WO1996023543A1 - Systemes de liberation de medicaments photolytique - Google Patents

Systemes de liberation de medicaments photolytique Download PDF

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Publication number
WO1996023543A1
WO1996023543A1 PCT/US1996/001333 US9601333W WO9623543A1 WO 1996023543 A1 WO1996023543 A1 WO 1996023543A1 US 9601333 W US9601333 W US 9601333W WO 9623543 A1 WO9623543 A1 WO 9623543A1
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agent
irradiating
therapeutic agent
therapeutic
agents
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PCT/US1996/001333
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English (en)
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Robert A. Van Tassel
Richard H. Clarke
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Angiomedics Ii Incorporated
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Priority to AU46590/96A priority Critical patent/AU4659096A/en
Publication of WO1996023543A1 publication Critical patent/WO1996023543A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0613—Apparatus adapted for a specific treatment
    • A61N5/062—Photodynamic therapy, i.e. excitation of an agent
    • 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
    • A61K41/0042—Photocleavage of drugs in vivo, e.g. cleavage of photolabile linkers in vivo by UV radiation for releasing the pharmacologically-active agent from the administered agent; photothrombosis or photoocclusion
    • 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
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • 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
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0601—Apparatus for use inside the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/22—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for
    • A61B2017/22051—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for with an inflatable part, e.g. balloon, for positioning, blocking, or immobilisation
    • A61B2017/22057—Optical properties
    • A61B2017/22059—Optical properties transparent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/22—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for
    • A61B2017/22082—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for after introduction of a substance
    • A61B2017/22087—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for after introduction of a substance photodynamic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
    • A61B18/22—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor
    • A61B2018/2255—Optical elements at the distal end of probe tips
    • A61B2018/2261—Optical elements at the distal end of probe tips with scattering, diffusion or dispersion of light
    • 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
    • A61M25/00—Catheters; Hollow probes
    • A61M25/0043—Catheters; Hollow probes characterised by structural features
    • A61M2025/0057—Catheters delivering medicament other than through a conventional lumen, e.g. porous walls or hydrogel coatings
    • 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
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A61M2025/1043—Balloon catheters with special features or adapted for special applications
    • A61M2025/105—Balloon catheters with special features or adapted for special applications having a balloon suitable for drug delivery, e.g. by using holes for delivery, drug coating or membranes
    • 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
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/05—General characteristics of the apparatus combined with other kinds of therapy
    • A61M2205/051—General characteristics of the apparatus combined with other kinds of therapy with radiation therapy
    • A61M2205/053—General characteristics of the apparatus combined with other kinds of therapy with radiation therapy ultraviolet

