Stable formulation of indocyanine green

Abstract

The present invention relates to a composition comprising an association of stabilizing compounds including ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, and sodium chloride, and indocyanine green.

Description

Technical Field

[0001] The present invention relates to the technical fields of medicine and pharmacy. The present invention relates to indocyanine green compositions with improved stability, particularly improved storage stability. In particular, the present invention relates to indocyanine green compositions containing ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, and sodium chloride. The present invention further relates to a method for producing and using the composition.

Background Art

[0002] Indocyanine green (ICG) is a water-soluble tricarbocyanine fluorescent dye approved by the US Food and Drug Administration for medical diagnosis, and is used for the determination of liver function, cardiac output, liver blood flow, microcirculation of skin flaps, and ophthalmic angiography. Since ICG has a high absorbance in the spectral region (750 - 800 nm) that is relatively permeable to human tissues, it is used for such medical applications. The extremely low toxicity is also the reason for such medical applications. After intravenous administration, ICG is rapidly excreted into bile in the liver and has an effective half-life of about 3 - 4 minutes, depending on liver function.

[0003] In the above applications, it is necessary to administer ICG in the form of an aqueous solution. ICG is commercially available as a lyophilized powder that can be dissolved in sterile water for injection, and is often marketed as a kit. However, since ICG has poor stability and rapid degradation in an aqueous environment, its usefulness is limited in some applications such as time-sensitive surgeries. The attached documents of ICG vary among vendors, stating that the re-dissolved ICG solution should be used immediately, and in addition to use within 10 hours, the unused portion should be discarded.

[0004] Studies have shown that ICG molecules in aqueous solvents undergo physicochemical changes, such as aggregation, especially at high concentrations. While ICG in water readily forms dimers and oligomers, it maintains its monomeric state in human plasma, methanol, and dimethyl sulfoxide (DMSO) (Non-Patent Literature 1). Furthermore, ICG can generate singlet oxygen to form dioxetanes, which can then undergo thermal decomposition to produce multiple carbonyl compounds (Non-Patent Literature 2). These degradation products may reduce cell viability in vitro.

[0005] Physicochemical changes in ICG are more likely to occur depending on exposure to light, high temperatures, the presence of oxygen, and even the concentration of ICG itself (Non-Patent Documents 3, 4, and 5). The type and intensity of light irradiated onto ICG also affect degradation. Physicochemical changes rapidly degrade the optical properties of ICG, causing discoloration, decreased fluorescence intensity, and shifts in absorbance peaks. It has been reported that storing ICG in water under direct light for 10 hours results in a 10% decrease in the absorbance of its spectral peaks (Non-Patent Document 4).

[0006] To overcome the aforementioned shortcomings, numerous attempts have been made to improve the stability of indocyanine green in aqueous solutions.

[0007] Engel et al. have reported that the chemical decomposition of ICG can be suppressed by adding sodium azide (NaN3), a singlet oxygen suppressant (Non-Patent Literature 2).

[0008] Mindt et al. investigated the stability of ICG samples when stored in the dark or in transparent vials at various temperatures. From absorbance and fluorescence measurements, they found that ICG is stable for 3 days when stored in the dark at 4°C (however, 20% of the fluorescence intensity is lost during this period). Based on these tests, it has been suggested that ICG can be used for a period of more than 1 day if the re-prepared ICG solution is stored in the dark at 4°C (Non-Patent Literature 6).

[0009] Other researchers have proposed encapsulating ICG molecules within nanometer-sized carriers to prevent their degradation. For example, CN103301482 (Patent Document 1) discloses a three-layer polypeptide type ICG-filled micelle consisting of a polyleucine core, a polylysine intermediate layer, and a polyethylene glycol shell, with indocyanine green dispersed within the core. The indocyanine green is encapsulated in the core-shell structure, which effectively prevents aggregation of ICG molecules, thus improving the stability of ICG.

[0010] Kirchherr et al. have disclosed the encapsulation of ICG within Solutol HS15 (polyoxyethylene esters of 12-hydroxystearic acid) micelles. This formulation exhibited less aggregation behavior compared to free ICG in aqueous solution and showed high stability in aqueous solution for 4 weeks (Non-Patent Document 7).

[0011] US 6,944,493 (Patent Document 2) discloses an indocyanine green composition with a high indocyanine green concentration and improved stability. This invention is based on an indocyanine green liposome formulation that is stable for more than 24 hours after redissolution. Any formulation disclosed in the document can be redissolved in a diluent containing ethanol, polysorbate 80, etc.

[0012] WO2016 / 123864 (Patent Document 3) discloses a composition in which ICG is embedded in a lipid membrane of lipid nanoparticles. The fluorescence intensity of these nanoparticles is 4 to 5 times that of free ICG. After storage at 4°C for 0 to 300 days, these nanoparticles have a fluorescence intensity 4 to 100,000 times that of free ICG in an aqueous solution.

[0013] Dedora et al. have disclosed the complexation of ICG with highly soluble methyl β-CyD and FDA-approved sulfobutyl ether β-CyD (Captisol®) in aqueous solution. Such complexes suppress ICG aggregation and provide more than twice the sustained fluorescence enhancement over 24 hours compared to free ICG in water. However, ICG complexed with methyl β-CyD has been found to severely reduce the viability of some fibroblasts (Non-Patent Literature 8).

[0014] The encapsulation and complexation of ICG using the aforementioned systems have drawbacks, such as poor compatibility with cells, and may reduce the ability of ICG molecules to interact with plasma proteins after entering the bloodstream. In such cases, the excretion from the vascular system may be prolonged.

