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WO2003007798A2 - Utilisation de 5 fluorourcil, administre par iontophorese en tant qu'inhibiteur de la proliferation cellulaire dans l'oeil, la conjonctive bulbaire et palpebrale, la paupiere, les tissus mous et la peau periorbitaires - Google Patents

Utilisation de 5 fluorourcil, administre par iontophorese en tant qu'inhibiteur de la proliferation cellulaire dans l'oeil, la conjonctive bulbaire et palpebrale, la paupiere, les tissus mous et la peau periorbitaires Download PDF

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Publication number
WO2003007798A2
WO2003007798A2 PCT/US2002/022860 US0222860W WO03007798A2 WO 2003007798 A2 WO2003007798 A2 WO 2003007798A2 US 0222860 W US0222860 W US 0222860W WO 03007798 A2 WO03007798 A2 WO 03007798A2
Authority
WO
WIPO (PCT)
Prior art keywords
living subject
based medicament
ocular
approximately
uracil based
Prior art date
Application number
PCT/US2002/022860
Other languages
English (en)
Other versions
WO2003007798A3 (fr
Inventor
Stephen Warren
Steven Hamilton
Original Assignee
Iomed, Inc.
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 Iomed, Inc. filed Critical Iomed, Inc.
Priority to AU2002316724A priority Critical patent/AU2002316724A1/en
Priority to EP02747054A priority patent/EP1418919A4/fr
Priority to JP2003513412A priority patent/JP2004535462A/ja
Publication of WO2003007798A2 publication Critical patent/WO2003007798A2/fr
Publication of WO2003007798A3 publication Critical patent/WO2003007798A3/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/20—Applying electric currents by contact electrodes continuous direct currents
    • A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates in general to methods for treating neoplastic, angiogenic, fibroblastic, and/or immunosuppressive ocular irregularities, and more particularly, to methods for treating the same via administration of one or more 5' fluorouracil based medicament(s) which are capable of acting as an inliibitor of DNA synthesis, and blocking the proliferation of multiple types of neoplastic cells, including malignant and non-malignant lesions.
  • the present invention further relates to the controlled administration of 5' fluorouracil based medicaments to an affected area of a living subject's eye.
  • 5' fluorouracil based medicaments have been known in the art for years, and have been shown to possess anti-neoplastic, anti-angiogenic, anti-fibroblastic, and/or immunosuppressive activities. While administering 5' fluorouracil based medicaments have been identified as a promising remedy to treat many of the above-identified irregularities, delivering 5' fluorouracil based medicaments to an affected area of a living subject's eye has remained heretofore largely problematic. Indeed, known prior art methods of administering 5' fluorouracil based medicaments, identified hereinbelow, are replete with substantial drawbacks and/or life threatening complications.
  • delivering 5' fluorouracil based medicaments to an affected, local area of a living subject's eye using a systemic delivery method is problematic because of the many severe, sometimes life threatening, side effects associated with systemic delivery of 5' fluorouracil based medicaments, such as, for examples, hepatitis, liver fibrosis, cirrhosis, leukopenia (bone marrow suppression), mucositis, ulcerative stomatitis, skin rash, nausea, abdominal distress, malaise, fatigue, chills and fever, diarrhea, gastrointestinal ulceration or perforation, pancreatitis, pericarditis, hypotension, deep venous thrombosis, thrombophlebitis, interstitial pneumonitis, headaches, drowsiness, cognitive dysfunction, reduced immunity, rash, photosensitivity, nephropathy, hematuria, alopecia, defective oogenesis, oligospermia, infertility, mis
  • Topical administration of 5' fluorouracil based medicaments to an affected, local area of a living subject's eye is problematic due to its ineffectiveness for many applications, including affected areas in the back of the eye.
  • the present invention is directed to a method for treating neoplastic, angiogenic, fibroblastic, and/or immunosuppressive ocular irregularities of a living subject comprising the steps of: (a) providing a living subject, wherein the living subject includes an affected ocular area having a neoplastic, angiogenic, fibroblastic, and/or immunosuppressive irregularity; (b) providing a 5' fluorouracil based medicament, wherein the 5' fluorouracil based medicament is capable of inhibiting DNA synthesis; (c) associating a therapeutically effective concentration of the 5' fluorouracil based medicament with the affected ocular area of the living subject; and (d) decreasing the neoplastic, angiogenic, fibroblastic, and/or immunosuppressive ocular irregularity of the living subject.
  • the step of providing a 5' fluorouracil based medicament includes the step of providing
  • R,. 3 are the same or different and comprise H, NH 2 , a hydroxy group, a straight or branched alkyl, cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl, alkaryl, aralkyl, alkoxy, alkenyl, alkynyl group containing approximately 1 to approximately 25 carbon atom(s), a silyl or siloxyl group containing approximately 1 to approximately 25 silicon atom(s), and combinations thereof, wherein X comprises F, Cl, Br, I, At, and/or any -1 monoatomic or polyatomic anion; wherein Y,. 2 comprises N or P; and wherein Z,_, comprises O or S.
  • the step of providing a fluoro5' fluorouracil based medicament includes the step of providing a medicament represented by the following chemical structure:
