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WO1992000106A2 - Methode de traitement et compositions utilisees a cet effet - Google Patents

Methode de traitement et compositions utilisees a cet effet Download PDF

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Publication number
WO1992000106A2
WO1992000106A2 PCT/GB1991/001044 GB9101044W WO9200106A2 WO 1992000106 A2 WO1992000106 A2 WO 1992000106A2 GB 9101044 W GB9101044 W GB 9101044W WO 9200106 A2 WO9200106 A2 WO 9200106A2
Authority
WO
WIPO (PCT)
Prior art keywords
compound
tissue
infra red
radiation
wavelength
Prior art date
Application number
PCT/GB1991/001044
Other languages
English (en)
Other versions
WO1992000106A3 (fr
Inventor
Anthony Raven
Christopher John Stanley
Original Assignee
Diomed Limited
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 Diomed Limited filed Critical Diomed Limited
Priority to EP91911771A priority Critical patent/EP0536211A1/fr
Priority to AU81926/91A priority patent/AU8192691A/en
Publication of WO1992000106A2 publication Critical patent/WO1992000106A2/fr
Publication of WO1992000106A3 publication Critical patent/WO1992000106A3/fr

Links

Classifications

    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent

Definitions

  • the present invention relates to a method of selectively removing tissue material from a human or animal body, and to a compound and composition for use in such a method.
  • Such known methods of laser treatment are, however, problematic insofar as they are unselective in respect of the tissue that is destroyed by the laser light.
  • high powers of irradiation are required to cause the vaporization of tissue material.
  • Such high power radiation will destroy healthy as well as unhealthy tissue with which it comes into contact.
  • Some selectivity can be introduced in surface applications by focusing the laser radiation onto the area of interest or non-surface applications by introducing the laser radiation through an optical fibre.
  • locating unhealthy tissue is difficult and, once located, ablation of the unhealthy tissue requires high power levels.
  • there is no selectivity between healthy and unhealthy tissue material This is a problem at the boundary between healthy and unhealthy tissue and especially when the laser radiation has to pass through healthy tissue material before reaching the unhealthy tissue material.
  • the present invention provides a method of selectively removing tissue material from a human or animal body, which method
  • SUBSTITUTE SHEET comprises:
  • the compound which is highly absorbent of such infra red radiation may be any such compound that is soluble in water or "soluble” in serum (by “soluble” in serum it is meant that the compound is capable of binding to serum proteins which may transport it to the appropriate site; such compounds need not be fully water soluble) .
  • Suitable compounds are dyes capable of absorbing near infra red radiation such as polymethine dyes which are soluble in water or bind readily to proteins. Examples of suitable polymethine dyes are:
  • ICG indocyanine green
  • ICG indocyanine green
  • ICG indocyanine green
  • ICG strongly absorbs infra red radiation at wavelengths of 780-820 nm.
  • ICG is clinically proven, non-toxic and is safe.
  • Such a compound has a strong IR absorbance at 805nm and also fluoresces under IR irradiation.
  • Fig. 1 shows an absorption spectrum of normal serum containing 5mg/l of ICG; the marked absorption peak at around 805nm is apparent. This coincides with the wavelength region over which normal tissue has its minimum absorbance, as exemplified in the rat liver in the Table above and as shown in the increased reflectance of human skin in this range (see Fig. 2) .
  • Such a "window" is advantageous since the peak of absorbance for ICG corresponds to a trough of absorbance for normal body tissue, thus maximizing the ablation of unhealthy tissue whilst minimizing the destruction of healthy tissue.
  • Suitable compounds will preferably have an absorption coefficient of at least 0.5cm '1 , more preferably 0.5 to 10 cm '1 for infra red radiation of wavelength 750 to 860nm.
  • suitable infra red absorbing compounds include chlorophyll and other porphyrin or haeme- containing compounds, or compounds containing a polyene structure, all of which must be capable of strongly absorbing IR radiation of wavelength 750 to 860 nm.
  • Irradiation may be achieved using any laser operating in this infra red wavelength range.
  • gas lasers or diode lasers may be used.
  • High power diode lasers are particularly suitable, typically emitting infra red radiation of wavelengths of 780 to 830 nm.
  • Such lasers may typically have a power range of 2 to 3W, and diode lasers are particularly advantageous over gas lasers in that they are inexpensive, robust and
  • Typical power levels which will cause destruction of treated tissue whilst leaving untreated tissue substantially unvapourized are 50-1000W/cm 2 depending on the particular tissue the quantity of highly infra-red absorbent compound present in the tissue and the spot diameter.