[0015] US 2010 / 0181535 (Patent Document 4) discloses a method for enhancing the fluorescence intensity of a fluorescent dye by mixing it with a redox buffer. The fluorescent dye can be selected from rhodamines and / or carborhodamines and / or oxazine dyes and / or cyanine dyes, including indocyanine green. The redox buffer may contain carotenoids (especially tocopherols), thiols (especially glutathione, N-acetylcysteine, and dihydrolipoic acid), amino acids (especially tryptophan and / or tyrosine and / or histidine and / or cysteine ​​and / or methionine) and / or peptides and proteins containing them. The authors of the same document point out that another advantage of using the redox buffer described in the document is that the shelf life of a fluorescent dye solution containing the redox buffer can be increased by 10% to 20% compared to a solution without the redox buffer. However, the document does not contain any information regarding the long-term storage stability of this composition.

[0016] WO2020 / 240514 (Patent Document 5) discloses an indocyanine green formulation containing disodium hydrogen phosphate, sodium dihydrogen phosphate, and sodium chloride. The composition may optionally contain other pharmaceutically acceptable excipients such as sodium carbonate, sodium bicarbonate, boric acid, lactic acid, glutaric acid, malic acid, succinic acid, and carbonic acid, as well as buffers of amino acids such as arginine, alanine, histidine, glycine, and lysine. The solution remains stable for up to 24 hours after redissolution with an aqueous diluent.

[0017] The prior art described above all reports on improving the stability of ICG in aqueous solutions, but they do not provide ICG aqueous solutions that are stable for more than 1 to 3 days. Therefore, there is a demand for ICG aqueous compositions that exhibit greater stability than the formulations of the prior art.

[0018] WO9423646 (Patent Document 6) discloses a storage-stable composition containing a voltage-sensitive dye (particularly indocyanine green) for use as a contrast agent for optical imaging. The composition contains air-protective reagents to suppress the degradation of ICG, such as antioxidants and surfactants. The air-protective reagents can be selected from sodium sulfite, sodium ascorbate, glutathione, dithiothreitol, EDTA, polysorbate 80, and carboxymethylcellulose. By storing the composition away from light and without air, the amount of ICG degradation in the composition, measured by the decrease in maximum absorbance in the UV-Vis spectrum from 600 to 900 nm, was suppressed. According to the examples in the same document, a composition containing ICG and EDTA does not exhibit storage stability.

[0019] Some prior art formulations require expensive equipment, / or lengthy manufacturing processes, and / or special excipients. Furthermore, some of these formulations contain excipients, such as alcohols or polysorbates, that make the injection of ICG compositions painful and difficult. [Prior art documents] [License]

[0020] [License 1] Chinese Patent No. 103301482 Detail Book [License 2] U.S. Patent No. 6944493 [License 3] International Publication No. 2016 / 123864 [License 4] U.S. Patent and Trademark Office Publication No. 2010 / 181535 [Patent Document 5] International Publication No. 2020 / 240514 [License 6] International Publication No. 94 / 23646 [Non-licensed literature]

[0021] [Non-licensed Document 1] Holzer W, Mauerer M, Penzkofer A, Szeimies RM, Abels C, Landthaler M, Baumler W. Photostability and thermal stability of indocyanine green. J Photochem Photobiol B. 1998 Dec; 47(2-3):155-64. [Non-licensed Document 2] Engel E, Schraml R, Maisch T, Kobuch K, Konig B, Szeimies RM, Hillenkamp J, Baumler W, Vasold R. Light-induced decomposition of indocyanine green. Invest Ophthalmol Vis Sci. 2008 May; 49(5):1777-83. [Non-licensed Document 3] Saxena V, Sadoqi M, Shao J. Degradation kinetics of indocyanine green in aqueous solution. J Pharm Sci. 2003 Oct; 92(10):2090-7.

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

[0022] In particular, there is a demand for ICG aqueous compositions that are stable at room temperature for one month or several months.

[0023] Furthermore, there is a demand for intravenous ICG compositions that are compatible with target tissues, non-toxic, and rapidly metabolized.

[0024] Furthermore, the present invention aims to provide an ICG composition that is easy to formulate, uses readily available raw materials, and has a sufficient ICG concentration for use in the same applications as prior art ICG formulations with short shelf lives.

[0025] Surprisingly, it was found that ICG compositions containing specific combinations of stabilizing compounds exhibited higher stability compared to prior art compositions.

[0026] The formulation according to the present invention contains ICG at a concentration comparable to or exceeding that of the prior art. The formulation can be formulated as a lyophilized powder or an aqueous solution. The formulation exhibits improved storage stability and shelf life compared to the prior art.

[0027] Another object of the present invention is to provide a stable, cost-effective, and easy-to-manufacture formulation. Yet another object of the present invention is to provide a formulation that does not cause discomfort to the patient during administration. [Means for solving the problem]

[0028] The present invention relates to a composition containing indocyanine green, ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, and sodium chloride, wherein the decrease in the amount of indocyanine green content in the composition after storage at room temperature for one month or more, as measured by the area percentage (%) at 240 nm by HPLC, is 10% or less.

[0029] Advantageously, the ICG (indocyanine green) content in the composition of the present invention before storage, as measured as the area percentage (%) at 240 nm by HPLC, is 90% or more.

[0030] Preferably, the total amount of impurities in the ICG composition before storage, as measured as the area percentage (%) at 240 nm by HPLC, is 10% or less.

[0031] Preferably, the increase in impurities in the composition according to the present invention, measured as the change in area percentage (%) at 240 nm by HPLC, after storage at room temperature for one month or more, is 10% or less.

[0032] The present invention further relates to a composition containing indocyanine green, ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, and sodium chloride.

[0033] The present invention further relates to a kit comprising, in separate compartments, at least: (1) a composition containing indocyanine green, ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, and sodium chloride; and (2) an aqueous diluent.

[0034] The present invention further relates to a kit comprising, in separate compartments, at least: (1) indocyanine green (a) and (2) an aqueous solution containing at least ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, and sodium chloride.

[0035] The present invention further relates to a composition for use as a pharmaceutical or diagnostic agent, comprising indocyanine green, ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, and sodium chloride.

[0036] The present invention further relates to a method for diagnosing and / or treating a patient, comprising the step of administering, in particular by intravenous route, an effective amount of a composition containing indocyanine green, ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, and sodium chloride.