Definitions

  • This invention relates to methods and devices for photolytically delivering therapeutic agents to various vascular and non- vascular sites within the body.
  • Vascular injury associated with angioplasty procedures can initiate a complex cascade of biologic events, such as thrombosis, vascular smooth muscle cell migration and proliferation and production of extracellular matrix (see e.g., Ip, et al., J. Am. Coll. Cardiol. (1990) 1 : 1667-87; Cassells, W., Circulation (1992) _ : 723-9; Schwartz et al., J. Am. Coll. Cardiol. (1992) 2 ⁇ : 1284-93).
  • biologic events such as thrombosis, vascular smooth muscle cell migration and proliferation and production of extracellular matrix
  • the inhibition of smooth muscle cell proliferation has been the primary target for local intravascular drug delivery so far.
  • the local delivery approach is likely to prove useful for treating a variety of other cardiovascular diseases as well. This includes local delivery of antithrombotic agents, antibiotics, genes, vectors and other biological agents to vascular segments prone to thrombosis, local deposition of angiogenic growth factors designed to promote neovascularization of an ischemic focus and local administration of agents designed to selectively alter vasomotor tone.
  • Intravascular delivery systems generally employ balloon catheters which are easily guided through blood vessels to a region in need of treatment and can then be inflated to fully contact and dilate the entire surrounding vessel wall.
  • a therapeutic agent can then be delivered to the surrounding vessel wall, for example, by diffusion through the balloon or by hydrostatic pressure, as occurs when using a porous balloon catheter.
  • clinical use of such catheters is limited by certain practical problems, such as leakage of the solution through side branches and relatively long incubation times of 15 to 30 minutes.
  • the inflation pressure required to accomplish a satisfactory seal between the balloon and the surrounding vessel wall can lead to additional vessel injury proximal and distal to the target site, potentially increasing the proliferative response or creating a nidus for thrombus formation.
  • balloon catheters which have been used for drug delivery to blood vessel walls are drug-coated catheters (e.g., hydrogel catheters). Upon inflation of the balloon in a blood vessel, the therapeutic agent is "pressed" onto or into the surrounding vessel wall.
  • drugs are rapidly washed off the balloon by exposure to the blood-stream during the catheter's passage to the site (see, e.g., Sheriff et al., J. Am. Coll. Cardiol. (1993) 21 : 188A).
  • the balloon must be chaperoned by a protective sheath as the catheter is advanced toward the target vessel.
  • the time between sheath removal and balloon inflation must be minimized to avoid premature shedding of the drug into the blood stream at the site prior to balloon inflation.
  • polymeric stents have also been used for sustained local drug delivery of antithrombotic or antiproliferative drugs, genes or the like.
  • Several approaches have been investigated to achieve continuous drug release from a stent including, for example, seeding the stent with genetically modified endothelial cells to elute agents such as tissue plasminogen activator, and coating the stent directly with drugs or with drug-eluting biodegradable polymers.
  • a system which delivers a controlled amount of a therapeutic or diagnostic agent to a blood vessel wall, without creating additional tissue damage or significant inflammatory responses, would satisfy a great need in the art.
  • the invention pertains to an intravascular or intraluminal drug delivery device having a therapeutic or diagnostic agent photoreleasably linked to its exterior surface.
  • the linkage is mediated by a photoactivable agent, such as a chromophore, which releases the therapeutic or diagnostic reagent from the exterior surface upon exposure to light.
  • therapeutic agent refers to any agent or combination of agents that may affect the cells or structure of a body region, including drugs, peptides, chromophores, nucleic acids, vectors, or the like, which can be used to treat, study or diagnose certain conditions within the body region.
  • Photoactivatable agents suitable for releasing the bound therapeutic or diagnostic agent from the surface of a medical device include any agent which can be linked to a functional group (e.g., a phenol) of the therapeutic or diagnostic agent and which, upon exposure to light, releases the therapeutic or diagnostic agent in functional form.
  • the photoactivatable agent is a chromophore.
  • Suitable chromophores are generally selected for absorption of light that is deliverable from common radiation sources (e.g. UV light ranging from 240-370 nm). Examples of chromophores which are photoresponsive to such wavelengths include, but are not limited to, acridines, nitroaromatics and arylsulfonamides.
  • the efficiency and wavelength at which the chromophore becomes photoactivated and thus releases or "uncages" the therapeutic agent will vary depending on the particular functional group(s) attached to the chromophore.
  • the absorption wavelength can be significantly lengthened by addition of methoxy groups.
  • the drug delivery device of the invention can be guided into a position adjacent to the region to be treated, using conventional techniques. After positioning the device adjacent to the region to be treated, the device can be inflated or expanded so that its drug-containing exterior comes into contact with the surrounding tissue. Light is then transmitted to the drug derivitized surface of the device, e.g., by transmission throughout the interior of the device, causing photolytic release of the therapeutic agent from the exterior of the device onto the surrounding tissue.
