WO1994023646A1 - Stabilisation de colorants sensibles a la tension - Google Patents

Stabilisation de colorants sensibles a la tension Download PDF

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Publication number
WO1994023646A1
WO1994023646A1 PCT/US1994/004267 US9404267W WO9423646A1 WO 1994023646 A1 WO1994023646 A1 WO 1994023646A1 US 9404267 W US9404267 W US 9404267W WO 9423646 A1 WO9423646 A1 WO 9423646A1
Authority
WO
WIPO (PCT)
Prior art keywords
dye
composition
indocyanine green
antioxidant
blue
Prior art date
Application number
PCT/US1994/004267
Other languages
English (en)
Inventor
Julie A. Beaty
Steven R. Cooper
Margaret A. Mcloughlin
Original Assignee
Mallinckrodt Medical, 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 Mallinckrodt Medical, Inc. filed Critical Mallinckrodt Medical, Inc.
Priority to AU67076/94A priority Critical patent/AU6707694A/en
Priority to JP6523530A priority patent/JPH08509260A/ja
Priority to EP94914830A priority patent/EP0695138A4/fr
Publication of WO1994023646A1 publication Critical patent/WO1994023646A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0032—Methine dyes, e.g. cyanine dyes
    • A61K49/0034—Indocyanine green, i.e. ICG, cardiogreen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0023—Di-or triarylmethane dye
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0041—Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal
    • A61K49/0043—Fluorescein, used in vivo
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B67/00—Influencing the physical, e.g. the dyeing or printing properties of dyestuffs without chemical reactions, e.g. by treating with solvents grinding or grinding assistants, coating of pigments or dyes; Process features in the making of dyestuff preparations; Dyestuff preparations of a special physical nature, e.g. tablets, films
    • C09B67/0071—Process features in the making of dyestuff preparations; Dehydrating agents; Dispersing agents; Dustfree compositions