[0037] In one embodiment, the indocyanine green composition according to the present invention contains indocyanine green, one or more salts of ethylenediaminetetraacetic acid, histidine, and sodium chloride.

[0038] Advantageously, the ethylenediaminetetraacetic acid salt in this embodiment is selected from disodium EDTA, calcium sodium EDTA, tetrasodium EDTA, dicalcium EDTA, or a mixture thereof.

[0039] Preferably, the indocyanine green composition according to the present invention is provided in a weight percentage of the total weight of the following four compounds: 10-70% indocyanine green, 0.1-15% EDTA or its salt, 1-20% histidine, 20-80% sodium chloride, It contains.

[0040] Preferably, the indocyanine green composition is present in a weight percentage of the total weight of the following four compounds: 10-70% indocyanine green, 0.1-15% of one or more salts of ethylenediaminetetraacetic acid, 1-20% histidine, 20-80% sodium chloride, It contains.

[0041] In one embodiment, the composition further contains 5% by weight or less of sodium iodide relative to the weight of indocyanine green.

[0042] In one preferred embodiment, the indocyanine green composition according to the present invention is an aqueous composition.

[0043] In a more preferred embodiment, the indocyanine green composition according to the present invention is an aqueous composition filled in a vial or ampoule.

[0044] In one embodiment, the aqueous composition is redissolved from a kit comprising at least: (1) a composition containing indocyanine green, ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, and sodium chloride (particularly in the aforementioned amounts); and (2) an aqueous diluent; in separate compartments.

[0045] In other embodiments, the aqueous composition is redissolved from a kit comprising at least: (1) indocyanine green and (2) an aqueous solution containing at least ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, and sodium chloride, in separate compartments.

[0046] In other embodiments, the aqueous composition is redissolved from a kit comprising indocyanine green in a first part and an aqueous solution in a second part, the kit comprising at least ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, and sodium chloride (all of which are stabilizing compounds), one of which is present in one part and the other two in the other part.

[0047] Advantageously, the concentration of indocyanine green in the aqueous composition is 0.1 to 50 mg / ml, preferably 0.1 to 30 mg / ml.

[0048] In another embodiment, the composition is in the form of a freeze-dried powder. [Modes for carrying out the invention]

[0049] If the phrase "essentially consists of..." includes one or more components or processes / steps, it means that, in addition to the components or processes / steps explicitly stated, other components or processes / steps that do not significantly affect the characteristics or properties of the present invention may be included in the method or substance of the present invention.

[0050] The expression "X~Y" includes boundary values ​​unless otherwise specified. This expression means that the range includes not only the values ​​of X and Y themselves, but also all values ​​from X to Y.

[0051] Any description of treatment methods in this specification should be interpreted as a description of the use of the compounds, pharmaceutical compositions, and pharmaceuticals of the present invention in treatment or diagnostic methods of the human body (or animal body).

[0052] (Stability of the indocyanine green composition according to the present invention) The present invention aims to provide an indocyanine green composition with improved stability compared to prior art compositions.

[0053] The terms "stable composition" and "stability" refer to a composition in which the indocyanine green content remains stable even after a certain storage period (e.g., one week, one month, two months, six months, one year, two years, etc.).

[0054] The stability of the aforementioned composition is evaluated by measuring the change in the indocyanine green content in the composition after long-term storage.

[0055] Preferably, the compositions according to the present invention are advantageous in that they show virtually no signs of aggregation, decomposition, or precipitation even after long-term storage, and the formation of impurities due to chemical modification of indocyanine green is virtually nonexistent or minimal. Furthermore, the compositions according to the present invention are advantageous in that they do not undergo significant discoloration or a substantial decrease in fluorescence intensity or peak absorbance after long-term storage.

[0056] In particular, the present invention provides a composition containing indocyanine green that has improved stability compared to currently available indocyanine green formulations.

[0057] Advantageously, the compositions according to the present invention exhibit 10 times, more preferably 30 times, more preferably 50 times, and even more preferably 100 times greater stability than currently approved indocyanine green formulations.

[0058] In one embodiment, the composition according to the present invention is stable for at least one month, preferably three months or more, more preferably six months or more, even more preferably twelve months or more, and most preferably two years or more, when stored at room temperature.

[0059] "Room temperature" in the United States Pharmacopeia refers to a room temperature maintained at 20-25°C (with a slight tolerance of 15-30°C), while in the European Pharmacopoeia it refers to a room temperature maintained at 15-25°C.

[0060] Preferably, the composition according to the present invention is stable at room temperature for 1 month to 3 years, preferably 3 months to 3 years, more preferably 1 year to 3 years, and even more preferably 1 year to 2 years.

[0061] Advantageously, the compositions according to the present invention are stable for at least one month, preferably at least three months, more preferably at least six months, and most preferably at least two years, when stored in a container protected from natural light and / or ultraviolet light and / or fluorescence.

[0062] A container capable of protecting the composition from natural light and / or ultraviolet light and / or fluorescence is a container having walls with a maximum light transmittance of at least 50% at any wavelength. Generally, such a container may be an opaque or amber-colored container and / or an opaque secondary packaging material (e.g., a carton, overwrap, etc.).

[0063] Advantageously, the compositions according to the present invention are stable for at least one month, preferably at least three months, more preferably at least six months, and most preferably at least two years when stored in a highly sealed container or a sealed container.

[0064] The stability of the composition according to the present invention can be evaluated by visual inspection of color and / or transparency, and / or by other analytical methods.

[0065] Analytical techniques used to evaluate the stability of the aforementioned composition are known to those skilled in the art and include nuclear magnetic resonance (NMR), high-performance liquid chromatography (HPLC), size exclusion chromatography (SEC), liquid chromatography-mass spectrometry (LC-MS), dynamic light scattering (DLS), differential scanning calorimetry (DSC), UV spectroscopy, Fourier transform infrared spectroscopy (FTIR), or combinations thereof.