  • Suitable medical devices for use in the invention include, for example, balloon catheters, endoscopes, polymer stents, and the like.
  • a conventional balloon angioplasty catheter containing one or more optical fibers is modified by photoreleasably linking a therapeutic agent to the exterior of the balloon.
  • the catheter is guided into position adjacent to an area to be treated using, for example, a guide wire, and the balloon is then inflated so as to contact and dilate the surrounding tissue.
  • radiation from an irradiation source is delivered via one or more optical fibers which extend through the terminal end of the catheter into the balloon.
  • a diffusive radio-opaque tip is optionally attached to the terminal end through which the radiation is delivered and scattered throughout the balloon.
  • the light delivered through the balloon subsequently causes photolytic release of one or more therapeutic agents bound to the exterior of the balloon, thereby delivering the therapeutic agent to the surrounding body tissue.
  • the therapeutic agent itself is photoactivatable (e.g., a photoactivatable psoralen or hematopo ⁇ hyrin)
  • the light delivered through the balloon can also be used to activate the therapeutic agent, following its delivery to the surrounding body tissue.
  • Radiation to promote photorelease of the therapeutic or diagnostic agent can be provided by a variety of sources including, but not limited to, non-coherent UV light sources and excimer sources.
  • sources including, but not limited to, non-coherent UV light sources and excimer sources.
  • a KrF excimer laser operating at 248 nanometers can be used.
  • a frequency-quadrupled, solid state, Neodymium-doped YAG laser or the like operating at 266 nm can be used, or an Argon ion laser operating at 257 or 275 nm can be used.
  • the surface is generally first primed with a substrate, typically an organic polymer, having functional groups available for reaction with a photoactivatable linking agent.
  • a substrate typically an organic polymer, having functional groups available for reaction with a photoactivatable linking agent.
  • the substrate is an acrylic derivative such as, polymethacrylic acid.
  • Other polymers which can be used include, but are not limited to, polyacrylamides, polyethylene, polystyrene, polyethylene terephthalate (PET), polypropylene, polyolefin, polyurethane and other thermoplastic elastic polymers.
  • Polymer resins such as methylbenzhydrylamine, and copolymers, for example copolystyrene-divinylbenzene, can also be used.
  • Non-polymer surface chemistries may also be employed.
  • metallic, glass or silica-based surfaces can be modified with, for example, dialkyldichlorosilanes to provide a reactive surface suitable for further derivatization.
  • the photoactivatable agent can then be linked to the substrate either alone or following its attachment to the drug or compound to be delivered.
  • Linkage to the substrate can be achieved using, for example, solution-phase conjugation (i.e., contacting the interface of the substrate with a liquid carrying the photoactivatable agent or the photoactivatable agent-drug conjugate).
  • linkage can be achieved by direct reaction of the photoactivatable agent or the photoactivatable agent-drug conjugate on the substrate.
  • the photoactivatable agent is reacted with the therapeutic agent to create a photoreleasable linkage.
  • the excitation wavelength may be chosen so as to selectively excite particular chromophores. For example, it is possible to photoreleasably attach two different drugs or to two different chromophores to the substrate, and then independently or sequentially release the two drugs by selecting the excitation wavelength to match the corresponding chromophore.
  • the chromophore and the excitation wavelength may further be selected to avoid undesired photolytic reactions of the drug (e.g., inactivation) or of the surrounding tissue.
  • the photosensitivity of nucleic acids is well known. When the drug is a nucleic acid, excitation energy which may damage the nucleic acid (e.g. wavelengths shorter than 280 nm) should be avoided.
  • therapeutic agents which can be delivered by this method include any agent or combination of agents that may affect the cells in the vessel wall, including drugs, chromophores, and nucleic acids.
  • therapeutic agents also include diagnostics which will aid in later treatment, such as radiopaque compounds that allow the vessel to be visualized by fluoroscopy or similar methods.
  • Therapeutic agents may further include antimicrobial agents, such as antibacterial and antiviral agents.
  • drugs which prevent platelet aggregation and adhesion can be used, such as antiplatelets and anticoagulants.
  • receptor blockers, growth factors and other hormones may be used to limit the normal repair response.
  • anticoagulants including heparin, hirudin, hirulog, tissue plasminogen activator, and fibrinogen
  • anti- inflammatory agents such as steroids, ibuprofen, aspirin, somatostatin, angiopeptin, and anti-inflammatory peptide 2
  • cytotoxins including colchicine, dexamethasone, doxorubicin, methotrexate, and psoralen
  • antibiotics and enzyme inhibitors, including urokinase, 2,4-dinitrophenol, and thiol protease inhibitor.
  • photoactivatable chemical agents which inhibit smooth muscle cell proliferation upon exposure to light can be used as therapeutic agents to prevent restenosis.
  • photoactivatable psoralens and hematopo ⁇ hyrins can significantly inhibit the proliferation of smooth muscle cells within blood vessel walls upon irradiation with long-wave UV light (PUVA) (see e.g., U.S. Patent No. 5, 1 16, 864 (March et al.).
  • PUVA long-wave UV light
  • these photoactivatable agents can be photolytically delivered to specific tissue, such as a region of a blood vessel wall, by the devices and methods of the present invention.