  • the power level required will, of course, depend to a certain extent on the type of tissue to be ablated, and so certain tissues may require even higher power levels in order to achieve ablation.
  • the low power levels required compare exceptionally favourably with typical power levels required to achieve destruction of untreated tissue - e.g. power levels of over 1000 W/cm 2 are required to ablate untreated tissue material from pig aorta, whereas power levels of only approx. 100 W/cm 2 are required to ablate tissue material from pig aorta after immersion for 30 minutes in 25 mg/1 ICG in saline, using a laser beam of 3 mm diameter.
  • the compound which is highly absorbent of infra red radiation of wavelength 750 to 860nm is preferably administered to the tissues by intravenous administration. Although less preferable, administration may also be by the intradermal, subcutaneous or intramuscular route. Thus, selective administration may be achieved utilizing the differential take up of infra red absorbing compounds, e.g. ICG, by different tissues. For example, dyes are known to clear more slowly from cancerous tissue than from normal tissue; arteriosclerotic plaque absorbs dyes more strongly than the intima of the arterial wall.
  • the compound which is highly absorbent of infra red radiation of wavelength 750 to 860nm may be administered through the medium of a binding agent chosen to bind the compound to the selected region only of body tissue.
  • a binding agent chosen to bind the compound to the selected region only of body tissue.
  • SUBSTITUTESHEET removing tissue material from a human or animal body which method comprises:
  • composition comprising a compound which is highly absorbent of infra red radiation of wavelength 750 to 860nm bound to a substance capable of binding said compound substantially to a selected region of body tissue, in the manufacture of an agent for use in such a method.
  • a compound which is highly absorbent of infra red radiation of wavelength 750 to 860nm in the manufacture of an agent for use in such a method.
  • tissue/site specific agents may be used to bind the infra red absorbing compound to the tissue, for example cancerous tissue or atherosclerotic plaque - i.e. this is highly tissue selective.
  • monoclonal antibodies may be used as the binding agent to which the infra red absorbing compound becomes attached.
  • Such antibodies may be chosen to attach preferentially or specifically
  • SUBSTITUTE SHEET to the tissue which is to be ablated.
  • Suitable monoclonal antibodies are known for a variety of cancerous tissues and arteriosclerotic plaque.
  • monoclonal antibodies which bind to antigens in cancerous cells, examples of such antigens being CEA (carcino embryonic antigen) and CA 125 (cancer antigen no. 125) .
  • Attachment of the highly infra red absorbent compound to the monoclonal antibody may be achieved via an analogue of the highly infra red (wavelength 750- 860nm) absorbent compound, e.g. an analogue of ICG, which reacts directly with the antibody molecule.
  • the highly infra red absorbing compound, e.g ICG may be bound to a carrier molecule, e.g. human serum albumin, which molecule may be cross-linked to the antibody molecule of interest.
  • bispecific monoclonal antibody is a hybrid molecule which has one binding site for the cell of the tissue of interest, e.g. a cancer cell or a cell of atheroselerotic tissue, and a second binding site with a different specificity, in the case of the present invention a specificity for the highly infra red absorbent compound, e.g. ICG.
  • Bispecific monoclonal antibodies may be made using the method of Milstein (Milstein, C. Nature 305, 573 (1983)).
  • bispecific monoclonal antibodies may be prepared by fusing cell lines producing molecules specific for cancer cells or atherosclerotic tissue cells and cell lines producing molecules specific for ICG to produce resultant hybrid antibodies.
  • Use of such bispecific monoclonal antibodies is preferred since they are simple molecules that do not require the presence of cross-linking or other agents which may prove to be antigenic.
  • Monoclonal antibodies are particularly useful as binding agents in the removal of blood clots in arteries.
  • a monoclonal antibody raised against fibrin may be administered followed by administration of the highly infra red (wavelength 750 to 860nm) absorbent compound.
  • the highly infra red absorbent compound e.g. ICG, will bind to the bound antibody and an infra red laser may be targeted on the thus-labelled fibrin to ablate the blood clot and thereby clear the artery.
  • low density lipoproteins (LDL) and very low density lipoproteins (VLDL) are particularly suited to binding compounds which are highly absorbent of infra red radiation of wavelength 750 to 860nm, such as ICG, specifically to atherosclerotic plaque tissue.
  • Blood proteins for example synthetic blood proteins, which identify the early stages of the build-up of atherosclerotic plaque on artery walls may be used.
