, alkylmonoamidine, alkylbisamidine, aSkoxyrnonoaroidine, or aikoxybisamidinβ; or an amino; a heterocyclic aSkyl group with at least one nitrogen, phospfroαss, oxygen, sulfur, or selenium as a heteroatom; a heteroaryl group with at least one nitrogen, phosphorus, oxygen, sulfur or selenium as the heteroatom; a nucleotide or a nucleotide residue; a biomacromolecule; or a pyrimidine or a purine base.
(O023J Suitable substituents for R1 to R6 can be independently selected from; halide substituents, such as fluorine, chlorine bromine, or iodine; pseudohaiide substituents, such as cyano (-CN)1 isocyano (-NC), thiocyano (- SCN), isothiocyano (-NCS), cyanato (-OCN), isocyanato (-NCO), azido (-N3) groups; substituents such as nitro- (-HO2) and nitrito (-NO) groups; partially substituted alkyl groups, such as haloalkyl; heteroaryl such as imidazoyl, oxazolyl, thiazoiyi, pyrazolyl derivatives; or purine and pyrimidine bases such as guanidines, amidines and other ureido derivatives of the base structure.
[0030] As used herein, alky! (R), alkoxy (-OR), aikylsuifonyl (-SO2R), aikyl amino (-NHR), diaSkyl amino (-NR2), carboxyϋc acid ester (-
(alkadiyl)C(O)OR or -alkadiyl)OC(O)R)), ureido {-NHC(G)NH2, -NRC(O)NH2(
-NHC(O)NHR, -NRC(O)NHR, -NHC(O)NR2, -NRC(O)NR2, and their aikadiyl- linked analogs), alkylmonoamidine (including ~N=C(NR2)R, -(alkadiyl)N-C-
(NR2)R. -C(NR2)=NR, and -(aikadiyi)C(NR2)=NR), aikylbisamidine (including -N=C(NR2)2, -(alkadiyl)N=C(NR2)2, -NRC(NR2)=NR, and
(alkadiyl)NRC(NR2)=NR>, alkoxymonoamidine (-0(alkadiyl)N=C(NR2)R, - OC(NR2)=NR, and -O(alkadiyl)C(NR2)=NR)), and aikoxybisamidine (~ O(aikadiyi)N=C(NR2)2. -O(alkadiyl)NRC(NR2)=NR, and
O(a!kadiy!)NRC(NR2)=NR) moieties are defined by the corresponding formula shown, in which R can be selected independentiy from a linear, branched, and/or cyclic ("cycloalkyl") hydrocarbyl moieties, including alkyl (saturated hydrocarbons) as well as aikeny! &nά alkynyi moieties, having from 1 to 20 (for example, from 1 to 12, or 1 to 6) carbon atoms.
25
82« J 7a i [0031] The inclusion of aikenyi and aikynyl moieties provides, among other things, the capability to cross-link the polyphosphazeπe moieties to any extent desired, Exampies of aikyl groups include, but are not limited to, methyl, ethyi, propyi, isopropyi, n-butyl, t-butyl, isobutyi, sec-butyl, pentyl, isopentyi. neopentyi, hexyl, isohexyi. heptyl, 4,4-dimethylpentyi, octyi, 2,2,4- trim ethyl pentyi, nonyl, decyi, undecyl and dodecyl. Cycioaikyi moieties may be monocyclic or muiticyciic, and examples include cyclopropyl, cyclobutyl, cyciopentyl, cyciohexyi, and adamantyl. Additional examples of alky! moieties have Sinear, branched and/or cyclic portions (e.g., 1 -ethy!-4-methyi~ cyciohexyi}.
[0032J According to this definition and usage (supra), specific examples of R (aSkyl) groups include unsubstituted alkyl, substituted aikyl such as halo- substituted alkyl (haSoaikyS), unsubstituted aikenyi, substituted aikenyi such as halo-substituted alkenyl, and unsubstituted alkynyi, and substituted alkynyi such as halo-substituted aikynyl.