  • the step of associating a therapeutically effective concentration of the 5' fluorouracil based medicament with the living subject includes the step of ocular iontophoretic delivery of the medicament in a concentration ranging from approximately 0.5 to approximately 50 mg/'mL per day for approximately 1 to approximately 30 days.
  • the present invention is also directed to a method for treating an affected area of a living subject's eye, comprising the steps of: (a) associating a 5' fluorouracil based medicament with an ocular iontophoretic device; (b) positioning at least a portion of the ocular iontophoretic device on the eye of a living subject; and (c) iontophoretically delivering the 5 'fluorouracil based medicament to an affected area of the living subject's eye.
  • the step of associating the 5' fluorouracil based medicament includes the step of associating a 5' fluorouracil based medicament capable of decreasing neoplastic, angiogenic, fibroblastic, and/or immunosuppressive ocular irregularities of the living subject.
  • the step of iontophoretically delivering the 5' fluorouracil based medicament includes delivering the same to ' at least one of the group consisting of the sclera, ciliary body, iris, lens, cornea, aqueous fluid, vitreous body, retina, choroids, optic nerve, and regions of the eye thereabout.
  • the step of iontophoretically delivering the 5' fluorouracil based medicament may include the step of iontophoretically delivering the 5' fluorouracil medicament using a negative polarity current between approximately 0.5 mA and approximately 5 mA for a period of between approximately 1 and approximately 60 minutes.
  • the present invention is further directed to an ocular iontophoretic device for delivering a 5' fluorouracil based medicament to an affected area of a living subject's eye, comprising an active electrode assembly associated with a matrix, wherein the matrix includes a 5' fluorouracil based medicament capable of decreasing neoplastic, angiogenic, fibroblastic, and/or immunosuppressive ocular irregularities of the living subject.
  • the ocular iontophoretic device further comprises: (a) a counter electrode assembly, wherein the counter electrode assembly is configured for completing an electrical circuit between the active electrode assembly and an energy source; and (b) an energy source for generating an electrical potential difference.
  • the active electrode assembly may include an open-faced or high current density electrode.
  • the present invention is also directed to an ocular iontophoretic device for delivering a 5' fluorouracil based medicament to an affected area of a living subject's eye, comprising: (a) a matrix, wherein the matrix is capable of temporarily retaining a solution having a 5' fluorouracil based medicament capable of decreasing neoplastic, angiogenic, fibroblastic, and/or immunosuppressive ocular irregularities of the living subject; (b) an active electrode assembly associated with the matrix, wherein the active electrode assembly is configured for iontophoretically delivering the 5' fluorouracil based medicament to the affected area of the living subject's eye; (c) a counter electrode assembly, wherein the counter electrode assembly is configured for completing an electrical circuit between the active electrode assembly and an energy source; and (d) an energy source for generating an electrical potential difference.
  • the present invention further includes an ocular iontophoretic device for delivering a 5' fluorouracil based medicament to an affected area of a living subject's eye, comprising: (a) a reservoir, wherein the reservoir includes a 5' fluorouracil based medicament capable of decreasing neoplastic, angiogenic, fibroblastic, and/or immunosuppressive ocular irregularities of the living subject; (b) a matrix, wherein the matrix is capable of temporarily retaining a solution having a 5' fluorouracil based medicament; (c) an active electrode assembly associated with the matrix, wherein the active electrode assembly is configured for iontophoretically delivering the 5' fluorouracil based medicament to the affected area of the living subject's eye; (d) a counter electrode assembly, wherein the counter electrode assembly is configured for completing an electrical circuit between the active electrode assembly and an energy source; and (e) an energy source for generating an electrical potential difference.
  • Fig. 1 of the drawings is a cross-sectional schematic representation of a first embodiment of an ocular iontophoretic device fabricated in accordance with the present invention
  • Fig. 2 of the drawings is a cross-sectional schematic representation of a first embodiment of an ocular iontophoretic device fabricated in accordance with the present invention showing the association of a counter electrode assembly and an energy source;
  • Fig. 3 of the drawings is a cross-sectional schematic representation of a second embodiment of an ocular iontophoretic device fabricated in accordance with the present invention.
  • a first embodiment of an ocular iontophoretic device 10 is shown, which generally comprises active electrode assembly 12 and matrix 14. It will be understood that Fig. 1 is merely a cross-sectional schematic representation of ocular iontophoretic device 10. As such, some of the components have been distorted from their actual scale for pictorial clarity.
  • ocular iontophoretic device 10 is configured for delivering one or more 5' fluorouracil based medicament(s) which are capable of acting as an inliibitor of DNA, and, therefore, treating, among other things, neoplastic, angiogenic, fibroblastic, and/or immunosuppressive ocular irregularities.
