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EP2242481A1 - Article et procédé d'administration focalisée de matières thérapeutiques et/ou de diagnostic - Google Patents

Article et procédé d'administration focalisée de matières thérapeutiques et/ou de diagnostic

Info

Publication number
EP2242481A1
EP2242481A1 EP08869438A EP08869438A EP2242481A1 EP 2242481 A1 EP2242481 A1 EP 2242481A1 EP 08869438 A EP08869438 A EP 08869438A EP 08869438 A EP08869438 A EP 08869438A EP 2242481 A1 EP2242481 A1 EP 2242481A1
Authority
EP
European Patent Office
Prior art keywords
microfiber extrudate
microfiber
extrudate
excitation
active load
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08869438A
Other languages
German (de)
English (en)
Inventor
Peter D. Gabriele
Michael S. Flemmens
Jeffrey H. Robertson
Andrew Hogan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Armark Authentication Technologies LLC
Original Assignee
Armark Authentication Technologies LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Armark Authentication Technologies LLC filed Critical Armark Authentication Technologies LLC
Publication of EP2242481A1 publication Critical patent/EP2242481A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5094—Microcapsules containing magnetic carrier material, e.g. ferrite for drug targeting
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug

Definitions

  • the present disclosure is generally directed to an article and method for delivering therapeutic and/or diagnostic materials and more particularly to an article and method for focused delivery of pharmaceuticals or other therapeutic materials and/or diagnostic materials to humans and other living organisms.
  • Hyperthermia is one such approach to cancer therapy.
  • Hyperthermia associated with radiotherapy or chemotherapy is a method for cancer treatment, although the molecular mechanisms of this process are not well understood.
  • Hyperthermia exhibits various anti-tumor effects, including damage of tumor vasculature.
  • Cancer cells are more sensitive to higher body temperatures than are normal cells. Hyperthermia destroys cancer cells by raising the tumor temperature to a "high fever" range, similar to the way the body uses fever naturally when combating other Attorney Docket No ⁇ 02910-0014
  • Radio frequency (RF) hyperthermia is a non-ionizing form of radiation therapy that can substantially improve results from cancer treatment
  • hyperthermia used in combination with chemotherapy enhances blood flow in tumor tissues, increasing the uptake of chemotherapy drugs in tumor membranes
  • Hyperthermia also induces disassembly of the cytoskeleton, which enlarges the tumor pores for easier drug entry
  • hyperthermic temperatures can be used as a drug activator, accelerating chemical reactions through heat and drawing essential oxygen molecules to tumor tissue for chemical reaction with the drug
  • This technology can be designed to optimize those factors that are antagonistic to neoplastic growth
  • RF ablation where direct radio-stimulation of cancerous tissues creates a local intense heat enough to kill neoplastic cells
  • Another RF approach is to direct RF at nanoparticle targets localized in the tumor site These nanospheres are affixed with antibodies to focus the delivery of the nanoparticle to the tumor site that then becomes the target of RF stimulation to directly deliver heat to the local tissue
  • Still another approach is to combine the separate actions of chemotherapeutic agents with tissue hyperthermia Attorney Docket No .. 02910-0014
  • a microfiber extrudate includes a bio -compatible polymer matrix forming a body of the microfiber extrudate, an exogenously excitable mate ⁇ al arranged within the body, and an active load arranged within the body
  • a discrete exogenously excitable domain includes an exogenously excitable mate ⁇ al
  • the exogenously excitable mate ⁇ al is configured to be excited by an exogenous stimulus
  • the exogenously excitable domain is arranged for positioning in a microfiber extrudate
  • the microfiber extrudate includes a bio -compatible polymer mat ⁇ x forming a body of the microfiber extrudate, the exogenously excitable mate ⁇ al in a discrete domain within the body
  • a discrete active load domain includes a therapeutic mate ⁇ al
  • the therapeutic mate ⁇ al is configured to be released into a living organism.
  • the active load domain is arranged for positioning in a microfiber extrudate
  • the microfiber extrudate includes a bio-compatible polymer mat ⁇ x forming a body of the microfiber extrudate, with the active load arranged as a discrete domain within the body
  • a microfiber extrudate delivery process includes medically identifying a region for treatment by the active load, administe ⁇ ng a microfiber extrudate, and applying the exogenous stimulus to the region for treatment, thereby releasing an active load into the region for treatment
  • the microfiber extrudate includes a bio-compatible polymer matnx forming a body of the microfiber extrudate, an exogenously excitable matenal arranged within the body, and the active load arranged within the body
  • a microfiber extrudate includes a bio -compatible polymer mat ⁇ x forming a body of the microfiber extrudate, an exogenously excitable material arranged within the body, and an active load Attorney Docket No.: 02910-0014
  • the bio-compatible polymer matrix includes a polymer selected from the group consisting of poly(FAD-SA), poly(CCP- SA), poly(FA-SA), poly(EAD-SA), poly glycolide, poly lactic acid, copolymers thereof, and combinations thereof.