[0066] Advantageously, the stability of the composition is assessed by measuring the change in indocyanine green content in the composition before and after long-term storage using HPLC. More advantageously, the ICG content in the composition and the change in said content are assessed by the area percentage (%) at 240 nm using HPLC.

[0067] Preferably, the stability of the composition of the present invention corresponds to a decrease of 10% or less in the amount of indocyanine green content in the composition, as measured by the area percentage (%) at 240 nm by HPLC, when the composition is stored at room temperature for 1 month or more, preferably 3 months, more preferably 6 months, even more preferably 12 months, and most preferably 2 years or more.

[0068] Preferably, the stability of the composition of the present invention is evidenced by a decrease of 5% or less in the amount of indocyanine green content in the composition, measured by the area percentage (%) at 240 nm by HPLC, when the composition is stored at room temperature for 1 month or more, preferably 3 months, more preferably 6 months, even more preferably 12 months, and most preferably 2 years or more.

[0069] More preferably, the stability of the composition of the present invention is evidenced by a decrease of 2% or less in the amount of indocyanine green content in the composition, as measured by the area percentage (%) at 240 nm by HPLC, when the composition is stored at room temperature for 1 month or more, preferably 3 months, more preferably 6 months, even more preferably 12 months, and most preferably 2 years or more.

[0070] In the context of this application, "decrease in content" should be understood as the difference (%) between the measured value of the ICG content in the composition before storage, measured by the area percentage (%) at 240 nm using HPLC, and the measured value of the ICG content in the same composition after a predetermined storage period, also measured by the area percentage (%) at 240 nm using HPLC.

[0071] Preferably, the measured value of the ICG (indocyanine green) content in the composition before storage, measured as an area percentage (%) at 240 nm by HPLC, is 90% or higher, preferably 95% or higher, more preferably 97% or higher, and most preferably 99% or higher.

[0072] Furthermore, the stability of the indocyanine green composition of the present invention may correspond to the fact that the total amount of impurities contained in the composition of the present invention does not increase during storage, and in particular, does not increase to the extent that it reduces the ability of the indocyanine green composition to be used in medical and / or diagnostic applications.

[0073] For example, if the aforementioned composition is stored at room temperature for more than one month and then the impurities are measured by HPLC, only small amounts of impurities are detected in the composition, and they do not increase significantly over time.

[0074] In the context of this invention, the term "impurity" should be understood to mean a chemical substance that is neither indocyanine green nor an excipient or other additive of the indocyanine green composition of this invention.

[0075] The aforementioned impurities may be process-related impurities such as by-products and intermediates that may be formed during the production of indocyanine green, or decomposition-related impurities that arise from chemical changes in indocyanine green during storage. Decomposition-related impurities are products that may be formed during storage due to exposure to light, temperature, humidity, oxygen, etc.

[0076] In one embodiment, the increase in impurities in the composition according to the present invention, measured as the change in area percentage (%) at 240 nm by HPLC, when the composition is stored at room temperature for 1 month or more, preferably 2 months, more preferably 6 months, and most preferably 2 years or more, is 10% or less, preferably 5% or less, and more preferably 2% or less.

[0077] In one embodiment, the total amount of impurities in the ICG composition before storage, as measured as the area percentage (%) at 240 nm by HPLC, is 10% or less, preferably 5% or less, and more preferably 1% or less.

[0078] The term "total amount of impurities" includes both the manufacturing-related impurities and decomposition-related impurities mentioned above.

[0079] (Indocyanine green composition according to the present invention) The present invention provides a composition containing indocyanine green and an association of compounds comprising ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, and sodium chloride. The inventors of the present invention have found that the aforementioned association of compounds remarkably enables the stabilization and / or avoidance and / or inhibition of degradation of the ICG composition in an aqueous dilution, and / or improvement and / or extension of its shelf life. Hereafter, this association will be referred to as the "stabilizing compound."

[0080] Optionally, the compositions according to the present invention may contain, in addition to the above, one or more pharmaceutically acceptable additives different from the stabilizing compounds described in detail below.

[0081] (Indocyanine Green) The term indocyanine green refers not only to indocyanine green itself, but also to its pharmaceutically acceptable salts, solvates, hydrates, acids, anhydrides, and free bases, but preferably to indocyanine green itself.

[0082] [ka]

[0083] Indocyanine green can be prepared by any method known to those skilled in the art. For example, indocyanine green can be prepared according to the methods described in WO95 / 07888 and WO2017093889. Preferably, the preparation of indocyanine green includes a purification step of the obtained product.

[0084] Advantageously, the indocyanine green used in the compositions according to the present invention is substantially pure. Preferably, the indocyanine green used in the compositions according to the present invention is prepared as a composition with a purity measured by HPLC of over 90.0%, preferably over 95.0%, more preferably over 97.0%, and even more preferably over 99.7%.

[0085] As used herein, the term "purity" means that the raw material indocyanine green is free from unwanted or quality-degrading chemicals.

[0086] In this invention, the purity and impurities of the indocyanine green substance are evaluated by the area percentage (%) at 240 nm using HPLC.

[0087] Preferably, the indocyanine green used in the composition according to the present invention is prepared as a composition having an impurity content of less than 5.0%, preferably less than 1.0%, and more preferably less than 0.5%, as measured by HPLC.

[0088] Preferably, the indocyanine green used in the composition according to the present invention is prepared as a composition in which any impurity is less than 0.50%, preferably less than 0.40%, more preferably less than 0.20%, and most preferably less than 0.15%, as measured by HPLC.

[0089] The impurities contained in the indocyanine green may be any reaction by-products or intermediates generated during the manufacturing process. For example, as described in US2019 / 0337896, the impurities may include, but are not limited to, N-phenylacetamide, 4-(1,1,2-trimethyl-1H-benzo[e]indlium-3-yl)butane-1-sulfonate, and 4-(1,1,2-dimethyl-2-((1E,3E,5E)-6-(N-phenylacetamide)hexa-1,3,5-trienyl)-1H-benzo[e]indlium-3-yl)butane-1-sulfonate.