  • 5' fluorouracil based medicament capable of acting as an inliibitor of DNA, and, therefore, treating, among other things, neoplastic, angiogenic, fibroblastic, and/or immunosuppressive ocular irregularities.
  • Ocular iontophoretic device 10 offers many advantages over the previously discussed prior art devices and associated delivery methods, including, but not limited to, simultaneous enablement of non-invasive and deep 5 ' fluorouracil based medicament delivery, non-invasive local delivery of an effective, therapeutic level of 5' fluorouracil based medicament while minimizing systemic concentrations, and enablement of, for example, sclera loading for prolonged delivery (of controlled, sometimes, low concentrations of medicaments) into regions in the back of the eye.
  • Active electrode assembly 12 generally comprises a conductive material, which upon application of an electrical potential difference thereto, drives an ionic 5' fluorouracil based medicament (i.e. an anionic medicament), received from matrix 14 and delivers the 5' fluorouracil based medicament into predetermined tissues and surrounding structures of a living subject's eye.
  • active electrode assembly 12 may comprise an anode or a cathode depending upon whether the medicament is cationic or anionic in form.
  • active electrode assembly may include an open-faced or high current density electrode.
  • any one of a number of conventional active electrode assemblies are contemplated for use in accordance with the present invention.
  • the only contemplated limitation relative to active electrode assembly 12 is that it must be geometrically and compositionally compatible for ocular applications of living subjects, most relevantly, humans.
  • Matrix 14 extends contiguously from active electrode 12, and is preferably fabricated from a material capable of temporarily retaining 5' fluorouracil based medicament 16 in solution.
  • the solution may also contain supplemental agents, such as electrolytes, stability additives, medicament preserving additives, pH regulating buffers, etc.
  • Matrix 14 may comprise, for example, a natural or synthetic amorphous member, a natural or synthetic sponge pad, a natural or synthetic lint free pad, a natural or synthetic low particulate member - just to name a few. Indeed, numerous other materials that would be known to those having ordinary skill in the art having the present disclosure before them are likewise contemplated for use.
  • active electrode assembly 12 the only contemplated limitation relative to matrix 14 is that it must be geometrically and compositionally compatible for ocular applications of living beings, most relevantly, humans.
  • Medicament 16 is retained within matrix 14.
  • ionic medicament 16 comprises one or more 5' fluorouracil based medicament(s) which are capable of treating, among other things, neoplastic, angiogenic, fibroblastic, and/or immunosuppressive ocular irregularities.
  • 5' fluorouracil based medicaments may be represented by the following chemical structure:
  • R N3 are the same or different and comprise H, NH 2 , a hydroxy group, a straight or branched alkyl, cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl, alkaryl, aralkyl, alkoxy, alkenyl, alkynyl group containing approximately 1 to approximately 25 carbon atom(s), a silyl or siloxyl group containing approximately 1 to approximately 25 silicon atom(s), and combinations thereof; and the . pharmaceutically acceptable acid addition salts thereof.
  • the availability of 5' fluorouracil medicaments will be readily l ⁇ iown to those having ordinary skill in the art, and that derivatives thereof may be obtained using conventional organic synthetic routes.
  • the 5' fluorouracil based medicament may comprise the chemical structure:
  • ocular iontophoretic device 10 may also include counter electrode assembly 18 and energy source 20.
  • Counter electrode assembly 18 may be housed within ocular iontophoretic device 10, or alternatively, may be remotely associated with ocular iontophoretic device 10 via conventional electrical conduit.
  • Counter electrode assembly 18 is configured for completing an electrical circuit between active electrode assembly 12 and energy source 20.
  • counter electrode 18 may comprise an anode or a cathode depending upon whether the medicament is cationic or anionic in form.
  • any one of a number of counter electrodes are contemplated for use in accordance with the present invention.
  • energy source 20 may be housed within ocular iontophoretic device 10, or alternatively, may be remotely associated with ocular iontophoretic device 10 via conventional electrical conduit.
  • Energy source 20 preferably supplies low voltage constant direct current between approximately 0.5 milliamps (mA) and approximately 5 mA for generating an electrical potential difference.
  • the energy source may also provide for an initial higher voltage during current ramp-up to break down higher initial tissue resistance as in commercial power supply units used for transdermal iontophoresis.
  • energy source 20 may include one or more primary or secondary electrochemical cells. While specific examples of energy source 20 have been disclosed, for illustrative purposes only, it will be understood that other energy sources l ⁇ iown to those having ordinary skill in the art having the present disclosure before them are likewise contemplated for use.