[0033] Furthermore, these examples of R (alkyl) provide that the alkoxy
(OR) substituents can be unsubstituted alkoxy {"aikyloxy"), substituted alkoxy such as halo-substituted alkoxy (haioaikoxy), unsubstituted aikenyioxy, substituted aikenyioxy such as halo-substituted aikenyioxy, unsubstituted alkynyloxy, and substituted alkynyloxy such as halo-substituted alkynyioxy. In this aspect, vinyioxy and aiiyioxy can be useful.
|0034J A silyl group is a ~8iR3 group and a silyloxy group is an ~O$iR3 group, where each R moiety is selected independently from the R groups defined supra. That is, R in each occurrence is selected independently from a linear, branched, and/or cyclic ("cycioalkyl") hydrocarbyl moieties, including alkyl (saturated hydrocarbons) as well as alkenyl and alkynyi moieties, having from 1 to 20 (for example, from 1 to 12, or 1 to 8) carbon atoms.
[0035] Unless otherwise specified, any R group can be unsubstituted or substituted independently with at ieast one substituent selected from a halogen (fluorine, chlorine, bromine, or iodine), an alkyl. an aikylsuifonyl, an amino, an aikylamino, a diaikylamino, an amidino (-N=C{NH2)2), an alkoxidβ, or an aryloxide, any of which can have up to 6 carbon atoms, if applicable.
26
82« J 7a i Thus, the term substituted "aikyi" and moieties which encompass substituted aikyl r such as "alkoxy", include haSoaikyl and haloalkoxy, respectively, including any fluorine-, chlorine-, bromine-, and iodine-substituted alky! and aikoxy. Thus, terms haloalkyl and haSoalkoxy refers to alky! and alkoxy groups substituted with one or more haiogen atoms, namely fluorine, chlorine, bromine, or iodine, including any combination thereof,
[0036] Unless otherwise indicated, the term "aryl" means an aromatic ring or an aromatic or partially aromatic ring system composed of carbon and hydrogen atoms, which may be a single ring moiety, or may contain multiple rings bound or fused together. Examples of aryl moieties include, but are not limited to, phenyl, anthracenyS, azulenyl, biphenyl, fSuorenyl, indan, indenyl, naphthyl, phenanthrenyl, 1 ,2,3,4-tetrahydro-πaphthaleπe, tolyl, and the like, any of which having up to 20 carbon atoms. An aryloxy group refers to an ~O(aryl) moiety. [0037] The terms haioaryl and haSoaryioxy refer to aryl and aryloxy groups, respectively, substituted with one or more halogen atoms, namely fluorine, chlorine, bromine, or iodine, including any combination thereof.
[0038J A heterocyclic aikyl group with at least one nitrogen as a heteroatom refers to a non-aromatic heterocycle and includes a cycloaikyl or a cycloalkenyl moiety in which one or more of the atoms in the ring stαscture is nitrogen rather than carbon, and which may be monocyclic or muiticyclic, and may include exo-carbony! moieties and the like. Examples of heterocyclic aikyl group with nitrogen as a heteroatom include, but are not limited to, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydropyrimidinyl, morphoiinyl, aziridinyl, imidazoSidinyl, 1-pyrro!ine, 2-pyrroiine, or 3-pyrroline, pyrrolidinonyl, piperazinonyl, hydantoinyi, piperidin-2-one, pyrroiidin~2~one, azetidin-2-one, and the like. Thus, these groups include heterocyclic exocycϋc ketones as well.
[0039] A heteroaryl group with at least one nitrogen as the heteroatom refers to an aryi moiety in which one or more of the atoms in the ring structure is nitrogen rather than carbon, and which may be monocyclic or muiticyclic.