[0090] Preferably, the indocyanine green is prepared as a composition in which the content of metal contaminants is less than 200 ppm by weight, preferably less than 100 ppm by weight, more preferably less than 50 ppm by weight, and even more preferably less than 20 ppm by weight, relative to the weight of the indocyanine green. The content of metal contaminants in the indocyanine green can be measured by inductively coupled plasma mass spectrometry (ICP-MS).

[0091] Please understand that "metallic contaminants" refer to so-called "heavy" metals, particularly Al, As, Cd, Cr, Cu, Fe, Sn, Mn, Hg, Mo, Ni, Pb, Zn, and their organic and inorganic derivatives.

[0092] More preferably, the indocyanine green does not contain lead and arsenic, or contains less than 2 ppm of lead and arsenic.

[0093] The indocyanine green used in the composition of the present invention is prepared as a composition that may further contain sodium iodide. Sodium iodide is an additive that is often present in commercially available indocyanine green compositions. If present, it is desirable that the iodide content be kept to less than 5% by weight relative to the weight of the indocyanine green. The sodium iodide content in the indocyanine green can be measured by potentiometric assay.

[0094] The indocyanine green used in the composition of the present invention may be provided in any form, such as a freeze-dried product or a crystalline powder, as long as it is in an appropriate form.

[0095] (stabilizing compound) The composition according to the present invention contains indocyanine green and an association of stabilizing compounds comprising ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, and sodium chloride.

[0096] Advantageously, the salt of ethylenediaminetetraacetic acid can be selected from disodium EDTA, calcium sodium EDTA, tetrasodium EDTA, dicalcium EDTA, or mixtures thereof. Furthermore, these salts of ethylenediaminetetraacetic acid may be in the form of hydrated salts.

[0097] "These mixtures" refers to mixtures containing various salts of EDTA in any proportion.

[0098] For the purposes of this invention, "histidine" refers to the L-type optical isomer or D-type optical isomer of the amino acid histidine. More advantageously, histidine refers to the L-type optical isomer of the amino acid histidine.

[0099] In a preferred embodiment, the composition contains indocyanine green, one or more salts of EDTA, histidine, and sodium chloride.

[0100] In a preferred embodiment, the salt of EDTA is selected from tetrasodium EDTA, calcium sodium EDTA, or a mixture thereof.

[0101] The inventors of this invention have found that, surprisingly, the stability of indocyanine green compositions in aqueous solvents is improved by using a combination of ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, and sodium chloride.

[0102] In one preferred embodiment of the present invention, the composition essentially comprises indocyanine green, ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, and sodium chloride.

[0103] In another preferred embodiment of the present invention, the composition essentially comprises indocyanine green, ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, sodium chloride, and iodide.

[0104] Advantageously, the composition according to the present invention contains, in weight % of the total weight of the following four types of compounds: 10-70% indocyanine green, 0.1-15% EDTA or its salt, 1-20% histidine, 20-80% sodium chloride, It contains, and preferably consists essentially of, these.

[0105] More preferably, the composition according to the present invention is present in a weight % of the total weight of the following four types of compounds: 15-60% indocyanine green, 1-10% EDTA or its salt, 2-15% histidine, 30-70% sodium chloride, It contains, and preferably consists essentially of, these.

[0106] Advantageously, in the second embodiment, the composition according to the present invention is, in weight % of the total weight of the following five compounds: 10-70% indocyanine green, 0.1-10% EDTA or its salt, 1-20% histidine, 20-80% sodium chloride, 0-5% sodium iodide and It contains, and preferably consists essentially of, these.

[0107] More preferably, in this embodiment, the composition according to the present invention is present in weight % of the total weight of the following five compounds: 15-60% indocyanine green, 1-10% EDTA or its salt, 2-15% histidine, 30-70% sodium chloride, 0-5% sodium iodide and It contains, and preferably consists essentially of, these.

[0108] In the third embodiment, the composition according to the present invention is, in weight % of the total weight of the following six compounds: 10-70% indocyanine green, 0.1-10% EDTA or its salt, 1-20% histidine, 20-80% sodium chloride, 0-5% sodium iodide and 0.1-15% of one or more pharmaceutically acceptable excipients, It contains, and preferably consists essentially of, these.

[0109] More preferably, in this embodiment, the composition according to the present invention is present in weight % of the total weight of the following six compounds: 15-60% indocyanine green, 1-10% EDTA or its salt, 2-15% histidine, 30-70% sodium chloride, 0-5% sodium iodide and 0.1-15% of one or more pharmaceutically acceptable excipients, It contains, and preferably consists essentially of, these.

[0110] In another embodiment, the present invention relates to the use of associations of previously disclosed stabilizing compounds to improve the storage stability of ICG compositions.

[0111] (Other additives) The composition according to the present invention may further contain one or more pharmaceutically acceptable additives.

[0112] As used herein, the term “pharmaceutically acceptable” refers to compounds, substances, and compositions suitable for use in a manner that is free from excessive toxicity, irritation, or other problems or complications, such as contact with human or animal tissues, and is commensurate with a reasonable benefit-risk ratio.

[0113] The term "additives" includes components in the composition other than ICG, ethylenediaminetetraacetic acid (EDTA) or its salts, histidine, sodium chloride, and sodium iodide. Examples of such additives include buffers, pH adjusters, isotonic agents, surfactants, preservatives, tonicifying agents, antimicrobial agents, wetting agents, and emulsifiers.

[0114] For example, the compositions of the present invention may contain one or more additives selected from the group including: sodium hydroxide; potassium hydroxide; methylparaben; propylparaben; sodium acetate; sodium citrate; sodium carbonate; ammonium carbonate; sodium bicarbonate; benzoates or benzoates; acetates or acetates; boric acid; lactic acid; glutaric acid; malic acid; succinic acid; carbonate; alkali salts or alkaline earth salts of these acids; meglumine; hydrochloric acid; cyclodextrin derivatives; sorbitan monolaurate; triethanolamine acetate; triethanolamine oleate; citric acid; lactic acid; phosphoric acid; sulfuric acid; arginine; alanine; glycine; and lysine.