  • the photoactivatable agent is releasably linked to the substrate (contained on the exterior of the drug delivery device) in an inactive form, and then photolytically delivered to an adjacent area of tissue, as previously described. Once delivered to the targeted tissue, the agent is activated by exposure to radiation of an appropriate wavelength.
  • genes, or vectors containing genes can be delivered which express proteins involved in modulating biologic processes in a body region, such as cell proliferation or matrix production by autocrine means.
  • genes which overexpress non-secreted growth inhibitors e.g., tumor suppressor genes
  • genes encoding proteins which cause the death of smooth muscle cells upon exposure to certain drugs can be delivered to blood vessel walls.
  • genes encoding thymidine kinase are transfected into vascular smooth muscle cells, rendering the cells vulnerable to gancyclovir.
  • the devices and methods of the present invention can also be used to treat blood vessel and arterial blockages.
  • genes encoding growth factors such as vascular endothelial growth factor (VEGF), which stimulate new blood vessel growth, are delivered to the walls of blocked vessels to promote the generation of new vessels which bypass the obstruction.
  • VEGF vascular endothelial growth factor
  • the methods and drug delivery devices of the present invention provide a safe and effective means for local, site-specific delivery of a wide variety of therapeutic agents to vascular and other body tissues.
  • the systems provided by the present invention use non-damaging radiation to photolytically release the therapeutic agent.
  • the drug delivery systems provided by the invention also help avoid the problem of overdosage associated with systemic delivery of drugs, by enabling a controlled amount of a selected therapeutic or diagnostic agent to be directly deposited onto a specific region of tissue.
  • the systems allow for selective delivery of therapeutic or diagnostic agents to vessel walls by using photoactivatable linking agents having differing abso ⁇ tion profiles.
  • the system also solves the problem of drug wash- off or leakage by photoreleasably linking the drug to the exterior of the delivery device.
  • the system further solves the problem of adverse immunogenicity associated with implantable stents, since the catheter is removed immediately following drug delivery.
  • FIG. 1 is an illustration of a photolytic drug delivery device for insertion into a body lumen.
  • FIG. 2 is a schematic illustration of the photolytic release of a bioactive ligand from a polymer-coated surface matrix using a chromophoric linker to sensitize the cleavage reaction.
  • a drug delivery device 10 for photolytic delivery of one or more therapeutic or diagnostic agents to a body lumen wall including inflatable section 25 and a guide wire 14. Also disposed within the device are one or more optical fibers 11 for delivery of radiation 40 which causes photolytic release of the drug or therapeutic agent 12 from the the exterior of the device 25.
  • the optical fibers 11 can be disposed around the central guide wire 14, as shown in FIG. 1.
  • the drug delivery device can also optionally include a diffusive tip 15 and a radio-opaque tip marker 19.
  • the guide wire 14 is first introduced into a body lumen and used to guide the device into position adjacent to an area to be treated, such as a stenotic lesion. As shown in FIG. 1, the inflatable section 25 is then expanded which applies pressure against the surrounding lumen wall 18. If the area being treated is obstructed, expansion of the inflatable section 25 serves to dilate the obstruction. Expansion and contraction of the inflatable section 25 is controlled by an inflation controller 20. In all cases, the inflatable section 25 is expanded so as to be in full contact with the surrounding lumen wall 18.
  • radiation from an irradiation source 30 is delivered via one or more optical fibers 11 which extend through the terminal end of the device 16 into the inflatable section 25.
  • a diffusive radio-opaque tip is attached to the terminal end through which the radiation is delivered and scattered throughout the inflatable section 25.
  • the light delivered through the inflatable section 25 subsequently causes photolytic release of a therapeutic or diagnostic agent 12 bound to the exterior surface of the inflatable section 25, thereby delivering the therapeutic or diagnostic agent to the surrounding lumen wall 18.
  • any medical device may be used in the photolytic drug delivery system of the invention, following modification to include a source of radiation and one or more therapeutic agents photoreleasably linked to its exterior surface.
  • a fiber optic track is inco ⁇ orated through the body of the device 17 so that light can be delivered throughout the interior of the device.
  • the optical fibers 11 may be of any type appropriate to deliver radiation required for photolytic release of the drug from at least a portion of the exterior of the device.
  • the optical fibers 11 are connected to a radiation source 30.
  • the source can be a
  • UV light source which delivers light having a wavelength ranging from about 200 to about 400 nanometers, more preferably from about 240 to about 370 nanometers.
  • the radiation can be provided by a variety of sources, including non-coherent UV light sources and excimer laser sources (e.g., a KrF excimer laser operating at 248 nanometers or an Argon ion laser at 257 or 275 nm.)
  • FIG. 2 a reaction scheme for photolytically releasing a bioactive ligand from a polymer-coated surface matrix using a chromophoric linker to sensitize the cleavage reaction is shown.
  • Attachment of the chromophoric linker and bioactive ligand to the surface matrix of a medical device may be accomplished by way of several methods known in the art (for examples of surface chemistries, coupling reagents, and protecting groups, see e.g. M. Bodanszky, Principles of Peptide Synthesis, 2nd Ed. (1993) and references cited therein).