Examples of heterocyclic alky! group with nitrogen as a heteroatom include,
27
82« J 7a i but are not limited to. acridinyl, benzimidazoiyi, quinazoiinyl, benzoquinazoiinyl imidazoiy!, indolyl, isothiazolyl, isoxazolyL oxazoly! or oxadiazolyl, phthaiazinyi, pyrazinyi, pyrazolyl, pyridaziny!, pyridyl, pyrimidinyl, pyrimidyi, pyrroiyi, quinazolinyl, quinolinyi, tetrazoSyl, thiazolyS, triazinyi, and the like. In this aspect, this disclosure includes or encompasses chemicai moieties found as subunits in a wide range of pharmaceutical agents, natural moieties, natural biomolecuies, and biomacromoSecuies. For example, this disclosure encompasses a number of pharmaceutical agents available with the tβtrazoiβ group (for example, losartan, candesartan, irbesartan, and other Angiotensin receptor antagonists); the triazoie group (for example, fluconazole, isavuconazole, itraconazole, voriconazole, pramiconazole, posaconazoie, and other antifungal agents); diazoles (for example, fungicides such as Miconazole,, Ketoconazole, Clotrimazole , Econazole, Bifonazole, Butoconazoie, Fenticonazole, Isoconazoie, Oxiconazoie, Sertaconazole, Sulconazole, Tioconazole, and the like); and imidazoles (histidine, histamine, and the like). Thus in one aspect, some of the R1 to R6 moieties in the formula I can encompass chemical moieties found as subunits in a wide range of pharmaceutical agents, natural moieties, natural biomolecuies, and biomacromoSecules. [0040] A heterocyclic alkyl group with at least one phosphorus, oxygen, sulfur, or selenium as a heteroatom refers to a non-aromatic heterocycie and includes a cycloaikyl or a eycloaSkenyl moiety in which one or more of the atoms in the ring structure is phosphoαis, oxygen, sulfur, or selenium rather than carbon, and which may be monocyclic or muiticyclic, and may include exo~carbony! moieties and the like. Similarly, a heteroaryl group with at least one phosphorus, oxygen, sulfur, or selenium as the heteroafom refers to an aryl moiety in which one or more of the atoms in the ring structure is phosphorus, oxygen, sulfur, or selenium rather than carbon, and which may be monocyclic or muiticyclic. Examples of heterocyclic alkyl groups or heteroaryls with phosphorus, oxygen, sulfur, or selenium as a heteroatom include, but are not limited to, substituted or unsubstituted ethylene oxide (epoxides, oxiranes), oxirene, oxetane, tetrahydrofuran (oxolane), dihydrofuran, furan, pyran, tetrahyd ropy ran, dioxane, dioxin, thiirane
28
82« J 7a i (episulfides), thietane, tetrahydrothiophene (thioiane) dihydrothiophene, thiophene, thiane, thiine (thiapyrane), oxazine, thiazine, dithiane, dithietane, and the like. Thus, these groups include a!! isomers, including regioisomers of the recited compounds. For example, these groups include 1 ,2- and 1 ,3- oxazoles, thiazoies, seienazoles, phosphazoles, and the like, which include different heteroatoms from the group 15 or group 16 elements.
[0041] As used herein, a nucleotide refers to an organic compound containing a nitrogenous base, a sugar moiety, and one or more phosphate groups. The most common nucleotides contain either a purine or pyrimidine nitrogenous base (for exampie, guanine, adenine, thymine, cytosine and uracil), typically bonded to a pentose (5-carbon) sugar such as a ribose or a deoxyribose sugar, which itself is bonded to one or more phosphate groups. The term nucleotide is also used to include those materiaSs commonly known for use as monomers for nucleic acids (such as RNA and DNA) as well as cefaclors, moieties, derivatives, and portions thereof including, for exampie Coenzyme A (CoA), FAD (flavin adenine dinucleotide), NAD (nicotinamide adenine dinucieotidβ), NADP (nicotinamide adenine dinucleotide phosphate), other dinucieotides, and the like. Similarly, as used herein, a nucleotide residue includes nucleosides, deoxynucleosides, and similar materials, examples of which include but are not limited to, adenosine, guanosine, 5- rm ethyl uridine, uridine, cytidine, deoxyadenosine, deoxyguanosine, deoxythymidine, deoxyuridine, and deoxycytidine, and the like,
[0042] As used herein, a purine base is a class of heterocyclic aromatic compounds containing a pyridimine ring fused to an imidazole ring, and including substituted purines and their tautomers. Examples of purines include, but are not limited to, purine, adenine, guanine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, isoguanine, and the like. Examples of a pyrimidine base include, but are not limited to, pyrimidine, uracil, thymine, and cytosine. [0043] In various embodiments directed to the polyphosphazenes of formula (I), R1 to R8 are all trill uoroethoxy (OCH2CF3) groups, and whereinthe n value may vary from at least about 40 to about 100,000 Daltons. Alternatively, one may use derivatives of polymer of formula (I). The
29
82« J 7a i term "derivative" or "derivatives" is meant to refer to polymers made up of monomers having the structure of formula (I), wherein one or more of the R1 to R6 functionai grouρ(s) is replaced by a different functional group(s), such as an unsubstifufed alkoxide, a halogenated alkoxide, a fluorinated alkoxide, or any combination thereof, or where one or more of the R1 to R6 is repiaced by any of the other functional group(s) disclosed herein, but where the biological inertness of the polymer is not substantially aitered.