  • the exogenously excitable material configured to be excited by an exogenous stimulus is selected from the group of stimuli consisting of radio frequency excitation, microwave excitation, terahertz excitation, mid infrared excitation, near infrared excitation, visible excitation, ultraviolet excitation, x- irradiation excitation, magnetic excitation, electron beam irradiation excitation, and combinations thereof.
  • the active load has therapeutic properties.
  • Exemplary embodiments may be used for selectively attacking cancer cells by administering a microfiber extrudate having an exogenously excitable material that may be excited to selectively attack cancer cells while leaving healthy cells intact.
  • An advantage of the present disclosure includes selectively delivering a therapeutic material, which may, for example, be used for selective attack of cancer cells.
  • Another advantage of the present disclosure includes selectively delivering a diagnostic mate ⁇ al, which may, for example, be used for identifying cancer cells.
  • Yet another advantage of the present disclosure includes the ability to combine two components that would otherwise impose compositional difficulties into the same structure.
  • Still another advantage is the diminished effect of an active pharmaceutical ingredient on matrix degradation and diffusion activity.
  • Another advantage is controlled diffusion of therapeutic and/or diagnostic material in conjunction with the release of material in response to an exogenous stimulus.
  • Figure 1 shows a photograph of an exemplary embodiment of a microf ⁇ ber extrudate
  • Figure 2 shows another exemplary embodiment of a microf ⁇ ber extrudate
  • Figure 3 shows a cross-section of an exemplary embodiment of a microfiber extrudate
  • Figure 4 shows a relationship between temperature and microwave dose exposure time for microcells with differing materials according to several exemplary formulae
  • Figure 5 shows a photograph of an exemplary embodiment of a microfiber extrudate
  • Figure 6 shows a photograph of an exemplary embodiment of a microfiber extrudate
  • Figure 7 shows plate counts for exemplary microcell formulae in comparison to microwave dose exposure time
  • Figure 8 shows a cross-section of another exemplary embodiment of a microfiber extrudate
  • Figure 9 shows a cross-section of yet another exemplary embodiment of a microfiber extrudate
  • FIG. 1 illustrates an exemplary embodiment of a microfiber extrudate 100
  • microfiber extrudate includes microvectors, microcells, microspheres, artificial cells, and other suitable devices
  • Microfiber extrudate 100 includes a matrix, an exogenously excitable material, and an active load The matrix forms a body 102 of the microfiber extrudate Body 102 defines the exte ⁇ or of microfiber extrudate 100.
  • the body may be, but is not necessanly circular in cross- section and may be designed to have a diameter as small as about 5-10 micrometers or up to about 300 micrometers or larger As illustrated, body 102 has a diameter D of about 100 micrometers The body may have a transverse thickness as small as about 5 micrometers or may be elongate or spherical As illustrated, body 102 has a transverse thickness T of about 10 micrometers
  • FIG. 2 illustrates another exemplary embodiment of a microfiber extrudate 200
  • microfiber 200 is elongate
  • Microfiber extrudate 200 may be transversely sliced along its cross-section to make a plurality of axial slices substantially the same as microfiber extrudate 100
  • the microfiber extrudate may have a predetermined size and geometry.
  • microfiber extrudate is spatially resolvable, which permits a deliberate placement of active and passive components within the microfiber extrudate, as will be discussed in more detail herein
  • Feature size and shape are also controllable, which permits creation of the microfiber extrudate in actual sizes and geometry that correspond to desired sizes and geometries
  • the predetermined size and geometry may be intended to mimic the size of a cell
  • the microfiber extrudate may be configured to have a size and geometry similar to a red blood cell or a white blood cell for a specific animal (including humans)
  • microfiber extrudate may be performed using a micro- extrusion fiber spinning process
  • a precision engineered die defines intended domains as nano-fiber regions that, when combined at the spinning head, anneal into one single fiber having any number of deliberately defined internal Attorney Docket No 02910-0014
  • the micro -extrusion process includes several extruder barrels that intersect into a specially designed "die head " Each barrel delivers a single component for subsequent combination within the die head
  • the die head is configured such that the matrix, the exogenously excitable materials, and the active load exiting the multiple extruder barrels enter a se ⁇ es of pixilated stacked die plates, called a die-pack
  • a unique die-pack may be provided for each different microfiber extrudate design
  • the total pixel bundle exiting the last plate may contain up to 21,000 or more nano-fibers, which coalesce at the spin head into a single fiber Referring to Figures 3 and 5, a cross-section of a fiber shows the "placement" of domains resulting from the channel directed enginee ⁇ ng of the die pack plates
  • the fibers are then bundled into hanks and prepared into blocks, such as by using cellulose solutions in water as a potting media, which are then frozen
  • the hanks are so oriented to have all long axis structures substantially parallel
  • the frozen block is preferably mounted in a cryotome such that the blade edge cuts perpendicular to the fibers
  • Multiple transverse cuts at precise thickness may be made to produce the structure of microfiber extrudate 100
  • Microfiber extrudate 100 can include three to four matenal components, more or fewer may be incorporated
  • the matenal components can be spatially resolved and freely positioned by design within the body of the microfiber extrudate It will be appreciated that the microfiber extrudate may be created by co-extruding pure materials for the matrix and each domain, but more Attorney Docket No 02910-0014
  • the components of the microfiber extrudate may themselves be a mixture of mate ⁇ al(s) with the desired properties (for example, the properties of the exogenously excitable mate ⁇ als and/or the active load) arranged in discrete domains or as the matrix, which may assist in the coextrusion of the mate ⁇ als
  • FIGS 3, 8, and 9 show cross-sections of exemplary embodiments of a microfiber extrudate 300
  • microfiber extrudate 300 is formed and designed to arrange discrete domains 304, 306 of different mate ⁇ als or combinations of mate ⁇ als, such as an exogenously excitable material and/or an active load within a mat ⁇ x 302
  • Each domain can harbor a preferred chemistry for a specific action
  • Each domain may include the exogenously excitable mate ⁇ al, the active load, or a combination of them or other mate ⁇ als
  • Each domain may also include a certain percent of mat ⁇ x mate ⁇ al to facilitate excitement or to prevent excitement It will be appreciated the number and location of discrete domains of different mate ⁇ als is exemplary and may be modified depending on the application.