  • an additional chemical linking or spacing arm may be preferable to achieve the desired chemical stability or loading.
  • the surface matrix of the device may benefit from chemical modification before the chromophoric linker can be attached (for examples of linkers, surface chemistries, and several chromophores, see Grant, G.R., Ed. Synthetic Peptides: A User's Guide (1992), Chapter 3).
  • Methods for derivatization of surfaces are well known in the art.
  • a variety of functional groups for example aminoalkyl, benzhydrylamino, halobenzyl, haloalkyl, phenol, alkoxy or carboxylate groups, can be formed on the surface installed by choice of an appropriate derivative.
  • Somatostatin a growth hormone inhibitor
  • a device for photolytic delivery of somatostatin to a specific region of a body lumen e.g., a stenotic lesion
  • a photoactivatable agent 3-nitro-4-(N- dithiasuccinimido)methyl benzoic acid
  • the drug moiety is then releasably coupled to the photoactivatable moiety.
  • the exterior of the device is first coated with an amino-functionalized polystyrene substrate, using standard techniques.
  • the polystyrene substrate is then derivatized with the 3-nitro-4-(N- dithiasuccinimido)methyl benzoic acid, a protected photoactivatable linking moiety, under standard coupling conditions (see F. Albericio et al., Peptides: Chemistry and Biology: Proceedings of the Tenth American Peptide Symposium, G.R. Marshall, Ed. ESCOM: Leiden (1988), p. 159-161).
  • Somatostatin is then releasably linked to the dithiasuccinimido-protected photoactivatable moiety by removing the dithiasuccinimido group, for example, by reaction with 2-mercaptoethanol and triethylamine for 5 minutes, to yield the free amine.
  • the unprotected benzylamine functionality is then coupled to the carboxy terminal of somatostatin, using the coupling reagent dicyclohexyl-carbodiimide (DCC).
  • the device To photolytically deliver somatostatin to a specific region of a lumen wall, the device is guided through the lumen into a position adjacent to the region. The device is then expanded so as to cause its drug-containing surface to come into contact with the surrounding lumen wall. Following expansion of the device, its interior is irradiated via one or more optical fibers which emit light having a wavelength of approximately 350 nm, thereby activating the benzylamine chromophore on the exterior of the device. Photoactivation of the benzylamine then causes release of the somatostatin (as the C- terminal amide) onto the surrounding lumen wall.
  • Ibuprofen an analgesic agent
  • Ibuprofen has useful antiinflammatory properties and can be used to treat inflammation within a body lumen.
  • a drug-delivery device for photolytic delivery of ibuprofen to a specific region of a body lumen the following procedure can be used.
  • a photoactivatable linking agent 2- nitroaniline
  • Ibuprofen is then releasably linked to the photoactivatable agent.
  • the device is coated with a polystyrene substrate.
  • the polystyrene substrate is then derivatized according to standard protocols (see e.g. Merrifield, R.B. J. Am. Che . Soc. (1962) & > : 2149), to yield the reactive chlorobenzyl derivative.
  • the substrate is reacted with the photoactivatable linking agent, 2- nitroaniline (Amit, B. and Patchomik, A. Tetrahedron Lett. (1973) 24 : 2205), yielding an immobilized chromophore.
  • Ibuprofen is then coupled to the chromophore-containing device under standard conditions using the coupling reagent DCC.
  • the device To photolytically deliver the ibuprofen to a specific region of a lumen wall, the device is guided through the lumen into a position adjacent to the region. The device is then expanded so as to cause its drug-containing surface to come into contact with the surrounding lumen wall. Following expansion of the device, its interior is irradiated via one or more optical fibers which emit light having a wavelength of approximately 350 nm, thereby activating the immobilized 2-nitroaniline chromophore on the exterior of the device. Photoactivation of the 2-nitroaniline then causes release of the ibuprofen onto the surrounding lumen wall.
  • Lovastatin an inhibitor of HMG-CoA reductase
  • a drug-delivery device which achieves this goal by photolytically delivering lovastatin to a specific region of a body lumen wall can be prepared according to the following procedure. In this procedure, the drug and a photoactivatable linking agent. 2- (p-chlorosulfonyl)phenyl t-butyl acetate, are first coupled together. The drug-linker conjugate is then coupled to the surface of a device containing a light source to yield a complete drug delivery system.
  • the conjugate is linked to the surface of a device containing a light source, as follows:
  • the device is coated with a poly(acrylic acid) substrate using standard techniques.
  • the polymer is then reacted with ethylenediamine (which functions as a linking or spacing arm) in the presence of a coupling reagent such as DCC or benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) to yield an amine- functionalized polymer substrate.
  • a coupling reagent such as DCC or benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP)
  • the device To photolytically deliver the lovastatin to a specific region of a lumen wall, the device is guided through the lumen into a position adjacent to the region. The device is then expanded so as to cause its drug-containing surface to come into contact with the surrounding lumen wall. Following expansion of the device, its interior is irradiated via one or more optical fibers which emit light having a wavelength of approximately 300 nm, thereby activating the sulfonate chromophore on the exterior of the device. Photoactivation of the arylsulfonate then causes release of the lovastatin onto the surrounding lumen wall.