[0044] in various embodiments directed to the poiyphosphazenes of formula (i), for example, at least one of the substituents R1 to R6 can be an unsubstituted aikoxy substituent: such as methoxy (OCH3), ethoxy (OCH2CH3) or n-propoxy (OCH2CH2CH3). In another aspect, for example, at least one of the substituents R1 to R6 is an aikoxy group substituted with at least one fluohne atom. Examples of useful fluorine-substituted aikoxy groups R1 to Re include, but are not limited to OCF3, OCH2CF3, OCH2CH2CF3, OCH2CF2CF3, OCH(CF3)2, OCCH3(CF3)2,
OCH2CF2CF2CF31 OCH2(CF2)SCF3, OCH2(CF2J4CF3, OCH2(CF2)5CF3ϊ OCH2(CF2)6CF3, OCH2(CF2)7CF3, OCH2CF2CHF2, OCH2CF2CF2CHF2, OCH2(CF2)3CHF2, OCH2(CF2J4CHF2, OCHΞ(CFΞ)5CHF2, OCH2(CF2)6CHF2, OCH2(CF2)TCHF2, and the iike. Thus, while tήfluoroethoxy (OCH2CF3) groups are preferred, these further exemplary functional groups also may be used alone, in combination with trifiuoroβthoxy, or in combination with each other. In one aspect, examples of especially useful fluorinated aikoxide functional groups that may be used include, but are not limited to, 2,2,3,3,3-pentafluoropropyioxy (OCH2CF2CF3), 2(2,2,2\2:,2'~ hexafluoroisopropyloxy (OCH(CFs)2) r 2,2,3,3,4 A4~heptafluorobuty!oxy (OCH2CF2CF2CF3), 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyioxy
(OCH2(CF2)TCF3), 2,2.3,3,-tetraHuoπopropyloxy (OCH2CF2CHF2), 2,2,3,3,4,4-hexafSuorobutyioxy (OCH2CF2CF2CHF2),
3,3,4,4,5.5,6,6,7,7,8,8-dodecafiυorooctyloxy (OCH2(CF2)ZCHF2), and the like, including combinations thereof.
[0045] Furthermore, in alternative embodiments, 1 % or less of the
R1 to R6 groups may be alkenoxy groups, a feature that can promote crosslinking to produce a phosphazene polymer exhibiting more
30
82« J 7a i eiastomeric properties. Io this aspect, alkenoxy groups include, but are not limited to, OCH2CH=CH2, OCH2CH2CH=CH2, aliylphenoxy groups, and the like, including combinations thereof. Also in formula (I), the residues R1 to R6 are each independently variabie, and therefore can be the same or different.
[0046] By indicating that the n value can be as large as *> in formula
{!), wherein R1 through R8 are all trifluoroethoxy (OCH2CF3) groups, the polymers of formula (I) include polyphosphazene polymers that can have an average molecular weight of up to about 75 million Daltons. [0047] in various embodiments, consistent with n values, the polymers of formula (i) include poiyphosphazene polymers having an average molecular weight ranging from about 40 to about 100,000 Daltons, In another embodiment, the polymers of formula (!) include polyphosphazene polymers having an average molecular weight ranging from about 1 ,000 to about 70,000 Daltons; from about 4,000 to about 50,000 Daltons; from about 7,000 to about 40,000 Daltons; or from about 13,000 to about 30,000 Daltons. in various embodiments, the degree of polymerization (n) of the biocompatible polymer according to FormuSa (!) is typically in a range from about 20 to about 200,000 Daltons, and generally from about 40 to about 100,000 Daltons.