Definitions

  • the invention relates to voltage sensitive dyes. More particularly, the invention relates to storage stable compositions comprising voltage sensitive dyes.
  • Indocyanine green for example, is a voltage sensitive dye with an absorption maxima around 805 nm (the isosbestic point of the hemoglobin/deoxyhemoglobin system) . This absorption makes it possible to monitor blood concentrations by ear densitometry. Indocyanine green has been used for determining cardiac output, hepatic function and liver blood flow. It also has been used for plasma volume measurement and for regional angiography of organs including the eyes, kidneys and lungs (Gennaro, A. R. , Ed Remington's Pharmaceutical Sciences Easton, PA: Mack Publishing Company, 1990, 1279. Indocyanine green, in vivo, is readily bound by plasma proteins and remains in the blood stream through one circulation of the heart and lungs.
  • Indocyanine green is removed from the plasma almost exclusively by hepatic function (Osol, A.; Pratt, R. The United States Dispensatory Philadelphia, Toronto: J. B. Lippincott Company, 1973, 615) .
  • indocyanine green pharmokinetics in the rabbit and relevant studies of its stability and purity, Heintz, R. ; Svensson, C.K.; Stoeckel, K. ; Powers, G. J. ; Lalka, D. J. Pharm. Sci. 1986, 75, 398- 402 .
  • indocyanine green in methanol or bile remain stable (Tl/2 > ly) , but indocyanine green in duodenal fluid or distilled water decompose rapidly (e.g., Tl/2 3.6d and Tl/2 3.6d and Tl/2 1.4 d, respectively)
  • ICG indocyanine green
  • Plasma proteins inhibit decomposition from incandescent light (Light-absorbing properties, stability and spectral stabilization of indocyanine green, Landsman, M.L.J.; Kwant, G. ; Mook, G.A.; Zijlstra, W.G. J. Appl. Phvsiol . 1976, 40, 575- 583) as does protection from light (Studies on the stability of indocyanine green in serums, Nimata, H.; Yoshida, S.; Shimizu, N. ; Yoneya, M. ; Nishibe, M. ; Matsubara, R. Rinsho Kensa 1974, 18, 320-322) .
  • the invention relates to stable aqueous solutions of voltage sensitive dyes. Particularly the invention relates to the proper formulation and storage conditions that provide marketable aqueous solutions of voltage sensitive dyes for use as optical imaging contrast agents.
  • the invention is advantageous in allowing shipment and storage of the disclosed compositions either alone or in pre-filled syringes. Prior to this invention-, on site preparation was necessary due to the poor stability of the solutions. In addition, prior to the invention, shipment and storage of such dyes occurred only with solid forms of the dyes.
  • Voltage sensitive dyes refers to those compositions that reflect a change in their fluorescence or absorbance with changes in voltage.
  • Storage stable refers to a composition of the invention that decomposes at a slower rate than a voltage sensitive dye without an air protecting reagent.
  • a decomposition inhibiting amount refers to that amount that renders the aqueous solutions of the invention storage stable.
  • Air protecting reagents refers to any composition capable of inhibiting decomposition of the voltage sensitive dyes due to air.
  • compositions of the invention have longer storage life (i.e., less decomposition) due to protection from light, and air, either separately, or in combinaticon.
  • Some of the advantages of aqueous solutions of voltage sensitive dyes include the speed with which they can be used (i.e., no wait for solids to dissolve), the convenience with which they can be used (i.e., no worry about preparation for solution and whether or not all of the solids dissolved) , the safety with which they can be used (i.e., less chance of microbial and particulate contamination) , and the ease with which they can be used (i.e., less chance of getting any particulates from the stopper into the solution because the needle would only be pushed through once as opposed to twice for a reconstituted kit; no chance for similar contamination if a prefilled syringe is uses) .
  • Voltage sensitive dyes for use in the present invention include Evans Blue (Aldrich) (C 34 H 24 N 6 Na 4 0 4 S 4 ) ,
  • Suitable light protection measures to be used with compositions of the invention include the use of wrappings such as opaque wrappings, cardboard boxes, and styrofoam containers. It is especially advantageous to protect compositions of the invention from light that is the same as that absorbed by the compositions.
  • Suitable air protection measures to be used with compositions of the invention include the use of air protecting reagents. Examples of air protecting reagent are antioxidants, gases, and surfactants.
  • Suitable air protecting reagents for use with the invention include gases such as argon and nitrogen.
  • gases such as argon and nitrogen.
  • the use of gases involves purging a vial containing solid dye with argon or nitrogen and sealing. Then bubble a buffered solution, which contains the desired antioxidant or surfactant in the appropriate proportion, with argon or nitrogen. Add the degassed solution to the solid dye and transfer the solution to a purged vial, or syringe. A stopper will not resist air indefinitely so a sealed ampule may be preferable.
  • Suitable antioxidants for use in practicing the invention include sodium sulfite, sodium metabisulfite, sodium thiosulfate, sodium formaldehyde sulfoxylate, acetone sodium metabisulfite, isoascorbic acid, thioglycerol, ascorbate, thiosorbitol, cysteine hydrochloride, sulfur dioxide, acetylcysteine, thiolactic acid, dithyiothreitol and glutathione (all available from Aldrich, Fisher and/or Fluka) .
  • Surfactants and compositions that exhibit surfactant-like properties suitable for use with the invention include tweens, polysorbates (ICI or Sigma) , Pluronics
  • ICI or Sigma Polyethylene glycols
  • sodium carboxymethyl celluloses Surfactant and compositions with surfactant-like capabilities are believed to protect from air by associating with the organic functionalities or incorporating the organic molecule into a micelle.