  • An example of such a synthetic protein which may be used is a peptide named SP-4 of Diatech, Inc. of Boston, Massachusetts, USA. Needless to say, all such agents must be capable of binding to both the infra red absorbing compound and the tissue of interest.
  • the absorption peak of the infra red absorbing compound will vary with the nature of the substance e.g. the binding substance to which it is bound.
  • albumin-bound ICG will have an absorption peak at about 805nm.
  • irradiation with IR radiation at a wavelength of about 805nm will be preferable.
  • the ICG absorption spectrum changes when mixed with blood, mainly due to bonding with plasma proteins. ICG dissolved in water shows a peak absorption at 786nm. Binding to collagen produces a slightly different wavelength maximum (see Example 2) .
  • the wavelength of the laser radiation will need to be adjusted to the absorption maximum of the infra-red absorbing substance in its particular environment.
  • the invention provides a method of selectively removing tissue material from a human or animal body, which method comprises:
  • step (d) irradiating said region with infra red laser radiation of wavelength 750 to 860nm at a power sufficient to cause vaporization of the tissue material to which said compound has been administered, but insufficient to cause substantial vaporization of tissue material to which said compound has not been administered.
  • the fluorescent radiation emitted from the tissue material treated in accordance with step (a) may be monitored during treatment in order to determine the extent of tissue removal.
  • the laser e.g. a diode laser
  • the laser will be operated at a power below that which
  • SUBSTITUTE SHEET would have a therapeutic effect.
  • the laser radiation is directed either as a focused beam or as a beam which is, for example, a few millimetres in diameter onto the tissue to which the infra red absorbing compound has been administered; fluorescent light from the compound, e.g. ICG, is monitored as the laser beam is scanned over the tissue. When treated tissue is in the beam, fluorescent light will be detected. At this point the laser power is increased by an amount sufficient to give a therapeutic effect. Monitoring of the fluorescent emission during treatment allows the extent of tissue destruction to be monitored; when all of the treated tissue has been removed the fluorescent signal will terminate.
  • the laser radiation may be delivered to the target area and fluorescence monitored via a body implantable optical fibre.
  • Suitable compounds which both absorb infra red radiation of wavelength 750-860nm and fluoresce under infra red irradiation are the above-mentioned polymethine dyes, especially ICG, and compounds such as
  • ICG is particularly suitable for use in this method of removing tissue, enabling location of the treated tissue and the monitoring of the extent of removal, especially in combination with a variable output diode laser.
  • the substance When applying the infra red absorbing substance directly, without the mediation of a binder substance, the substance may be applied by conventional intravenous administration, preferably in an injectable solution at a concentration of 1-100 mg/ l. As mentioned above, although less preferable, administration may alternatively may be by the intradermal, subcutaneous or intramuscular route.
  • the present invention provides the use of a compound which is highly absorbent of infra red radiation in the manufacture of an agent for use in a method of selectively removing tissue material from a human or animal body.
  • the compound When using a binding agent, for example a monoclonal antibody, to bind the compound which is highly absorbent of infra red radiation to the target tissue, the compound may be administered to the body or tissue first and then the binding substance, or vice versa.
  • a binding agent for example a monoclonal antibody
  • bispecific monoclonal antibodies they may be administered to the patient first, by intravenous injection, and then the infra red absorbing compound, e.g. ICG, may be added in a second intravenous injection. Only those antibodies bound to the tumour will bind the infra red absorbing compound.
  • the compound and binder are preferably administered together to the body.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound which is highly absorbent of infra red radiation of wavelength 750 to 860nm bound to a substance capable of preferentially binding said compound to a selected region of body tissue, together with at least one inert excipient.
  • the binder substance e.g. bispecific monoclonal antibodies
  • Monoclonal antibodies may conveniently be obtained as a freeze- dried powder which is then made up to the required strength with physiological saline.
  • Administration of the binder substance e.g. monoclonal antibodies or LDL's
  • the binder substance e.g. monoclonal antibodies or LDL's
  • Administration is a delicate procedure and due care has to be taken to try to minimise allergic or immune reactions.
  • infra red absorbing compound is also capable of emitting fluorescent radiation when irradiated with infra red radiation.