[0048] In various embodiments, the polyphosphazene, used to prepare the disclosed particles of interest, can have a molecular weight based on the above formula, which can be a molecular weight of at least about 70,000 g/moS, a molecular weight of at least about 1 ,000,000 g/mol, or a molecular weight from at least about 3x10e g/mol to about 20x10δ g/mol. In another embodiment, the polyphosphazenes have a molecular weight of at least about 10,000,000 g/moS. In each of these examples in which a typical lower limit of molecular weight is disclosed, the typical molecular weights can range up to about 25,000,000 g/moi, up to about 20,000,000 g/moi, or up to about 15,000,000 g/moi.
[0049J At least one of the groups R1 to R6 in the polymer is preferably an alkoxy group substituted with at least one fluorine atom,
31
82« J 7a i [0050] The aSkyl group in the aikσxy, aikyisuSfonyl and clialkyl amino groups include straight or branched chain alky! groups with 1 to 20 carbon atoms, wherein the alkyl groups may be substituted with at least one halogen atom, such as a fluorine atom. [0051] Examples of aikoxy groups include methoxy, ethαxy, propoxy and fautoxy groups, which preferably can be substituted with at ieast one fluorine atom. Particularly preferred is the 2,2,2-trifluoroethoxy group. Examples of alkylsulfonyl groups are methyl, ethyl, propyl and butylsulfony! groups. Examples of dialkyl amino groups are the dimethyl, diethyl, dipropyl, and dibutyiamino groups.
(O052J The ary! group in the aryloxy group is, for example, a compound with one or more aromatic ring systems, wherein the ary! group can be substituted with at least one of the previously defined aikyl groups, for example. Examples of aryioxy groups are phenoxy and naphthoxy groups and derivatives thereof,
[0063] The heterocyclic alky I group is for example a 3 or 7 membered ring system wherein at least one ring atom is a nitrogen atom. The heterocyclic alkyl group can, for example, be substituted by at least one of the previously defined alkyl groups. Examples of heterocyclic alkyl groups include piperidinyi, piperazinyl, pyrrolidinyl and morpholinyl groups and derivatives thereof. The heteroaryi group can be a compound with one or more aromatic ring systems, wherein at least one ring atom is a nitrogen atom. The heteroaryS group can be substituted with at least one of the previously defined alkyl groups, for example. Examples of heteroary! groups include pyrrolyl, pyridinyl, pyridinoyl, isoquinolinyl, and quinoiinyi groups and derivatives thereof.
(O054J All publications and patents mentioned in this disclosure are incorporated herein by reference in their entireties, for the purpose of describing and disclosing, for example, the constructs and methodologies that are described in the publications, which might be used in connection with the presently described methods, compositions, articles, and processes. The publications discussed throughout the text are provided solely for their
32
82« J 7a i disclosure poor to the filing date of the present application. Nothing heresn is to be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention. Should the usage or terminology used in any reference that is incorporated by reference conflict with the usage or terminology used in this disclosure, the usage and terminology of this disclosure controls. The Abstract of the disclosure is provided to satisfy the requirements of 37 C, F. R, § 1.72 and the purpose stated in 37 C.F.R. § 1.72(b) "to enable the United States Patent and Trademark Office and the public generally to determine quickly from a cursory inspection the nature and gist of the technical disclosure." The Abstract is not intended to be used to construe the scope of the appended claims or to limit the scope of the subject matter disclosed herein. Moreover, any headings are not intended to be used to construe the scope of the appended claims or to limit the scope of the subject matter disclosed herein. Any use of the past tense to describe an example otherwise indicated as constructive or prophetic is not intended to reflect that the constructive or prophetic example has actually been carried out. fOOSSJ Also unless indicated otherwise, when a range of any type is disclosed or claimed, for example a range of molecular weights, layer thicknesses, concentrations, temperatures, and the like, it is intended to disclose or claim individually each possible number that such a range could reasonably encompass, including any sub-ranges encompassed therein. For example, when the Applicants disclose or claim a chemical moiety having a certain number of atoms, for example carbon atoms, Applicants' intent is to disclose or claim individually every possible number that such a range could encompass, consistent with the disclosure herein. Thus, by the disclosure that an alky! substituent or group can hBs/e from 1 to 20 carbon atoms, Applicants intent is to recite that the alkyl group have 1 . 2, 3, 4, 5, 6, 7, 8, 9, 20, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms, including any range or sub-range encompassed therein. Accordingly, Applicants reserve the right to proviso out or exclude any individual members of such a group, including any sub-ranges or combinations of sub-ranges within the group, that can be claimed according to a range or in any similar manner, if for any reason Applicants choose to clasm iess than the full measure of the disclosure, for example, to account for a reference that Applicants are unaware of at the time of the filing of the application.