[0115] These additives are generally available to those skilled in the art and may be in any form, such as solid, liquid, or semi-solid.

[0116] Preferably, the amount of additives in the composition of the present invention is within a range that does not significantly adversely affect the activity of indocyanine green. Preferably, the composition of the present invention contains the minimum number and amount of additives necessary to provide a stable and effective composition.

[0117] (Form of composition according to the present invention) The compositions according to the present invention may be provided in any suitable form, but are preferably provided in the form of an aqueous composition or a freeze-dried solid composition.

[0118] (aqueous composition) In the first embodiment, the composition according to the present invention is in the form of an aqueous composition.

[0119] Please understand that "aqueous composition" refers to aqueous solutions, aqueous suspensions, colloidal aqueous suspensions, and aqueous dispersions, preferably aqueous solutions.

[0120] The term "aqueous solution" refers to the aforementioned indocyanine green composition in which the components are dissolved in an aqueous solvent.

[0121] Advantageously, the compositions of this example contain, in particular, an aqueous diluent, indocyanine green, ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, and sodium chloride, in the amounts disclosed above, and optionally, one or more pharmaceutically acceptable additives.

[0122] The aforementioned aqueous diluent is a pharmaceutically acceptable solvent, safe and non-toxic for administration to humans or animals, and useful for the preparation of pharmaceutical formulations.

[0123] The aqueous diluent consists of water and may contain one or more pharmaceutically acceptable additives. In some examples of the methods disclosed later, the previously defined ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, and sodium chloride are added to the aqueous diluent before ICG is mixed in. In such embodiments, one or more of these compounds may also be considered part of the aqueous diluent.

[0124] A suitable aqueous diluent may be any liquid that is biologically acceptable and capable of completely dissolving the composition of the present invention. Water, in particular sterile water for injection (SWFI) and / or bacteriostatic water for injection (BWFI), is a preferred diluent because it does not contain salts or other compounds that may affect the stability of the ICG. However, other aqueous diluents such as sterile saline, Ringer's solution, dextrose solution, and glucose solution may be used.

[0125] In one embodiment, the aqueous diluent is selected from the group consisting of water for injection, bacteriostatic water for injection, sterile physiological saline, Ringer's solution, dextrose solution, and glucose solution.

[0126] Those skilled in the art can select the diluent according to the desired application and in relation to compounds other than the diluent of the composition. Furthermore, those skilled in the art can adjust the amount of the excipient according to its solubility in the aqueous solution.

[0127] In one preferred embodiment, the aqueous diluent is water for injection, particularly sterile water for injection (SWFI) and / or bacteriostatic water for injection (BWFI).

[0128] The aqueous diluent may further contain a buffer, bacteriostats, and a solute to make the composition isotonic with the blood of the intended recipient.

[0129] In one embodiment, the aqueous diluent is not a buffer solution and does not contain a buffering agent.

[0130] Advantageously, the osmotic pressure of the aqueous solution is 1 mOsM or higher. More advantageously, the osmotic pressure of the aqueous solution is 1 to 300 mOsM, more preferably 1 to 200 mOsM.

[0131] The concentration of indocyanine green in the aqueous composition of the present invention may be any concentration suitable for use in medical procedures or diagnostics, in particular any concentration suitable for producing angiographic images of satisfactory quality.

[0132] In one preferred embodiment, the concentration of indocyanine green in the aqueous composition according to the present invention is 0.1 to 50 mg / ml, most preferably 0.1 to 30 mg / ml.

[0133] If the concentration of the ICG solution is less than 0.1 mg / ml, it will not produce sufficient fluorescence for satisfactory detection by analytical instruments.

[0134] In one preferred embodiment, the concentration of indocyanine green in the aqueous composition according to the present invention is 0.1 to 25 mg / ml, preferably 1 to 25 mg / ml, and more preferably 1 to 10 mg / ml.

[0135] When one or more components of the composition of the present invention are added in aqueous solution, the amount of aqueous diluent can be adjusted to an amount such that the concentration of ICG becomes the desired concentration.

[0136] In one embodiment of the present invention, the aqueous composition essentially comprises an aqueous diluent, indocyanine green, ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, and sodium chloride.

[0137] In other embodiments, the aqueous composition essentially comprises an aqueous diluent, indocyanine green, ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, sodium chloride, and sodium iodide.

[0138] The preferred proportion (%) of the compounds (ICG and stabilizing compounds) in the aqueous composition is the same as that specified in the "Stabilizing Compounds" section above.

[0139] (lyophilized solid composition) In another preferred embodiment, the composition according to the present invention is in the form of a freeze-dried composition or a freeze-dried powder.

[0140] The terms "freeze-dried composition," "freeze-dried powder," and "freeze-dried product" refer to the solid composition according to the present invention obtained by freeze-drying an aqueous solution.

[0141] The term "freeze-drying" refers to a process in which the composition in an aqueous solvent is first frozen, and then the frozen solvent is removed by sublimation under vacuum conditions.

[0142] When the composition according to the present invention is provided as a lyophilized product, it can be converted into a dosing solution using the aqueous diluent described herein before administration. In this case, the redissolved aqueous solution (which is also a composition according to the present invention) is stable at room temperature for at least one month, preferably two months, more preferably six months, and most preferably two years or more.

[0143] The limitations regarding ICG concentration, pH, osmotic pressure, and stability mentioned earlier in relation to aqueous diluents also apply to aqueous solutions obtained by redissolving the freeze-dried composition according to the present invention.

[0144] Furthermore, in one embodiment, the freeze-dried composition according to the present invention has a short re-dissolution time of less than 2 minutes, preferably less than 1 minute, making it suitable for intravenous administration after dilution with an aqueous diluent.