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  • Medicinal Preparation (AREA)

Abstract

L'invention concerne la libération photolytique d'un agent thérapeutique ou diagnostique depuis la surface d'un appareil permettant de libérer les médicaments sur un site spécifique du corps tel que la paroi des lumières. En particulier, l'agent thérapeutique peut être lié de sorte qu'il soit photolibérable, à un substrat polymère prévu à l'extérieur du dispositif de libération par l'intermédiaire d'un agent de liaison photosensible, tel qu'un chromophore. Lorsqu'il est exposé à un rayonnement, de préférence à un rayonnement ultraviolet ayant une longueur d'onde comprise environ entre 240 et 370 nanomètres, l'agent de liaison photosensible libère l'agent thérapeutique depuis la surface du dispositif pour l'administrer sur les parois des lumières environnantes. Ledit système permet la libération locale modulée sur un site spécifique de médicaments, de chromophores et d'acides nucléiques sur les parois de différentes lumières du corps telles que les vaisseaux sanguins, avec peu ou pas de dommages subis par les tissus périphériques.
PCT/US1996/001333 1995-01-30 1996-01-30 Systemes de liberation de medicaments photolytique WO1996023543A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU46590/96A AU4659096A (en) 1995-01-30 1996-01-30 Photolytic drug delivery systems

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US38221295A 1995-01-30 1995-01-30
US08/382,212 1995-01-30
US46281695A 1995-06-05 1995-06-05
US08/462,816 1995-06-05

Publications (1)

Publication Number Publication Date
WO1996023543A1 true WO1996023543A1 (fr) 1996-08-08

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/001333 WO1996023543A1 (fr) 1995-01-30 1996-01-30 Systemes de liberation de medicaments photolytique

Country Status (2)

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AU (1) AU4659096A (fr)
WO (1) WO1996023543A1 (fr)

Cited By (24)