  • the methods according to the present invention are applicable to a wide range of medical procedures in which tissue is to be removed or destroyed. Such procedures include (but are not limited to) oncology, angioplasty, gastrointestinal and urinary tract surgery, neurology and dermatology. Such methods are applicable to the human body and also to the (non-human) animal body.
  • Fig. 1 is a spectrophotometric curve (Absorption vs. Wavelength (nm) ) for normal serum containing 5mg/l of "Cardio-Green” (Sterile Indocyanine Green USP) .
  • Fig. 2 is a spectral reflectance plot for human skin (skin reflectance vs. wavelength ( ⁇ m) ) . fair-skin individuals
  • Fig. 3 is an absorption spectrum (Absorbance X1000 vs. wavelength (nm) for 0.02% (w/v) rat tail (RT) tendon (Type I) collagen dissolved in 0.1M acetic acid.
  • Fig. 4 is an absorption spectrum (% Maximum Absorbance vs. Wavelength (nm) for ICG dissolved in 0.1M acetic acid. Spectrum normalized to percent maximum of peak absorbance value.
  • Fig. 5 is an absorption spectrum (% Maximum Absorbance vs. Wavelength (n ) ) for collagen dissolved in acetic acid combined with ICG dissolved in acetic acid ( ) ; ICG/acetic acid absorption spectrum
  • An aqueous solution of ICG was prepared to concentration 25mg/litre (this was very pale green in colour) .
  • a 10mm cuvette of ICG was illuminated using laser diode radiation through an 800 nm filter. Fluorescence was observed through a 830 nm optical filter. Fluorescence was observed through the depth of the cell. No excitation radiation was transmitted through the cell.
  • Human femoral artery segments were defrosted, opened up into flat segments and soaked in concentrated (25mg/5ml) ICG for 1 hour. The samples were then rinsed in saline.
  • Type I collagen from rat tail tendon (Sigma) was dissolved according to the supplier's instructions at room temperature in 0.1M acetic acid to produce a 0.2% (w/v) solution ("collagen/acetic acid").
  • a 0.02% (w/v) solution of ICG was prepared by dissolving ICG (Sigma) in double distilled water. Then 100 ⁇ L of the ICG solution was added to 900 ⁇ L of 0.1M acetic acid ("ICG/acetic acid”) . The ICG/acetic acid solution was further diluted 1:10 in distilled water for spectral measurements. Samples of the solutions were placed in plastic cuvettes with the appropriate solvent (acetic acid) in a comparison cuvette. Following spectral absorbance measurements of ICG/acetic acid and RT collagen/acetic acid, the collagen solution was divided,
  • Spectral absorbance measurements were made using a Perkin-Elmer Spectrophotometer (Model 552) with a slit setting of 2nm, a time constant of 0.5 sec, and a scan rate of 120nm/min. Absorbance was measured every 4nm between 400 and 900nm from the plotted absorbance curves and entered into a computer program that allowed the data to be manipulated mathematically and plotted so the various spectra could be normalized.
  • Fig. 3 shows the absorption spectrum of Type I collagen dissolved in 0.1M acetic acid. Absorbance is equal at all wavelengths tested (i.e. the spectrum is "flat") indicating that Type I collagen does not absorb differentially within the 500-900nm band. Absolute absorbance is quite low (4 X 10 "4 Absorbance Units) because the collagen solution is relatively dilute which, in turn, is due to the relatively low solubility of Type I RT collagen.
  • the absorption spectra of ICG/acetic acid are shown in Fig. 4.
  • the ICG/acetic acid spectrum peak was at 778nm, with a plateau from 716nm to 728nm.
  • SUBSTITUTE SHEET The absorption spectrum of lagen/acetic acid combined with ICG/acetic ac exhibits two peaks (Fig. 5) .
  • the main peak is shifted by 28nm from the ICG/acetic acid peak (i.e. 778 to 806nm) .
  • the lower peak of the combined solution at 736nm (93% relative absorbance) does not correspond to a shift of 28nm of the knee of the plateau region of the ICG/acetic acid spectrum (716-728nm) .
  • the combined spectrum shifts toward longer wavelengths.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Radiation-Therapy Devices (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Procédé pour enlever de manière sélective du tissu d'un corps humain ou animal et qui consiste à administrer à une région choisie du tissu corporel un composé à absorption élevée de rayonnement infra-rouge d'une longueur d'onde de 750 à 860 nm, et à exposer la région à un rayonnement infra-rouge correspondant, d'une puissance suffisante pour effectuer la vaporisation thermique du tissu auquel le composé a été administré, mais insuffisante pour provoquer la vaporisation de tissus auxquels le composé n'a pas été administré. Ceci permet l'ablation sélective du tissu malade tout en n'affectant pas le tissu sain.
PCT/GB1991/001044 1990-06-27 1991-06-27 Methode de traitement et compositions utilisees a cet effet WO1992000106A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP91911771A EP0536211A1 (fr) 1990-06-27 1991-06-27 Methode de traitement et compositions utilisees a cet effet
AU81926/91A AU8192691A (en) 1990-06-27 1991-06-27 Method of treatment and compositions therefore