  • Microfiber extrudate 300 may thus be constructed to include discrete domains with approved excipient mate ⁇ als that contain active pharmaceutical ingredients (API) or a combination of API and inactive or functional domains within the microfiber extrudate. Outside of the domains, the microfiber extrudate may additionally or alternatively include approved excipient mate ⁇ als which contain API, inactive materials or functional mate ⁇ als, or a combination of API and inactive or functional materials As discussed above, the microfiber extrudate can be designed to have a wide range of sizes (e g , about 5-10 ⁇ m or up to about 300 ⁇ m or larger) Consequently, a self-contained drug delivery device in accordance with exemplary embodiments tn the size range of circulatory cells can be provided and medically administered intravenously or parenternally
  • API active pharmaceutical ingredients
  • a region for treatment is identified by diagnostic techniques
  • a microfiber extrudate contains both a therapeutic and an exogenously excitable mate ⁇ al is administered to the region for treatment (in some cases, beyond the region for treatment)
  • An exogenous stimulus is then applied to the region of Attorney Docket No . 02910-0014
  • this process can decrease the effect on regions not identified for treatment
  • this process increases the number of healthy cells left intact while attacking the unhealthy cells
  • periodic pulses of the exogenous stimulus are applied while the microf ⁇ ber extrudate is in situ
  • this can replace patient activated intravenous systems for administering pain medicine by providing the patient with control (or limited control) of a device configured to apply the exogenous stimulus
  • the exogenous stimulus can be activated, thereby causing pain medicine in the microfiber extrudate to be released into the patient's body
  • the API which may be the active load, may be any therapeutic mate ⁇ al Active pharmaceutical mgredients may include, but are not limited to, ABVD, AVICINE, Acetaminophen, Ac ⁇ dine carboxamide, Actinomycin, Alkylating antineoplastic agent, 17-N-Allylamino-17-demethoxygeldanamycin, Aminopte ⁇ n, Amsac ⁇ ne, Anthracycline, Antineoplastic, Antineoplaston, Antitumor!
  • Swainsonme Taxane, Tegafur-uracil, Temozolomide, ThioTEPA, Tioguanine, Topotecan, Trabectedin, Tretinoin, T ⁇ s(2-chloroethyl)amine, Troxacitabme, Uracil mustard, Valrubicin, Vinblastine, Vincristine, Vinorelbine, Vo ⁇ nostat, Zosuquidar, and combinations thereof.
  • therapeutic materials such as anti-tumor antibodies (including VEGH-A or other monoclonal antibodies, for example), antibiotics, bio-agents, bio- pharmaceuticals and/or other suitable therapeutic mate ⁇ als may be included Additionally or alternatively, diagnostic materials, matrix diffusion control mate ⁇ als, and/or other suitable mate ⁇ als may be included
  • the exogenously excitable material is selected to be excited by an exogenous stimulus
  • the exogenous stimuli mclude, but are not limited to, radiofrequency excitation, microwave excitation, terahertz excitation, mid infrared excitation, near infrared excitation, visible excitation, ultraviolet excitation, x-irradiation excitation, magnetic excitation, electron beam irradiation excitation, and combinations thereof
  • the exogenously excitable material can be excited.