[0145] "Redissolution time" refers to the time required to rehydrate the freeze-dried composition with an aqueous solution to obtain a particle-free clarified liquid.

[0146] After the composition has been redissolved as an aqueous solution for medical or diagnostic purposes, it is preferable to store it in a container that protects it from light and oxygen.

[0147] (kit) In a preferred embodiment, the present invention relates to a kit comprising, in a first part, a composition in the form of a freeze-dried powder according to the present invention, and in a second part, an aqueous diluent.

[0148] In other preferred embodiments, the present invention relates to a kit comprising: indocyanine green in the first part; and an aqueous solution in the second part containing at least ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, and sodium chloride;

[0149] In another embodiment, the present invention relates to a kit comprising indocyanine green in a first part and an aqueous solution in a second part, the kit comprising at least ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof (stabilizing compound), histidine (stabilizing compound), and sodium chloride (stabilizing compound), wherein one of these stabilizing compounds is present in one part and the other two stabilizing compounds are present in the other part.

[0150] In any embodiment of the kit, the solid portion containing indocyanine green is preferably in the form of a freeze-dried powder.

[0151] In any embodiment of the kit, the aqueous solution may optionally contain one or more of the additives described above.

[0152] All preferred embodiments described above for the ICG composition and the aqueous diluent are applicable to any example of the kit.

[0153] In one embodiment, the kit according to the present invention is composed of each component (powder (power) and diluent) in such amounts that the ICG concentration of the aqueous solution redissolved from the kit is in the range of 0.1 to 50 mg / ml, preferably 0.1 to 30 mg / ml, more preferably 0.1 to 25 mg / ml, even more preferably 1 to 25 mg / ml, and most preferably 1 to 10 mg / ml.

[0154] In the above preferred embodiments, the kit comprises at least two separate compartments in which the freeze-dried powder and the aqueous diluent are stored separately.

[0155] The kit may consist of two separate vials packaged with or without syringes, or it may consist of a pre-filled syringe having two compartments, such as a dual-chamber bypass syringe.

[0156] The above-described kit makes it possible to mix the powder and the aqueous solution before administration.

[0157] Regardless of which example kit is used, a stable aqueous solution of indocyanine green can be immediately redissolved as described. These kits offer the advantage of providing each component of the composition necessary for injection in the appropriate amount and under optimal storage conditions to achieve the desired concentration. In other words, the aqueous composition can be redissolved without the need to dilute it with a diluent other than the one included in the kit. This kit packaging helps to prevent administration errors and contamination.

[0158] (Method for preparing a composition according to the present invention) The compositions according to the present invention may be prepared by any known method, and are not limited to any particular method.

[0159] For example, the composition may be prepared by mixing the indocyanine green with ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, and sodium chloride (optionally, further one or more pharmaceutically acceptable excipients).

[0160] Preferably, the mixing of the components of the composition according to the present invention is carried out in the aqueous solvent described above. The order in which the components constituting the composition according to the present invention are added can vary. For example, indocyanine green may be dissolved in the aqueous diluent, and then ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, sodium chloride, and various additives may be added. The stabilizing compounds may be mixed together and then added to the dissolved indocyanine green. Alternatively, indocyanine green may be added to an aqueous solution in which the stabilizing compounds (and optionally, various pharmaceutically acceptable additives) have been dissolved beforehand.

[0161] Preferably, the mixing is carried out under an inert atmosphere such as an argon or nitrogen atmosphere. The aqueous diluent and / or liquid component is preferably degassed before use.

[0162] When the composition according to the present invention is provided as a freeze-dried product, freeze-drying can be carried out using standard freeze-drying or vacuum-drying equipment. The freeze-drying cycle may be modified by those skilled in the art by adjusting the equipment and facilities used.

[0163] Preferably, the aqueous solution before freeze-drying is an aqueous solution of indocyanine green as described above. The aqueous solution according to the present invention before freeze-drying can be sterilized before freeze-drying. Generally, this sterilization is performed by filtering the solution through a suitable membrane.

[0164] Preferably, the aqueous solution is freeze-dried shortly after preparation to prevent decomposition of the composition. The freeze-dried product can be used even after being stored for several months. Preferably, the freeze-dried product is stored under conditions protected from air and / or humidity and / or light.

[0165] Furthermore, if the indocyanine green composition according to the present invention is provided as an aqueous composition, it may be redissolved using the lyophilized product and aqueous diluent of the kit described above. When redissolving, the lyophilized composition may be introduced into the vial before the aqueous diluent is added.

[0166] Advantageously, the composition, prepared in lyophilized or aqueous form, is immediately placed in an airtight, light-protected container after preparation. The container may be, for example, a bottle, ampoule, vial, syringe, or tube. The container may be made of, for example, glass, polymer, or metal. The container may be a single-dose container or a multi-dose container.

[0167] In a preferred embodiment of the present invention, the container is preferably a colored glass vial or a colored glass ampoule. Advantageously, the container is selected from a colored glass vial with vacuum headspace or a colored glass ampoule. Preferably, the composition according to the present invention is stored in a colored glass ampoule.

[0168] Advantageously, the composition according to the present invention can be stored at room temperature.

[0169] (Use of the composition according to the present invention) The compositions of the present invention may be used in methods of diagnosing and / or treating (as therapeutic agents) patients. The method comprises the step of administering an effective amount of an aqueous solution according to the present invention. The administration may be carried out via an enteral route, a parenteral route, in particular by intravenous injection or topical application. Preferably, the administration is carried out by intravenous injection.

[0170] The term "effective dose" refers to the amount of indocyanine green that elicits a biological or medical response in a tissue, system, animal, or human, as desired by researchers, clinicians, etc.

[0171] Advantageously, the compositions of the present invention can be used in the diagnostic and / or therapeutic methods described above, and the aqueous ICG composition, which has been prepared or redissolved from any of the kits described above for at least one month, preferably at least six months, more preferably at least twelve months, and most preferably at least two years, is administered to the patient.