  • the amount of air protecting reagents for use with the invention range from about 0.01% to about 1.0% of an aqueous solution. Preferably a range from about 0.1% to about 0.25% is used.
  • the amount of air protecting reagent generally depends upon the solubility of the particular air protecting reagent in aqueous solution.
  • the storage stable aqueous solution of the invention be stable for at least the time period from the time of preparation (e.g., laboratory or pharmacy) until administration or use. Typica] lly this period is from about a few minutes to about a few hours.
  • the storage stability is from about a full day (24 hours) to about a few weeks. Most preferably the storage stability is for about a year (12 months) or longer.
  • a major advantage of voltage sensitive dyes is that time resolution is better than 1 millisecond (ms) compared to time resolution on the order of seconds for the commonly used intrinsic light signals.
  • the invention is suitable for imaging in patients, typically warm blooded animals.
  • a method for imaging using compositions of the invention comprises administering an imaging effective amount of a composition of the invention to a patient and then subjecting the patient to the desired imaging modality.
  • Examples of preferred voltage sensitive dyes for use with the invention include Evan's Blue, Indocyanine Green, Congo Red, Fluorescein Sodium, Sulphan Blue, and Indigo Carmine.
  • Examples of preferred air protecting reagents for use with the invention include Sodium Ascorbate, Glutathione, Dithiothreitol, Sodium Ascorbate, EDTA, Polysorbate 80, and Carboxymethylcellulose.
  • compositions for formulating diagnostic compositions include those compositions for formulating diagnostic compositions.
  • diagnostic compositions can be for enteral or parenteral administration and may include pharmaceutically acceptable buffers, electrolytes, surfactants, thixotropic agents, and the like.
  • the diagnostic composition is administered in an imaging effective amount, an imaging effective amount being that amount necessary for obtaining the desired image.
  • Diagnostic compositions contain an effective amount of the compositions of the invention along with conventional pharmaceutical carriers and excipients appropriate for the type of administration contemplated.
  • parenteral formulations advantageolusly contain a sterile aqueous solution or suspension of from about 0.05 to 1.0M of a composition according to the invention.
  • Preferred parenteral formulations have a concentration of about 0.1M to about 0.5M.
  • Such solutions also may contain pharmaceutically acceptable buffers and, optionally, electrolytes such as sodium chloride.
  • Parenteral compositions may be injected directly or mixed with a large volume parenteral composition for systemic administration.
  • Formulations for enteral administration may vary widely, as is well-known in the art. In general, such formulations are liquids which include an effective amount of a composition of the invention in aqueous solution or suspension. Such enteral compositions may optionally include buffers, surfactants, thixotropic agents, and the like.
  • Compositions for oral administration may also contain flavoring agents and other ingredients for enhancing their organoleptic qualities.
  • the diagnostic compositions are administered in doses effective to achieve the desired enhancement of the image.
  • doses may vary, depending upon the particular composition employed, the organs or tissues which are the subject of the imaging procedure, the imaging procedure, the imaging equipment being used, and so forth.
  • parenteral dosages will range from about 0.01 to about 1.
  • OMMol of composition of the invention per kg of patient body weight .
  • Preferred parenteral dosages range from about 0.05 to about 0.5MMol per kg of patient body weight.
  • Enteral dosages generally range from about 0.5 to about 100 MMol, preferably from about 1.0 to about 10 MMol per kg of patient body weight.
  • compositions of the invention are used in the conventional manner.
  • the compositions may be administered to a patient, typically a warm-blodded animal, either systemically or locally to the organ or tissue to be imaged, and the patient then subjected to the imaging procedure.
  • ICG Indocyanine green
  • EDTA dicalcium ethylenediaminetetraacetic acid
  • UV-Visible spectra were recorded on a Cary 3E spectrophotometer over a region of 600 to 900 nm.
  • the phosphate buffer was prepared by dissolving 0.2975 g of NaH 2 P0 4 H 2 0 and 1.0813 g of Na 2 HP0 4 in 250 mL of deionized water. The pH of the buffer was 7.39.
  • Example 2
  • Example 2 Analogous solutions to those in Example 1 were used, however they were not irradiated. Instead, the solutions were heated in a hot water bath at 50-53C. In the air free solution, the absorbance decreased from -1.1 to 1.05 after 90 min.; the solution with air showed a decrease in absorbance from 1.6 to 1.3 over the same time frame. Comparing these results to those in Example 2 indicates that it is light, not heat, that is the major factor affecting the rate of decomposition of the dye.
  • Example 5 A solution analogous to that used in Example 5 was used, except this time, a spatula tip of solid sodium ascorbate was added also. After 60 min., the absorbance of an air-containing solution decreased from 1.0 to 0.7.
  • Example 5 The same solution as in Example 5 was prepared, however 3 mL of a 0.0002 M solution of sodium ascorbate (4% of ICG concentration) was added, also. After 60 minutes, a degassed solution showed a decrease in absorbance from 1.0 to 0.15. Comparing this to the result in Example 5, the presence of 0.0002 M ascorbate does not retard the decomposition of the ICG.
  • a heaping scoop of sodium bisulfite was added to 3 mL of a solution containing 1.25 mg of ICG in 250 mL of phosphate buffer.
  • the initial absorbance is -0.3, however, after only 15 minutes, the absorbance is 0.0.
  • the bisulfite is destroying the dye.