  • the exogenously excitable material may be arranged within the domains in the microfiber extrudate or may be mixed within the microf ⁇ ber mat ⁇ x Va ⁇ ous therapies may combine exogenously excitable mate ⁇ als in the microfiber extrudate along with the API
  • the microfiber extrudate may include a radiofrequency (RF) sensitive additive as the exogenously excitable mate ⁇ al and a degradable polymer as a bio -compatible mat ⁇ x that can be administered
  • RF radiofrequency
  • the exogenously excitable mate ⁇ al may be exogenously excited in situ at the local site of tumor angiogenesis, such as a receptor specific region in advancing vascular tissue binding VEGF to facilitate localized heating and thereby denatu ⁇ ng angiogenesis factors and/or destroying abnormal cells at the advancing site
  • the excitation may be configured to expedite breakdown of the mat ⁇ x, thus releasing the pharmaceutical more quickly
  • the microfiber mat ⁇ x may be formulated with a known additive having a known radiofrequency, lambda max or excitation Attorney Docket No ⁇ 02910-0014
  • the natural RF response of the cell m the absence of a specific radiosensitive additive is determined by some spectroscopic mechamsm like NMR, and a tunable RP generator may be used to administer the exogenous non-ionizing radiation
  • An exemplary embodiment of the microfiber mat ⁇ x includes a radiosensitive active pharmaceutical drug arranged within a poly lac tide/polyglycolide copolymer prepared as one of four extrudable components
  • a second component includes the copolymer and an antibody
  • a third component includes the copolymer and a chemotherapeutic agent
  • a fourth mate ⁇ al is neat copolymer
  • the API is 5-fluorouracil (5-FU), doxorubicin, or acetaminophen
  • the mat ⁇ x of the microfiber extrudate may be any suitable thermoplastic mate ⁇ al that is biologically compatible
  • suitable bio-compatible mat ⁇ x material generally falls into one of two pnmary catego ⁇ es, diffusive or degradable In p ⁇ ma ⁇ ly diffusive mat ⁇ x mate ⁇ als, active load components diffuse from its initial domain, through the mat ⁇ x, and eventually into the environment ⁇ e g , bloodstream or tissue) over time, the rate of which may be enhanced or retarded through exogenous stimulation when an exogenously excitable matenal is also present
  • the stimulation may also modify the diffusive profile to increase the amount transmitted
  • Exemplary diffusive matnx mate ⁇ al includes ethyl cellulose polymer, such as that sold by Dow Chemical under the tradename Ethocel
  • Degradable matenal breaks down in body over time, which can be initiated or the rate enhanced, by stimulation in the presence of an exogenously excitable mate ⁇ al
  • Exemplary degradable polymers include poly(FAD-SA), poly(CPP-SA), poly(FA-SA), poly(EAD-SA), poly glycolide, poly lactic acid, copolymers thereof, and combinations thereof
  • the microfiber extrudate has a biocompatible polymer matnx including a polyglycolide/lactide copolymer.
  • the mat ⁇ x is vascular-infusible and bio-compatible mate ⁇ al that can be administered parenternally or intravenously into a tumor site to deliver a Attorney Docket No .: 02910-0014
  • chemotherapeutic agent released over time as the matrix breaks down Such a system may also be coupled with antibody technology.
  • microfiber extrudate 300 includes a matrix depicted as a bio-compatible polymer matrix 302 and a first discrete domain 304 at the core that may contain a suitable bio-active material that may be selected depending upon the desired therapy.
  • the arrangement of discrete domains 304, 306 and/or polymer matrix 302 can be varied. Varying the arrangement of the discrete domains and/or the polymer matrix can permit additional control of diffusion of materials from the microfiber extrudate and/or degradation of the matrix.
  • Discrete domains 306 of a second material may include the exogenously excitable material depicted as "exogenous activators" demonstrating the ability to custom model the microfiber extrudate to include radiosensitive materials.
  • microfiber extrudate 300 can be arranged for material in discrete domain 304 to travel through polymer matrix 302 and/or discrete domain 306, thereby permitting staged reactions of materials traveling through the various domains.
  • the staged reactions can be controlled by diffusion and/or by degradation due to the application of exogenous stimulus. Domains susceptible to differing exogenous stimuli can permit the reaction to be further controlled by providing the differing exogenous stimuli at differing times or in differing amounts.
  • the pathway of the reaction can be controlled.
  • domains 306 may include "immunospecific targeting agents" which permits the microfiber extrudate to include antibodies as an active load. While exemplary embodiments are described with respect to cancer therapy, it is contemplated that localized delivery of therapeutic materials in accordance with exemplary embodiments would be useful in the treatment of other diseases, conditions, and disorders by providing different compositions of therapeutic materials, by adjusting the microfiber extrudate size, or other modifications, all of which are within the scope of the invention.