[0056] The foregoing description, for purposes of explanation, used specific nomenclature to provide a thorough understanding of the invention.
However, it will be apparent to one skilled in the art that the specific detaiis are not required in order to practice the invention. The foregoing descriptions of specific embodiments of the present invention are presented for purpose of illustration and description. They are not intended to be exhaustive or to limit the invention to the precise forms disclosed. Obviousiy many modifications and variations are possible in view of the above teachings. The embodiments are shown and described in order to best explain the principles of the invention and its practical applications, to thereby enable others skilled in the art to best utilize the invention and various embodiments with various modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the following claims and their equivalent.
34
82« J 7a i

Claims

We claim:
1. An enclosable equilibration chamber, composing;
a set of particles selected from an average diameter size ranging from 10 μm to 1500 μm; a sealabSe housing member including an interna! space; at least one partitioning member positioned within the internal space, wherein the partitioning member is formed in a pre-determined configuration Io support the contiguous aiignment of the set of particies so that each particle is in direct physical contact with no more than two particles; at least one input port for directing the entry of a fluid of interest into the internal space to permit equilibration of the particles; and at least one output port for directing the exit of the pre-equilibrated particles suspended in the fluid of interest from the interna! space.
2. The enciosabie equilibration chamber of Ciaim 1 , wherein the average diameter size of a particle ranges: from about 10 μm to about 1500 μm; from about 10 μm to about 1 100 μm; from about 10 μm to about 1000 μm; from about 10 μm to about 900 μm; from about 10 μm to about 800 μm; from about 10 μm to about 700 μm; from about 10 μm to about 600 μm; from about 10 μm to about 500 μm; from about 10 μm to about 400 μm; from about 10 μm to about 300 μm; from about 10 μm to about 200 μm; from about 10 μm to about 175 μm; from about 10 μm to about 150 μm; from about 10 μm to about 120 μm; from about 10 μm to about 80 μm; and from about 10 μm to about 40 μm.
3. The enciosabie equilibration chamber of Claim 1 , wherein the average diameter size of a particie ranges: from about 20 μm to about 1500 μm; from about 20 μm to about 1200 μm; from about 20 μm to about 2000 μm; from about 20 μm to about 900 μm; from about 20 μm to about 800 μm; from about 20 μm to about 700 μm; from about 20 μm to about 600 μm; from about 20 μm to about 500 μm; from about 20 μm to about 400 μm; from about 20 μm to about 300 μm; from about 20 μm to about 200 μm; from about 20 μm to about
35
82« J 7a i 175 μm; from about 20 μm to about 150 μm; from about 20 μm to about 120 μm; from about 20 μm to about 80 μm; and from about 20 μm to about 40 μm,
4. The enciosabie equilibration chamber of Claim 1 , wherein the average diameter size of a particle ranges: from about 30 μm to about 1500 μm; from about 30 μm to about 1300 μm; from about 30 μm to about 3000 μm; from about 30 μm to about 900 μm; from about 30 μm to about 800 μm; from about 30 μm to about 700 μm; from about 30 μm to about 600 μm; from about 30 μm to about 500 μm; from about 30 μm to about 400 μm; from about 30 μm to about 300 μm; from about 30 μm to about 300 μm; from about 30 μm to about 175 μm; from about 30 μm to about 150 μm; from about 30 μm to about 130 μm; and from about 30 μm to about 80 μm.