Abstract

L'invention concerne des solutions aqueuses stables de colorants sensibles à la tension, et notamment les conditions de formulation et de stockage proprement dites permettant d'obtenir des solutions aqueuses commercialisables de colorants sensibles à la tension destinées à être utilisées comme agents de contraste d'imageries optiques.
PCT/US1994/004267 1993-04-20 1994-04-19 Stabilisation de colorants sensibles a la tension WO1994023646A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU67076/94A AU6707694A (en) 1993-04-20 1994-04-19 Stabilization of voltage sensitive dyes
JP6523530A JPH08509260A (ja) 1993-04-20 1994-04-19 電圧感受性染料の安定化
EP94914830A EP0695138A4 (fr) 1993-04-20 1994-04-19 Stabilisation de colorants sensibles a la tension

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US4993693A 1993-04-20 1993-04-20
US08/049,936 1993-04-20

Publications (1)

Publication Number Publication Date
WO1994023646A1 true WO1994023646A1 (fr) 1994-10-27

Family

ID=21962548

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1994/004267 WO1994023646A1 (fr) 1993-04-20 1994-04-19 Stabilisation de colorants sensibles a la tension

Country Status (5)

Country Link
EP (1) EP0695138A4 (fr)
JP (1) JPH08509260A (fr)
AU (1) AU6707694A (fr)
MX (1) MXPA94002884A (fr)
WO (1) WO1994023646A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999013916A2 (fr) * 1997-09-18 1999-03-25 Nycomed Imaging As Procedes et compositions pour l'imagerie medicale
EP0946203A1 (fr) * 1996-05-13 1999-10-06 Mallinckrodt, Inc. Colorants fonctionnels tricycliques pour l'amelioration du constraste en imagerie optique
WO2003057259A2 (fr) * 2001-12-27 2003-07-17 Akorn, Inc. Compositions de vert d'indocyanine et procedes d'utilisation correspondants
WO2015095344A1 (fr) * 2013-12-17 2015-06-25 University Of Chicago Composition sensible aux variations de tension et son procédé d'utilisation
WO2022026628A1 (fr) * 2020-07-31 2022-02-03 Cao Group, Inc Solutions vertes d'indocyanine stables au stockage et leurs procédés de fabrication
WO2022194734A1 (fr) * 2021-03-17 2022-09-22 Provepharm Life Solutions Formulations stables de vert d'indocyanine
WO2022194731A1 (fr) 2021-03-17 2022-09-22 Provepharm Life Solutions Formulations stables de vert d'indocyanine
WO2022194733A2 (fr) 2021-03-17 2022-09-22 Provepharm Life Solutions Formulations stables de vert d'indocyanine