  • the microfiber extrudate may be used for delivering other mate ⁇ als into an animal (including humans) for therapeutic and/or diagnostic purposes
  • nutrients, vitamins, toxins, poisons, tracers, and/or other components may be included within the domains of the microfiber extrudate to be released upon excitation of the exogenously excitable material
  • toxins may be administered to canines for the purpose of euthanizing
  • a harmless dye that is sensitive to gamma radiation may be administered for the purpose of monitoring exposure to gamma radiation
  • the body of the microfiber extrudate is an artificial cell-like article for focused therapeutic treatments
  • One such focused therapeutic treatment is hyperthermic cancer therapy for humans or other animals
  • the embodiments combine the feature aspects of focused chemotherapy and RF- sensitivity into a single cell-like device that approximates the cellular dimensions of the circulatory system
  • the artificial cell approach involves combining drug delivery and RF- sensitivity in the microfiber extrudate
  • the body of the microfiber extrudate is an artificial cell the size of a red or white blood cell and includes API that can degrade over time
  • the mat ⁇ x may be selected to expedite or extend the breakdown of the matnx
  • the mat ⁇ x may include the exogenously excitable material and, thus, be broken down by exogenous stimulus, thereby releasing the API Placement of the API (or another active load) and/or the exogenously excitable material active loads may be achieved by using high definition micro-extrusion technology capable of spatially resolving local domains within the microfiber extrudate, as described above
  • the microfiber extrudate may deliver a radio frequency sensitive body and a chemotherapeutic drug The mat ⁇ x can be eliminated by resorption following RF excitement
  • a smgle delivery microfiber extrudate acting as an artificial cell combines a controlled drug delivery vehicle (e g , a red or white blood cell) based on degradable FDA compliant drug delivery polymers (such as but not limited to polyglycolide copolymers), a radiosensitive target material or a Attorney Docket No 02910-0014
  • radio sensitive chemotherapeutic agent such as, but not limited to, a fluo ⁇ nated species
  • a non-radiosensitive chemotherapeutic agent such as, but not limited to, 5- fluorouracil
  • an optional antibody such as but not limited to anti-VEGH antibodies
  • Another embodiment includes a system with indigenous acidic properties like those of cancer cells
  • the microfiber extrudate can be used for treating melanoma Because acetaminophen is toxic to the liver, by providing an exogenous stimulus to a region of the body (instead of the whole body) for localized melanoma treatment, the amount of acetaminophen processed by the liver may be lower
  • a stable, multifunctional microcell acting as a nanocar ⁇ er can transport superparamagnetic iron oxide non-particles (SPIONs) and/or nanoparticle domains for simultaneous diagnostic imaging, hyperthermia or specific therapeutic action, a combination of anti-VEFG antibodies and anti-angiopoietin factors for targeted disruption of angiogenesis, a chemotherapeutic agent, and a microenvironment pH antagonist in a single microfiber extrudate
  • SPIONs superparamagnetic iron oxide non-particles
  • nanoparticle domains for simultaneous diagnostic imaging, hyperthermia or specific therapeutic action, a combination of anti-VEFG antibodies and anti-angiopoietin factors for targeted disruption of angiogenesis, a chemotherapeutic agent, and a microenvironment pH antagonist in a single microfiber extrudate
  • the microfiber extrudate can be delivered to plants and other living organisms
  • the exemplary embodiments incorporate ballistic techniques, such as those commonly employed in genetic transformation of crops and other plants for example (e g , via a gene gun, although the delivery methods desc ⁇ bed herein are generally not a genetic transformation process per se), to permanently embed microfiber extrudate s in plant tissue, which are secured through the use of bio-de ⁇ ved adhesions, such as Agrobacte ⁇ um sp , provided as the discrete domains within the matnx
  • the microfiber extrudate can be treated to transform its shape and/or geometry
  • the change in shape and/or geometry can include producing a biomimetic delivery system in the natural range of circulatory cells, transforming the entire shape and/or geometry of the microfiber extrudate (for example, transforming the matnx of the microfiber extrudate), and/or transforming Attorney Docket No 02910-0014
  • the microfiber extrudate can be transformed from a disc-like microfiber extrudate 100 as shown in Figure 1 to a sphere-like structure 600 shown in Figure 6.
  • the mat ⁇ x of the microfiber extrudate can be configured for transformation in a 50% ethanol and 50% water solution or any other suitable solution Additionally or alternatively poly ethylene glycol (PEG) can be used.
  • the matrix of the microfiber extrudate can be configured to have increased osmotic potential and may include hypertonic materials, for example, salt, that permit the microfiber extrudate to transform or swell under selected conditions.
  • the transformation into the sphere-like structure may increase the efficacy of a thermally-sensitive active pharmaceutical ingredient
  • the sphere-like microfiber extrudate can generally maintain its sphere-like geometry after being d ⁇ ed
  • the sphere-like structure can be configured to transform or swell with specific elements of the microfiber extrudate
  • the process of converting into the sphere-like structure can permit the microfiber extrudate to incorporate other mate ⁇ als introduced after extrusion
  • PEG can be used for performing "PEGilation” that brings a suitable mate ⁇ al, for example a nano-particle, into the microfiber extrudate.