5. The eπdosable equilibration chamber of CSaim 1 , wherein the partitioning member is formed as a conduit.
6. The enclosabie equilibration chamber of Ciaim 1 , wherein the partitioning member is formed as a conduit shaped as a coil, and the sealabie housing member is formed as a conduit shaped as a coiS that encapsulates the partitioning member,
7. The encSosabSe equilibration chamber of Ciaim 1 , wherein the input port is attachabie to a flu id-reservoir member, which in turn, is attachable to a driver member.
8. The enciosabie equilibration chamber of Ciaim 1 , wherein the output port is attachabie to a transport member.
9. A system for promoting in situ equilibrium of particies, the system comprising;
an enclosabie equiiibration chamber; including: a set of particies seiected from an average diameter size ranging from 10 μm to 1500 μm;
82« J 7a i a seaSable housing member including an interna! space; at least one partitioning member positioned within the interna! space, wherein the partitioning member is formed in a pre-determined configuration to support the contiguous alignment of the set of particles so that each particle is in direct physical contact with no more than two particles; at least one input port for directing the entry of a fluid of interest into the interna! space to permit equilibration of the particles; and at least one output port for directing the exit of the pre- equiiibratβd particies suspended in the fluid of interest from the interna! space;
10. The system of Claim 9, wherein the average diameter size of a particle ranges: from about 10 μm to about 1500 μm; from about 10 μm to about
1100 μm; from about 10 μm to about 1000 μm; from about 10 μm to about 900 μm; from about 10 μm to about 800 μm; from about 10 μm to about 700 μm; from about 10 μm to about 600 μm; from about 10 μm to about 500 μm; from about 10 μm to about 400 μm; from about 10 μm to about 300 μm; from about 10 μm to about 200 μm; from about 10 μm to about 175 μm; from about 10 μm to about 150 μm; from about 10 μm to about 120 μm; from about 10 μm to about 80 μm; and from about 10 μm to about 40 μm.
11. The system of Claim 9, wherein the average diameter size of a particle ranges; from about 20 μm to about 1500 μm; from about 20 μm to about 1200 μm; from about 20 μm to about 2000 μm; from about 20 μm to about 900 μm; from about 20 μm to about 800 μm; from about 20 μm to about 700 μm; from about 20 μm to about 600 μm; from about 20 μm to about 500 μm; from about 20 μm to about 400 μm; from about 20 μm to about 300 μm; from about 20 μm to about 200 μm; from about 20 μm to about 175 μm; from about 20 μm to about 150 μm; from about 20 μm to about 120 μm; from about 20 μm to about 80 μm; and from about 20 μm to about 40 μm,
12. The system of CSaim 9, wherein the average diameter size of a particle ranges; from about 30 μm to about 1500 μm; from about 30 μm to about 1300 μm; from about 30 μm to about 3000 μm; from about 30 μm to about 900 μm; from about 30 μm to about 800 μm; from about 30 μm to about 700
37
82« J 7a i μm; from about 30 μm to about 600 μm; from about 30 μm to about 500 μm; from about 30 μm to about 400 μm; from about 30 μm to about 300 μm; from about 30 μm to about 300 μm; from about 30 μm to about 175 μm; from about 30 μm to about 150 μm; from about 30 μm to about 130 μm; and from about 30 μm to about 80 μm.
13. The system of Claim 9 further comprising a driver member.
14. The system of Claim 9 further comprising a fiuid-reservoir member.
15. The system of Claim 9 further comprising a transport member,
16. The system of Claim 9, wherein the driver member and the fiuid- reservoir member are selected from the group consisting of various syringes and related component parts.
17. The system of Claim 9, wherein the transport member is selected from the group consisting of catheters and micro-catheters.