  • an ocular iontophoretic device 100 which generally comprises active electrode assembly 112, matrix 114, reservoir 115, counter electrode assembly 118, and energy source 120. It will be understood that active electrode assembly 112, matrix 114, counter electrode assembly 118, and energy source 120, are configured analogously to previously discussed active electrode assembly 12, matrix 14, counter electrode assembly 18, and energy source 20, respectively.
  • Ocular iontophoretic device 100 is configured for delivering a 5' fluorouracil based medicament to an affected area of a living subject's eye for treating neoplastic, angiogenic, fibroblastic, and/or immunosuppressive ocular irregularities.
  • Reservoir 115 includes 5' fluorouracil based medicament 116, in solution, which is capable of treating the above-identified ocular irregularities.
  • Reservoir 115 may include a releasable cover member 117 which, upon articulation, releases 5' fluorouracil based medicament 116 into matrix 114. Such a release cover enables prompt delivery of the-5' fluorouracil based medicament with very little device preparation.
  • the present invention is also directed to a method for treating an affected area of a living subject's eye comprising the following steps. First, a 5' fluorouracil based medicament is associated with an ocular iontophoretic device.
  • the 5' fluorouracil based medicament is metered from a syringe or single unit dose.
  • the ocular iontophoretic device is positioned on the eye of a living being.
  • the 5' fluorouracil based medicament is iontophoretically delivered to an affected area of the living subject's eye.
  • the delivery lasts for between approximately 1 and approximately 60 minutes.
  • the present invention enables a generally painless, non-invasive, and deep delivery of the 5' fluorouracil based medicament.
  • the 5' fluorouracil based medicament is locally delivered to an affected area of a living subject's eye at an effective, therapeutic level.
  • Preferred ocular delivery regions include the sclera, ciliary body, iris, lens, cornea, aqueous fluid, vitreous body, retina, choroids, optic nerve, and regions of the eye thereabout.
  • neoplastic, angiogenic, fibroblastic, and/or immunosuppressive ocular irregularities of a living subject can also be treated in accordance with the following method.
  • a living subject with a neoplastic, angiogenic, fibroblastic, and/or immunosuppressive irregularity is provided.
  • one or more of the above-identified 5' fluorouracil based medicaments is provided.
  • a therapeutically effective concentration of the 5' fluorouracil based medicament is associated with and/or administered to the affected ocular area of the living subject.
  • the 5' fluorouracil based medicament is administered in a concentration ranging from approximately 0.5 to approximately 50 mg/mL.
  • the duration of a single application may range from 1 minute to approximately 60 minutes.
  • the medicament may be administered on a schedule ranging from once every day to once every 30 days.
  • the duration of 5' fluorouracil based therapy may range from a single application to multiple applications that are administered over a period of months to years, depending upon the disease being treated.
  • the neoplastic, angiogenic, fibroblastic, and/or immunosuppressive ocular irregularity. -of the living subject is materially decreased.
  • 5' fluorouracil is dissolved in a balanced saline solution, for example, sodium chloride (e.g. 0.25 to 0.9% w/v).
  • the solution may be buffered with other salts, such as phosphate, carbonate, or citrate.
  • the pH is adjusted to a value between 4.0 and 9.0, preferably pH 7.5, using NaOH or HC1.
  • the final concentration of 5' fluorouracil is between 0.5 and 50 mg/mL.
  • Iontophoretic current is applied at 1.0 to 4.0 milliamperes for 1 to 60 minutes. It will be understood to those having ordinary skill in the art that the previously identified formulation, although being preferred, is not the only formulation which can be used.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Radiology & Medical Imaging (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Electrotherapy Devices (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une méthode permettant de traiter des irrégularités oculaires néoplasiques, angiogéniques, fibroplastiques et/ou immuno-suppressives chez un sujet vivant. Cette méthode consiste : à prendre un sujet vivant dont une zone oculaire présente une irrégularité néoplasique, angiogénique, fibroplastique et/ou immuno-suppressive ; à utiliser un médicament à base de 5' fluorouracil qui est capable d'inhiber la synthèse de l'ADN ; à associer une concentration efficace du point de vue thérapeutique du médicament à base de 5' fluorouracil avec la zone oculaire affectée du sujet vivant ; enfin, à réduire l'irrégularité néoplasique, angiogénique, fibroplastique et/ou immuno-suppressive du sujet vivant.
PCT/US2002/022860 2001-07-20 2002-07-19 Utilisation de 5 fluorourcil, administre par iontophorese en tant qu'inhibiteur de la proliferation cellulaire dans l'oeil, la conjonctive bulbaire et palpebrale, la paupiere, les tissus mous et la peau periorbitaires WO2003007798A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU2002316724A AU2002316724A1 (en) 2001-07-20 2002-07-19 Ophthalmic use of 5 fluorourcil
EP02747054A EP1418919A4 (fr) 2001-07-20 2002-07-19 Utilisation de 5 fluorourcil, administre par iontophorese en tant qu'inhibiteur de la proliferation cellulaire dans l'oeil, la conjonctive bulbaire et palpebrale, la paupiere, les tissus mous et la peau periorbitaires
JP2003513412A JP2004535462A (ja) 2001-07-20 2002-07-19 眼、眼球結膜、眼瞼結膜、瞼、眼窩周囲の軟組織及び皮膚の細胞増殖阻害剤として、イオン導入によって送達する５−フルオロウラシルの使用方法。