  • the geometry of the microfiber extrudate may be configured to provide increase surface area and/or decreased surface area This may be achieved by modifying the extrusion process or by modifying the microfiber extrudate after it is extruded
  • PEGilation can be used for b ⁇ nging binding agents, such as macrophages, into the microfiber extrudate, thereby permitting the binding agents to be released through diffusion and/or degradation of the mat ⁇ x.
  • PEGilation can used for bringing in mate ⁇ al, structures, or nano- particles that prevent white blood cells from attacking the microfiber extrudate Additionally or alternatively, the microfiber extrudate may be aerosolized
  • the sphere-like structure can be used as or in conjunction with insecticides, fertilizers, degradable applications of controlled release Attorney Docket No.: 02910-0014
  • bio-active compounds include taggants, lubricants, sound dampeners, insulators, and/or other suitable applications.
  • a multifunctional, polymeric microfiber extrudate having a dual action payload was created using high definition microextrusion (HDMEJ.
  • HDMEJ high definition microextrusion
  • An example of HDME is described in the previously referenced publication WO 2007/134192.
  • the microfiber extrudate was modeled for substantially simultaneous noninvasive antitumor hyperthermia and drug release.
  • a 75 micrometer (diameter) by 10 micrometer (thickness) microfiber extrudate in the form was a microcell was created by HDME and included an active load of the active pharmaceutical ingredient acetaminophen, an exogenously excitable material of a hyperthermia agent superparamagnetic iron oxide non-particle (SPION), and a bio-compatible polymer matrix of ethyl cellulose drug delivery polymer (for example, Ethocel®) (Ethocel® is a registered trademark of Dow Chemical, Co., Midland, MI).
  • SPION superparamagnetic iron oxide non-particle
  • the SPION was susceptible to exogenous excitation from RF.
  • a second microcell included an active load of acetaminophen as an API, an exogenously excitable material of SPION combined with polylactic acid (PLA), and several different bio-compatible polymer mixtures.
  • the SPION combined with PLA was susceptible to exogenous excitation from microwave RF.
  • the SPION particle size included in the microcells was 30 micrometers obtained from Rockwood Co. of St. Louis, MO.
  • the API was USP 99.95% acetaminophen obtained from Sigma-Aldrich, Milwaukee, WI.
  • Ethocel® was used as a core stable "passive observer" constituent carrier matrix in an effort to eliminate any contribution a degrading polymer would have on hyperthermia response and drug elution from the matrix.
  • the use of a "passive observer” isolated the hyperthermia and drug elution from any matrix contribution under the influence of RF.
  • Three 75 micrometer by 10 micrometer microcell device samples were prepared by HDME: (1) Ethocel® and SPION identified as Example 1, Attorney Docket No.: 02910-0014
  • micro-spatial cross-sectional resolution and general cross-section die design of the microcells were intended to include selected high concentration spatially resolved domains of SPION/polymer adjacent to API/polymer for microwave induction and local heating within the microcells.
  • the configuration of the die plate through which the molten thermoplastic polymer base stock passed during HDME was produced by photolithography to include about 21,000 individual nano fibrils eventually spun to a final total cross-section design of about 15 micrometers on a heated Godet role and collected on a high speed fiber bobbin.
  • Fiber on the bobbins was cut perpendicular to fiber spooling to release 8 inches in length parallel fiber hanks.
  • Hanks were bundled in parallel and potted in an aqueous 1% sodium cellulose solution and frozen into about -20 0 F (about -28.8°C) aqueous cellulose bricks.
  • the frozen bricks of parallel fiber hanks were then transversely sliced to about 10 micrometer thickness using a Leika Cryo microtome Model CM-3600 operating at about -1O 0 F (about 23.3°C). About 20 grams of each sample was collected.
  • the slices were collected and sieved to 75 micrometers final particle size at room temperature through Retch vertical sieve stacks under continuous aqueous flow. The final particles collected were dried under vacuum for about 24 hours.
  • microcells were suspended as an aqueous sample while exposed to microwave RF, Both water and mineral oil were evaluated as a liquid medium to expose microcell samples. 500 milligram samples of each microcell component were dispersed in both water and mineral oil and exposed to 130 watts of microwave RF for 60 seconds to determine the preferred fluid medium to carry out the experiment. As shown in Table 1, temperatures were recorded and illustrate that water had the broadest temperature range response.