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9014307.4 1990-06-27
GB909014307A GB9014307D0 (en) 1990-06-27 1990-06-27 Method of treatment and compositions therefor

Publications (2)

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WO1992000106A2 true WO1992000106A2 (fr) 1992-01-09
WO1992000106A3 WO1992000106A3 (fr) 1992-02-20

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EP (1) EP0536211A1 (fr)
AU (1) AU8192691A (fr)
GB (1) GB9014307D0 (fr)
WO (1) WO1992000106A2 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5258305A (en) * 1991-09-13 1993-11-02 Nitto Chemical Industry Co., Ltd. Manufacture of optically active 2-phenylpropionic acid and 2-phenylpropionamide from the nitrile using Rhodococcus equi
WO1996023525A1 (fr) * 1995-01-30 1996-08-08 Daiichi Pure Chemicals Co., Ltd. Marqueur de diagnostic
WO1997007734A1 (fr) 1995-08-29 1997-03-06 Spectrx, Inc. Realisation de micropores sur la peau humaine pour l'administration de medicaments et les applications de monitorage
WO1997033620A3 (fr) * 1996-03-15 1998-02-05 Pulsion Verw Gmbh & Co Medical Compose pour traiter des tumeurs
US5885211A (en) * 1993-11-15 1999-03-23 Spectrix, Inc. Microporation of human skin for monitoring the concentration of an analyte
WO1999040848A1 (fr) * 1998-02-17 1999-08-19 Abbott Laboratories Dispositif de collecte et de controle de liquide interstitiel
US6527716B1 (en) 1997-12-30 2003-03-04 Altea Technologies, Inc. Microporation of tissue for delivery of bioactive agents
US6899723B2 (en) 1999-01-15 2005-05-31 Light Sciences Corporation Transcutaneous photodynamic treatment of targeted cells
US6986782B2 (en) 1999-01-15 2006-01-17 Light Sciences Corporation Ambulatory photodynamic therapy
US7320786B2 (en) 2000-01-12 2008-01-22 Light Sciences Oncology, Inc. Photodynamic therapy treatment for eye disease
EP2314282A2 (fr) 2003-10-24 2011-04-27 Altea Therapeutics Corporation Procédé pour l'administration transdermique de substances infiltrantes
EP2921111A1 (fr) 1995-08-29 2015-09-23 Nitto Denko Corporation Réalisation de micropores sur la peau humaine pour l'administration de médicament et des applications de surveillance
US9918665B2 (en) 2002-03-11 2018-03-20 Nitto Denko Corporation Transdermal porator and patch system and method for using same