* Cited by examiner, † Cited by third party
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EP0751796A1 (fr) * 1994-03-16 1997-01-08 Arnold W. Lindall Systeme de catheter pour la liberation regulable d'un agent therapeutique sur un site tissulaire eloigne
WO2001087416A1 (fr) * 2000-05-17 2001-11-22 Kent Crossley Procede et dispositif servant a empecher des infections
WO2001035867A3 (fr) * 1999-11-19 2001-12-06 Hampp Norbert Implant ophtalmologique
EP1210146A1 (fr) * 1999-06-23 2002-06-05 Robert A. Ganz Appareil et procede permettant d'affaiblir ou de detruire des micro-organismes dans un corps
US6537195B2 (en) 2001-05-07 2003-03-25 Xoft, Microtube, Inc. Combination x-ray radiation and drug delivery devices and methods for inhibiting hyperplasia
WO2005058407A1 (fr) * 2003-12-16 2005-06-30 Inomicrotec Ltd Methode et dispositif permettant de liberer des substances chimiques et biologiques de façon controlee au moyen de reactions photochimiques
WO2006019848A1 (fr) * 2004-07-21 2006-02-23 Boston Scientific Scimed, Inc. Revêtements anti-infectieux activés par ultrasons et dispositifs réalisés à partir de ceux-ci
US7018371B2 (en) 2001-05-07 2006-03-28 Xoft, Inc. Combination ionizing radiation and radiosensitizer delivery devices and methods for inhibiting hyperplasia
WO2008065464A2 (fr) * 2006-11-28 2008-06-05 Universita' Degli Studi Di Padova Méthode pour aérostase pulmonaire et dispositif de mise en oeuvre de cette méthode
WO2010119906A1 (fr) * 2009-04-14 2010-10-21 日産化学工業株式会社 Dérivés d'haloalkylsulfonanilide
WO2012004399A1 (fr) * 2010-07-09 2012-01-12 Photocure Asa Compositions sèches et dispositifs les contenant destinés à être utilisés dans la thérapie photodynamique ou le diagnostic photodynamique
US8164074B2 (en) 2007-10-18 2012-04-24 The Invention Science Fund I, Llc Ionizing-radiation-responsive compositions, methods, and systems
US8168958B2 (en) 2007-10-18 2012-05-01 The Invention Science Fund I, Llc Ionizing-radiation-responsive compositions, methods, and systems
US8227204B2 (en) 2007-10-18 2012-07-24 The Invention Science Fund I, Llc Ionizing-radiation-responsive compositions, methods, and systems
US8492339B2 (en) 2009-10-26 2013-07-23 Empire Technology Development Llc Angiogenesis promoted by caged growth factors
US8529426B2 (en) 2007-10-18 2013-09-10 The Invention Science Fund I Llc Ionizing-radiation-responsive compositions, methods, and systems
US8684898B2 (en) 2007-10-18 2014-04-01 The Invention Science Fund I Llc Ionizing-radiation-responsive compositions, methods, and systems
US8883503B2 (en) 2011-06-23 2014-11-11 Indian Institute Of Technology Kanpur Hydrogel scaffolds for tissue engineering
US9271928B2 (en) 2008-06-06 2016-03-01 The Queen's University Of Belfast Drug delivery composition
US9557635B2 (en) 2007-10-18 2017-01-31 Gearbox, Llc Ionizing-radiation-responsive compositions, methods, and systems
ITUA20163654A1 (it) * 2016-05-02 2017-11-02 Andrea Cusano Dispositivo per il rilascio controllato di molecole indotto da luce mediante fibra ottica
US9974974B2 (en) 2013-04-09 2018-05-22 Photocure Asa Irradiation device
US10874875B2 (en) 2009-01-12 2020-12-29 Photocure Asa Irradiation device
EP3930820A4 (fr) * 2019-03-01 2022-12-14 Alucent Biomedical, Inc. Appareil et procédés pour restaurer un tissu

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US5125925A (en) * 1988-08-03 1992-06-30 Photoradiation Systems Intracavity laser catheter with sensing fiber
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EP0567788A1 (fr) * 1992-04-02 1993-11-03 Indiana University Foundation Méthode et appareillage pour délivrer un médicament par voie intravasculaire
WO1994009826A2 (fr) * 1992-10-30 1994-05-11 Medipro Sciences Limited Systemes de liberation de medicaments caracterises par une liaison photolabile