18. An in situ method for pre-eqυilibrating particles, the method comprising: providing an enclosabie equilibration chamber including a set of particles aligned contiguously so that each particle is in direct physical contact with no more than two particles; directing a fluid of interest within the enclosabie equilibration chamber so that the particles are exposed to the fluid of interest for a sufficient time to permit equilibration of the particles; and deploying the pre-equilibrated particles suspended in the fluid of interest from the enciosabie equiiibration chamber,
19. The in situ method of Claim 18 further comprising adding pharmaceutical and/or bioactive agents,
20, The in situ method of Claim 18, wherein the set of particles includes embolic agents.
38
82« J 7a i
21 . The in situ method of Claim 18, wherein the average diameter size of a particle ranges: from about 10 μm to about 1500 μm; from about 10 μm to about 1100 μm; from about 10 μm to about 1000 μm; from about 10 μm to about 900 μm; from about 10 μm to about 800 μm; from about 10 μm to about 700 μm; from about 10 μm to about 600 μm: from about 10 μm to about 500 μm; from about 10 μm to about 400 μm; from about 10 μm to about 300 μm; from about 10 μm to about 200 μm: from about 10 μm to about 175 μm; from about 10 μm to about 150 μm; from about 10 μm to about 120 μm; from about 10 μm to about 80 μm: and from about 10 μm to about 40 μm.
22. An in situ method for pre-eqυilibrating emboiic particles and for delivery, the method comprising: providing an enclosabie equiiibration chamber including a set of embolic particles aligned contiguously so that each emboiic particle is in direct physical contact with no more than two embolic particles; directing a fluid of interest within the enclosabie equilibration chamber so that the emboiic particles are exposed to the fluid of interest for a sufficient time to permit equilibration of the embolic particles; and deploying the pre-equilibrated embolic particles suspended in the fluid of interest from the enciosabie equilibration chamber into a transport member.
23. The in situ method of Claim 22, further comprising deploying the pre- equilibrated embolic particles from the transport member to a target vasculature of a recipient.
39
82« J 7a i
PCT/US2009/033922 2008-02-12 2009-02-12 Delivery systems and related methods for convenient preparation of particles for in vivo administration WO2009102868A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US2801008P 2008-02-12 2008-02-12
US61/028,010 2008-02-12

Publications (1)

Publication Number Publication Date
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ID=40957263

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8319582B2 (en) 2009-06-04 2012-11-27 Murata Manufacturing Co., Ltd. Elastic wave apparatus and duplexer

Citations (5)

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Publication number Priority date Publication date Assignee Title
JPH1147273A (en) * 1997-07-31 1999-02-23 Terumo Corp Medicinal liquid injection utensil
KR20010079338A (en) * 2001-07-07 2001-08-22 이영규 Drug injection unit having a drug mixer
JP2002325845A (en) * 2001-05-07 2002-11-12 Nipro Corp Drug solution injector suitable for small volume of drug solution dosing
JP2006068531A (en) * 2004-09-02 2006-03-16 Tecpharma Licensing Ag Automatic pen for two chamber ampule
JP2006230467A (en) * 2005-02-22 2006-09-07 Fujimori Kogyo Co Ltd Kit for injection and method of preparing prefilled syringe

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH1147273A (en) * 1997-07-31 1999-02-23 Terumo Corp Medicinal liquid injection utensil
JP2002325845A (en) * 2001-05-07 2002-11-12 Nipro Corp Drug solution injector suitable for small volume of drug solution dosing
KR20010079338A (en) * 2001-07-07 2001-08-22 이영규 Drug injection unit having a drug mixer
JP2006068531A (en) * 2004-09-02 2006-03-16 Tecpharma Licensing Ag Automatic pen for two chamber ampule
JP2006230467A (en) * 2005-02-22 2006-09-07 Fujimori Kogyo Co Ltd Kit for injection and method of preparing prefilled syringe

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8319582B2 (en) 2009-06-04 2012-11-27 Murata Manufacturing Co., Ltd. Elastic wave apparatus and duplexer

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