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US30678801P 2001-07-20 2001-07-20
US60/306,788 2001-07-20

Publications (2)

Publication Number Publication Date
WO2003007798A2 true WO2003007798A2 (fr) 2003-01-30
WO2003007798A3 WO2003007798A3 (fr) 2003-06-19

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PCT/US2002/022860 WO2003007798A2 (fr) 2001-07-20 2002-07-19 Utilisation de 5 fluorourcil, administre par iontophorese en tant qu'inhibiteur de la proliferation cellulaire dans l'oeil, la conjonctive bulbaire et palpebrale, la paupiere, les tissus mous et la peau periorbitaires

Country Status (4)

Country Link
EP (1) EP1418919A4 (fr)
JP (1) JP2004535462A (fr)
AU (1) AU2002316724A1 (fr)
WO (1) WO2003007798A2 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6245759B1 (en) * 1999-03-11 2001-06-12 Merck & Co., Inc. Tyrosine kinase inhibitors

Family Cites Families (7)

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Publication number Priority date Publication date Assignee Title
JP2889024B2 (ja) * 1991-08-28 1999-05-10 帝人株式会社 イオントフォレシス用装置
US5298017A (en) * 1992-12-29 1994-03-29 Alza Corporation Layered electrotransport drug delivery system
FR2773320B1 (fr) * 1998-01-05 2000-03-03 Optisinvest Dispositif pour le transfert intraoculaire de produits actifs par iontophorese
IL123290A (en) * 1998-02-13 2001-12-23 Hadasit Med Res Service Iontophoretic device
MXPA01008729A (es) * 1999-03-02 2003-06-24 Vitreo Retinal Technologies In Agentes para administracion intravitrea para tratar o prevenir desordenes del ojo.
US6477410B1 (en) * 2000-05-31 2002-11-05 Biophoretic Therapeutic Systems, Llc Electrokinetic delivery of medicaments
JP2004537551A (ja) * 2001-07-20 2004-12-16 イオメド インコーポレイテッド メトトレキサートに基づく薬剤を投与することによって腫瘍性、血管原性、繊維芽細胞性及び／又は免疫抑制性眼球異常を治療する方法及びメトトレキサートに基づく薬剤を送達するための眼球イオン導入装置。

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6245759B1 (en) * 1999-03-11 2001-06-12 Merck & Co., Inc. Tyrosine kinase inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1418919A2 *

Also Published As

Publication number Publication date
WO2003007798A3 (fr) 2003-06-19
JP2004535462A (ja) 2004-11-25
EP1418919A4 (fr) 2007-06-13
AU2002316724A1 (en) 2003-03-03
EP1418919A2 (fr) 2004-05-19

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