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4369250A (en) * 1981-07-31 1983-01-18 Sherwood Medical Industries Inc. Fatty acid determination
US4478818A (en) * 1982-12-27 1984-10-23 Alza Corporation Ocular preparation housing steroid in two different therapeutic forms
US4526701A (en) * 1981-08-31 1985-07-02 Lever Brothers Company Dye stabilized detergent compositions
US5266302A (en) * 1990-10-03 1993-11-30 Peyman Gholam A Method of performing angiography

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4369250A (en) * 1981-07-31 1983-01-18 Sherwood Medical Industries Inc. Fatty acid determination
US4526701A (en) * 1981-08-31 1985-07-02 Lever Brothers Company Dye stabilized detergent compositions
US4478818A (en) * 1982-12-27 1984-10-23 Alza Corporation Ocular preparation housing steroid in two different therapeutic forms
US5266302A (en) * 1990-10-03 1993-11-30 Peyman Gholam A Method of performing angiography

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Journal of Applied Physiology, Vol. 29, No. 2, issued August 1970 (USA), J. GATHJE et al., "Stability Studies on Indocyanine Green Dye", see pages 181-185, especially page 181. *
Journal of Applied Physiology, Vol. 40, No. 4, issued April 1976 (USA), M.L.J. LANDSMAN et al., "Light-Absorbing Properties, Stability, and Spectral Stabilization of Indocyanine Green", see pages 575-582, especially page 582. *
Journal of Pharmaceutical Sciences, Vol. 75, No. 4, issued April 1986, R. HEINTZ et al., "Indocyanine Green: Pharmacokinetics in the Rabbit and Relevant Studies of Its Stability and Purity", see pages 398-402, especially page 398. *
See also references of EP0695138A4 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0946203A1 (fr) * 1996-05-13 1999-10-06 Mallinckrodt, Inc. Colorants fonctionnels tricycliques pour l'amelioration du constraste en imagerie optique
EP0946203A4 (fr) * 1996-05-13 2000-03-29 Mallinckrodt Inc Colorants fonctionnels tricycliques pour l'amelioration du constraste en imagerie optique
WO1999013916A2 (fr) * 1997-09-18 1999-03-25 Nycomed Imaging As Procedes et compositions pour l'imagerie medicale
WO1999013916A3 (fr) * 1997-09-18 2001-12-20 Nycomed Imaging As Procedes et compositions pour l'imagerie medicale
WO2003057259A2 (fr) * 2001-12-27 2003-07-17 Akorn, Inc. Compositions de vert d'indocyanine et procedes d'utilisation correspondants
WO2003057259A3 (fr) * 2001-12-27 2003-09-18 Akorn Inc Compositions de vert d'indocyanine et procedes d'utilisation correspondants
WO2015095344A1 (fr) * 2013-12-17 2015-06-25 University Of Chicago Composition sensible aux variations de tension et son procédé d'utilisation
WO2022026628A1 (fr) * 2020-07-31 2022-02-03 Cao Group, Inc Solutions vertes d'indocyanine stables au stockage et leurs procédés de fabrication
WO2022194734A1 (fr) * 2021-03-17 2022-09-22 Provepharm Life Solutions Formulations stables de vert d'indocyanine
WO2022194731A1 (fr) 2021-03-17 2022-09-22 Provepharm Life Solutions Formulations stables de vert d'indocyanine
WO2022194733A2 (fr) 2021-03-17 2022-09-22 Provepharm Life Solutions Formulations stables de vert d'indocyanine
WO2022194733A3 (fr) * 2021-03-17 2022-11-10 Provepharm Life Solutions Formulations stables de vert d'indocyanine

Also Published As

Publication number Publication date
EP0695138A1 (fr) 1996-02-07
EP0695138A4 (fr) 1998-09-02
MXPA94002884A (es) 2002-06-18
JPH08509260A (ja) 1996-10-01
AU6707694A (en) 1994-11-08

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