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0751796A1 (fr) * 1994-03-16 1997-01-08 Arnold W. Lindall Systeme de catheter pour la liberation regulable d'un agent therapeutique sur un site tissulaire eloigne
EP0751796A4 (fr) * 1994-03-16 1998-12-09 Arnold W Lindall Systeme de catheter pour la liberation regulable d'un agent therapeutique sur un site tissulaire eloigne
EP1210146A4 (fr) * 1999-06-23 2009-06-03 Lumerx Inc Appareil et procede permettant d'affaiblir ou de detruire des micro-organismes dans un corps
EP1210146A1 (fr) * 1999-06-23 2002-06-05 Robert A. Ganz Appareil et procede permettant d'affaiblir ou de detruire des micro-organismes dans un corps
WO2001035867A3 (fr) * 1999-11-19 2001-12-06 Hampp Norbert Implant ophtalmologique
US6551346B2 (en) 2000-05-17 2003-04-22 Kent Crossley Method and apparatus to prevent infections
WO2001087416A1 (fr) * 2000-05-17 2001-11-22 Kent Crossley Procede et dispositif servant a empecher des infections
US6537195B2 (en) 2001-05-07 2003-03-25 Xoft, Microtube, Inc. Combination x-ray radiation and drug delivery devices and methods for inhibiting hyperplasia
US7018371B2 (en) 2001-05-07 2006-03-28 Xoft, Inc. Combination ionizing radiation and radiosensitizer delivery devices and methods for inhibiting hyperplasia
US7041046B2 (en) 2001-05-07 2006-05-09 Xoft, Inc. Combination ionizing radiation and immunomodulator delivery devices and methods for inhibiting hyperplasia
WO2005058407A1 (fr) * 2003-12-16 2005-06-30 Inomicrotec Ltd Methode et dispositif permettant de liberer des substances chimiques et biologiques de façon controlee au moyen de reactions photochimiques
WO2006019848A1 (fr) * 2004-07-21 2006-02-23 Boston Scientific Scimed, Inc. Revêtements anti-infectieux activés par ultrasons et dispositifs réalisés à partir de ceux-ci
US7356368B2 (en) 2004-07-21 2008-04-08 Boston Scientific Scimed, Inc. Light-activated anti-infective coatings and devices made thereof
WO2008065464A2 (fr) * 2006-11-28 2008-06-05 Universita' Degli Studi Di Padova Méthode pour aérostase pulmonaire et dispositif de mise en oeuvre de cette méthode
WO2008065464A3 (fr) * 2006-11-28 2008-09-04 Univ Padova Méthode pour aérostase pulmonaire et dispositif de mise en oeuvre de cette méthode
US8168958B2 (en) 2007-10-18 2012-05-01 The Invention Science Fund I, Llc Ionizing-radiation-responsive compositions, methods, and systems
US8529426B2 (en) 2007-10-18 2013-09-10 The Invention Science Fund I Llc Ionizing-radiation-responsive compositions, methods, and systems
US8164074B2 (en) 2007-10-18 2012-04-24 The Invention Science Fund I, Llc Ionizing-radiation-responsive compositions, methods, and systems
US9557635B2 (en) 2007-10-18 2017-01-31 Gearbox, Llc Ionizing-radiation-responsive compositions, methods, and systems
US8227204B2 (en) 2007-10-18 2012-07-24 The Invention Science Fund I, Llc Ionizing-radiation-responsive compositions, methods, and systems
US8684898B2 (en) 2007-10-18 2014-04-01 The Invention Science Fund I Llc Ionizing-radiation-responsive compositions, methods, and systems
US9271928B2 (en) 2008-06-06 2016-03-01 The Queen's University Of Belfast Drug delivery composition
US10874875B2 (en) 2009-01-12 2020-12-29 Photocure Asa Irradiation device
JP5741429B2 (ja) * 2009-04-14 2015-07-01 日産化学工業株式会社 ハロアルキルスルホンアニリド誘導体
WO2010119906A1 (fr) * 2009-04-14 2010-10-21 日産化学工業株式会社 Dérivés d'haloalkylsulfonanilide
EP2493572A4 (fr) * 2009-10-26 2015-06-03 Empire Technology Dev Llc Angiogenèse favorisée par des facteurs de croissance bloqués
US8492339B2 (en) 2009-10-26 2013-07-23 Empire Technology Development Llc Angiogenesis promoted by caged growth factors
WO2012004399A1 (fr) * 2010-07-09 2012-01-12 Photocure Asa Compositions sèches et dispositifs les contenant destinés à être utilisés dans la thérapie photodynamique ou le diagnostic photodynamique
US8883503B2 (en) 2011-06-23 2014-11-11 Indian Institute Of Technology Kanpur Hydrogel scaffolds for tissue engineering
US9974974B2 (en) 2013-04-09 2018-05-22 Photocure Asa Irradiation device
US10663655B2 (en) 2016-02-05 2020-05-26 Centro Regionale Information E Communication Technology—Cerict S.C.R.L. Optical fiber and device for releasing molecules
ITUA20163654A1 (it) * 2016-05-02 2017-11-02 Andrea Cusano Dispositivo per il rilascio controllato di molecole indotto da luce mediante fibra ottica
JP2019514892A (ja) * 2016-05-02 2019-06-06 アンナ アリベルティ 分子を放出する光ファイバーおよび装置
CN109475643A (zh) * 2016-05-02 2019-03-15 安娜·阿丽贝尔蒂 光学纤维和用于释放分子的装置
WO2017191552A1 (fr) * 2016-05-02 2017-11-09 Aliberti Anna Fibre optique et dispositif de libération de molécules
EP3930820A4 (fr) * 2019-03-01 2022-12-14 Alucent Biomedical, Inc. Appareil et procédés pour restaurer un tissu

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