  • Microwave RF exposure was performed in a Panasonic 1300 Watt Inverter Technology® Microwave Oven Model NN-SN667W at 130 Watts
  • the oven was retrofitted with all quartz platforms to reduce/eliminate dipole induction heating from standard glass structures
  • All containment and experimental material other than water or albumen in contact with the experimental samples was microwave transparent Containment devices such as test tubes, slides, and cover slips were either quartz or microwave transparent plastics
  • Microwave oven use was limited to less than 90 minutes per test pe ⁇ od to reduce/prevent incidental heating of the oven chamber A 500 milliliter water "reservoir-load" was maintained within the oven chamber to absorb microwave energy and prevent magnetron damage All tests were run in an environmentally-controlled room at about 65 0 F (about 18 3°C) and 50% RH
  • Microcell aqueous solution sample temperature increases were recorded with a Digi-Tech Digital Thermocouple K-I probe The temperature increases showed microcell dispersion is a function of microwave dose Infrared thermography images of isolated microcells dispersed albumen and aqueous solutions and exposed to 130 Watts microwave radiation were compared and recorded using a FLIR S65 HS infrared camera Thermographic analysis suggested that SPION filled microcells responded to microwave RF with a more relevant heating profile for hyperthermia therapy than an unfilled microcell in aqueous and albumin solutions The thermographic analysis showed a sustained generation of heat after microwave RF was discontinued
  • Sample vials containing microcells were prepared for microwave exposure First, 10 milliliters of deiomzed water containing 0 01% Igepal CO-360 non-ionic surfactant was placed into a 20 ml scintillation vial Second, 500 milligrams of the microcell sample was added to each vial and dispersed Duplicate samples for each 130 Watt interval point were prepared The samples were vortexed to uniformity The Attorney Docket No 02910-0014
  • samples included a control of aqueous, 500 grams of Example 2 identified above, and 500 grams of Example 3 identified above
  • the samples were exposed to 130 Watts of microwave radiation for twelve 30 second intervals with 30 seconds of no exposure between each interval Temperatures were recorded in the 30 seconds of no exposure using the DigiTec Thermocouple Samples were averaged and additional thermal imaging thermographic evaluations were performed as isolated samples using the FLIR infrared camera for microcells dispersed in albumen compared to water/surfactant
  • Sample vials were prepared in an identical manner and analyzed for API elution The elution of API from the microcell samples was studied as a passive aqueous diffusion and compared to active microwave induced elution The active event was induced by 130 Watts microwave RF for 30 second intervals with 30 seconds of no exposure between each interval for a total of 3 minutes Temperatures were recorded in the 30 seconds of no exposure
  • UV analysis of elution samples was determined from a standard curve
  • Samples were evaluated using a Perkin Elmer UV-Vis Model Lambda 900 Microcell aqueous samples were exposed to radiotherapy and 98 0 F (about 36 6 0 C) to observe acetaminophen elution from the delivery polymer mat ⁇ x and compared to aqueous samples exposed to microwave RF for 3 minutes, 5 minutes, and 10 minutes for 30 second intervals with 30 seconds of no exposure between each interval
  • Microcell and fiber acetaminophen migration was followed by FT-IR ATR spectroscopy using a ZnSe crystal or specular reflectance. Because ATR is a surface technique, "path length" is virtual and a function of the ATR crystal refractive index of the contact pressure All samples were compressed by the automatic stage to ensure full uniform contact at setting 95 (absorbance values are relative to controls) Dry samples of master batch pellets, fiber or dry microcell were placed in a 20 milliliter scintillation vial and exposed to radiotherapy, about 98°F (about 36 6°C), and about 110 0 F (about 43 3 0 C) for 96 hours and then surface scanned for the emergence of acetaminophen bands. Microcell samples were also stimulated as neat samples in the microwave for 90 seconds and examined by ATR Surfaces of the microcell s were analyzed under an SEM for detection of crystals
  • Example 1 Rabbit/anti-Saccharomyces cerevisiae antibody (from Affinity BioReagents, Golden, CO ) was used in the preparation of two sets of samples Example 1, as described above, was prepared for analysis with a first sample of the microcell without antibody and a second sample with antibody in the microcells Both samples were pretreated to an acid microetch to enhance absorption About 2 grams of the microcells desc ⁇ bed in Example 1 were bathed in a solution of 2 milliliters of 0 01 moles HCL in 100 milliliters of deiomzed water for 15 seconds followed by 5 times ⁇ nsing in deiomzed water Two 500 milligram samples of microetched microcells were transferred to 20 milliliter vials
  • the primary antibody was diluted with PBS to a concentration of 0 1 milligrams per milliliter 25 microliters of NuPAGE LDS Sample Buffer (4X) was added to 75 microliters of diluted antibody 50 microliters of IX PBS was added to the microcells and vortexed for about 3 minutes. The solution was then centnfuged at about 14000 rpm for 5 minutes at radiotherapy 25 microliters of the supernatant was then added to 25 microliters of NuPAGE LDS Attorney Docket No ⁇ 02910-0014
  • PLA Microcells were prepared by HDME with and without SPION. Samples were divided up into two groups Microcells were placed in PBS solution at pH 6 4, 7 0, and 7 4 and incubated at about 115°F (about 46 I 0 C) Each group remained m solution throughout their exposure except when samples were extracted for FT-IR analysis Convection oven exposure samples were run first to establish baseline microstructural changes Microwave samples were suspended from exposure when their spectra!