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000041726A2 (fr) 1999-01-15 2000-07-20 Light Sciences Corporation Therapie vasculaire non invasive
US20030078499A1 (en) 1999-08-12 2003-04-24 Eppstein Jonathan A. Microporation of tissue for delivery of bioactive agents
ES2612779T3 (es) 2002-03-11 2017-05-18 Nitto Denko Corporation Sistema de parches transdérmicos de administración de fármacos, método de fabricación del mismo y método de uso del mismo

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4806488A (en) * 1985-09-06 1989-02-21 Syntex (U.S.A.) Inc. Ligand-receptor assays employing squarate dye compositions
US4920143A (en) * 1987-04-23 1990-04-24 University Of British Columbia Hydro-monobenzoporphyrin wavelength-specific cytotoxic agents
HU204856B (en) * 1987-08-12 1992-02-28 Orszagos Mueszaki Fejlesztesi Process for releasing cell mixtures and tissues from undesired populations and for producing monoclonal antibody - hematoporphyrin conjugates
DE3828360A1 (de) * 1988-08-20 1990-02-22 Stanowsky Alexander Dr Farbstoff-markierter antitumor-antikoerper und verfahren zu seiner herstellung
CA2056431A1 (fr) * 1989-06-07 1990-12-08 David Dolphin Photosensibilisation de derives de la porphyrine obtenus par additions diels-alder

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5258305A (en) * 1991-09-13 1993-11-02 Nitto Chemical Industry Co., Ltd. Manufacture of optically active 2-phenylpropionic acid and 2-phenylpropionamide from the nitrile using Rhodococcus equi
US6142939A (en) * 1993-11-15 2000-11-07 Spectrx, Inc. Microporation of human skin for drug delivery and monitoring applications
US5885211A (en) * 1993-11-15 1999-03-23 Spectrix, Inc. Microporation of human skin for monitoring the concentration of an analyte
US5968479A (en) * 1995-01-30 1999-10-19 Daiichi Pure Chemicals Co., Ltd. Diagnostic marker
WO1996023525A1 (fr) * 1995-01-30 1996-08-08 Daiichi Pure Chemicals Co., Ltd. Marqueur de diagnostic
JP2006192285A (ja) * 1995-08-29 2006-07-27 Spectrx Inc 薬物送達および鑑視適用のためのヒト皮膚の微細穿孔
EP0858285A4 (fr) * 1995-08-29 2000-05-17 Spectrx Inc Realisation de micropores sur la peau humaine pour l'administration de medicaments et les applications de monitorage
WO1997007734A1 (fr) 1995-08-29 1997-03-06 Spectrx, Inc. Realisation de micropores sur la peau humaine pour l'administration de medicaments et les applications de monitorage
EP2921111A1 (fr) 1995-08-29 2015-09-23 Nitto Denko Corporation Réalisation de micropores sur la peau humaine pour l'administration de médicament et des applications de surveillance
WO1997033620A3 (fr) * 1996-03-15 1998-02-05 Pulsion Verw Gmbh & Co Medical Compose pour traiter des tumeurs
US6527716B1 (en) 1997-12-30 2003-03-04 Altea Technologies, Inc. Microporation of tissue for delivery of bioactive agents
WO1999040848A1 (fr) * 1998-02-17 1999-08-19 Abbott Laboratories Dispositif de collecte et de controle de liquide interstitiel
US6899723B2 (en) 1999-01-15 2005-05-31 Light Sciences Corporation Transcutaneous photodynamic treatment of targeted cells
US7018395B2 (en) 1999-01-15 2006-03-28 Light Sciences Corporation Photodynamic treatment of targeted cells
US6986782B2 (en) 1999-01-15 2006-01-17 Light Sciences Corporation Ambulatory photodynamic therapy
US7320786B2 (en) 2000-01-12 2008-01-22 Light Sciences Oncology, Inc. Photodynamic therapy treatment for eye disease
US9918665B2 (en) 2002-03-11 2018-03-20 Nitto Denko Corporation Transdermal porator and patch system and method for using same
EP2314282A2 (fr) 2003-10-24 2011-04-27 Altea Therapeutics Corporation Procédé pour l'administration transdermique de substances infiltrantes

Also Published As

Publication number Publication date
EP0536211A1 (fr) 1993-04-14
AU8192691A (en) 1992-01-23
GB9014307D0 (en) 1990-08-15
WO1992000106A3 (fr) 1992-02-20

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