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Abstract

L'invention concerne un extrudat de microfibres et un procédé d'administration qui comprennent une matrice polymère biocompatible formant un corps de l'extrudat de microfibres, une matière excitable par voie exogène disposée à l'intérieur du corps et une charge active disposée à l'intérieur du corps.
EP08869438A 2007-12-31 2008-12-23 Article et procédé d'administration focalisée de matières thérapeutiques et/ou de diagnostic Withdrawn EP2242481A1 (fr)

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US20100291214A1 (en) * 2008-12-23 2010-11-18 Armark Authentication Technologies, Llc Three-dimensional microfiber extrudate structure and process for forming three-dimensional microfiber extrudate structure
WO2010151746A2 (fr) * 2009-06-26 2010-12-29 Armark Authentication Technologies, Llc Structure d'extrudat en microfibres tridimensionnelle et procédé de formation de la structure d'extrudat en microfibre tridimensionnelle
AU2015324028B2 (en) 2014-09-29 2021-04-01 Board Of Regents Of The University Of Nebraska Nanofiber structures and methods of synthesis and use thereof
JP2019529050A (ja) 2016-09-28 2019-10-17 ボード オブ リージェンツ オブ ザ ユニバーシティ オブ ネブラスカ ナノファイバー構造体およびその使用方法
WO2018227078A1 (fr) 2017-06-09 2018-12-13 Board Of Regents Of The University Of Nebraska Structures nanofibreuses et procédés d'utilisation de celles-ci
AU2018335389B2 (en) 2017-09-19 2023-11-02 Board Of Regents Of The University Of Nebraska Nanofiber structures and methods of use thereof
US20210212949A1 (en) * 2018-04-23 2021-07-15 Board Of Regents Of The University Of Nebraska Nanofiber microspheres and methods os use thereof

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4640035A (en) 1981-09-03 1987-02-03 The Secretary Of State For Defence In Her Britannic Majesty's Government Of The United Kingdom Of Great Britain And Northern Ireland Identifying means
EP0413688B1 (fr) 1987-10-02 1994-06-22 Basf Corporation Procédé et appareil pour la fabrication de fibres profilées à composants multiples
US5162074A (en) 1987-10-02 1992-11-10 Basf Corporation Method of making plural component fibers
US6088613A (en) * 1989-12-22 2000-07-11 Imarx Pharmaceutical Corp. Method of magnetic resonance focused surgical and therapeutic ultrasound
DE4412651A1 (de) * 1994-04-13 1995-10-19 Mueller Schulte Detlef Dr Mittel zur selektiven AIDS Therapie sowie Verfahren zur Herstellung und Verwendung derselben
US5626862A (en) * 1994-08-02 1997-05-06 Massachusetts Institute Of Technology Controlled local delivery of chemotherapeutic agents for treating solid tumors
US20030157187A1 (en) * 1996-12-02 2003-08-21 Angiotech Pharmaceuticals, Inc. Compositions and methods for treating or preventing inflammatory diseases
UA54505C2 (uk) * 1997-04-03 2003-03-17 Гілфорд Фармасьютікалз Інк. Полімери, що біологічно розкладаються, зшиті фосфатами, композиції, вироби і способи для їх виготовлення і використання
US6632457B1 (en) * 1998-08-14 2003-10-14 Incept Llc Composite hydrogel drug delivery systems
US6350464B1 (en) * 1999-01-11 2002-02-26 Guilford Pharmaceuticals, Inc. Methods for treating ovarian cancer, poly (phosphoester) compositions, and biodegradable articles for same
US6530944B2 (en) * 2000-02-08 2003-03-11 Rice University Optically-active nanoparticles for use in therapeutic and diagnostic methods
WO2002030472A2 (fr) * 2000-10-12 2002-04-18 Guilford Pharmaceuticals, Inc. Compositions pour liberer des agents de radiosensibilisation, et procedes de production et d'utilisation de ces compositions
EP1406593B1 (fr) * 2001-06-22 2010-08-25 Johns Hopkins University School of Medicine Compositions polymeres biodegradables, compositions et leurs applications
US6861142B1 (en) 2002-06-06 2005-03-01 Hills, Inc. Controlling the dissolution of dissolvable polymer components in plural component fibers
GB0520902D0 (en) * 2005-10-14 2005-11-23 Chowdhury Dewan F H Nanotubes
US8945598B2 (en) * 2005-12-29 2015-02-03 Cordis Corporation Low temperature drying methods for forming drug-containing polymeric compositions
KR100819377B1 (ko) * 2006-02-24 2008-04-04 (주)에이티젠 양친매성 화합물을 이용한 자성 나노복합체 및 이를포함하는 조영제
AU2007249270A1 (en) 2006-05-10 2007-11-22 Armark Authentication Technologies, Inc Extruded filament for microscopic tagging system
EP2019691B1 (fr) * 2006-05-15 2020-08-12 Massachusetts Institute of Technology Polymères pour particules fonctionnelles

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2009088777A1 *

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