[0172] In particular, the compositions according to the present invention can be used in hyperthermia, ICG-enhanced selective photocoagulation, photodynamic therapy (PDT), and photodynamic hyperthermia (PHT). More specifically, the compositions according to the present invention can be used for PDT applications such as the treatment of infectious diseases, acne, macular surgery, and cancer. The compositions according to the present invention may also be used in conjunction with other therapeutic procedures such as immunotherapy, radiotherapy, ultrasound therapy, and chemotherapy.

[0173] Furthermore, the compositions according to the present invention may be used to obtain angiographic images of a patient's tissue, measure cardiac output, measure liver function and hepatic blood flow, and diagnose and treat age-related macular degeneration, associated choroidal neovascularization, and tumors.

[0174] The compositions according to the present invention are based on components that have been approved for administration to humans and / or animals after clinical trials.

[0175] For diagnostic purposes, the amount of ICG composition administered to a patient must be sufficient to ensure that the dye fluoresces when irradiated at an appropriate wavelength, taking into account that the absorption and emission peaks of ICG are in the range of 800-850 nm. Similarly, in therapeutic methods using ICG solution, sufficient dye must be administered to ensure efficient treatment. The dosage of the ICG composition can be easily determined by those skilled in the art, and it is desirable that it be at or above the currently permitted concentrations for ophthalmic angiography. For example, for diagnostic purposes, 2 ml of 20 mg / mL ICG solution is used. Those skilled in the art will understand that higher concentrations of the dye can be advantageous in any of the above diagnostic and therapeutic methods.

[0176] Because the ICG in solution according to the present invention has improved stability, patient diagnosis / treatment is improved even with the same injection volume of the compound as in prior art ICG compositions. This is possible because the improved stability of the ICG leads to a stronger response to fluorescence irradiation. [Examples]

[0177] (I. Raw Materials and Methods) (1. Reagents and chemicals) Indocyanine green was used without purification from the product marketed by Biophore India Pharmaceuticals. Tetrasodium EDTA hydrate (EDTA4Na) (CAS number: 194491-31-1), EDTA2NaCa (CAS number: 62-33-9), and histidine (CAS number: 71-00-1) were purchased from Aldrich and used without purification. NaCl solution (CAS number: 7647-14-5) was purchased from VWR.

[0178] (2.Equipment) The stability of the formulations in the examples was measured by high-pressure liquid chromatography (HPLC). The analysis was performed using an Agilent Infinity 1260 HPLC / MS system equipped with a diode array detector (UV to visible light), a Waters XbridgeShield RP18 (4.6 x 100; 5 μm) column, and an ESI mass spectrometer (solution input: 5 μL, flow rate: 1 ml / min, column temperature: 30°C, detection: 240 nm).

[0179] Elution was performed by gradient elution. The mobile phase consisted of a mixture of ammonium acetate / acetic acid buffer (10 mM, pH: 5.5) (eluent A) and acetonitrile (eluent B). The composition of the mobile phase was continuously changed during the elution process according to Table I below:

[0180] [Table 1]

[0181] (II. Sample Preparation) The following ICG composition was prepared as follows: The desired amount of EDTA salt and / or histidine was weighed into a Type I clear glass vial. Next, 25 mg of indocyanine green was weighed in, taking into account the tare weight of the vial. The vial was closed with a bromobutyl rubber stopper (VWS), and then purged with a nitrogen stream.

[0182] For compositions C3, C4, C7, and C8, an additional 10 ml of WFI, which has been degassed with nitrogen beforehand, is added using a syringe.

[0183] For compositions C1 and C5, 5 ml of pre-degassed WFI and 5 ml of pre-degassed 0.9% NaCl solution are added.

[0184] For compositions C2 and C6, 5 ml of pre-degassed WFI and 5 ml of pre-degassed 0.45% NaCl solution are added.

[0185] Composition C9 was prepared by weighing 25 mg of ICG into a vial, closing the vial with a bromobutyl rubber stopper, purging with a nitrogen stream, and then adding 5 ml of degassed WFI and 5 ml of degassed 0.9% NaCl solution.

[0186] Gently stir the vials manually to dissolve the solute. Then, store the vials at room temperature, away from light.

[0187] (III. Results)

[0188] [Table 2]

[0189] The results above show that even using only EDTA salts and histidine can improve the storage stability of ICG compositions containing them. Furthermore, these results indicate that using EDTA2NaCa or EDTA4Na salts in combination with histidine and NaCl produces a synergistic effect. ICG solutions C1 and C2 are significantly more stable than compositions containing only one or two of the (claimed) aggregates of the present invention. Furthermore, the present invention includes the following embodiments. (Aspect 1) 10-70% indocyanine green, 0.1-15% ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, 1-20% histidine, 20-80% sodium chloride, An indocyanine green composition containing at least (wherein the above percentage is a weight percentage relative to the total weight of the four compounds mentioned above). (Aspect 2) In the indocyanine green composition described in Aspect 1, 10-70% indocyanine green, 0.1-15% of one or more salts of ethylenediaminetetraacetic acid, 1-20% histidine, 20-80% sodium chloride, An indocyanine green composition containing (wherein the above percentage is the weight percentage relative to the total weight of the four compounds mentioned above). (Aspect 3) An indocyanine green composition according to aspect 1 or 2, wherein one or more salts of ethylenediaminetetraacetic acid are selected from EDTA disodium, EDTA calcium sodium, EDTA tetrasodium, EDTA dicalcium, or mixtures thereof. (Aspect 4) An indocyanine green composition according to any one of aspects 1 to 3, further containing 5% by weight or less of sodium iodide relative to the weight of indocyanine green. (Aspect 5) An indocyanine green composition according to any one of aspects 1 to 4, wherein the indocyanine green composition is an aqueous composition. (Aspect 6) An indocyanine green composition according to the indocyanine green composition of Aspect 5, wherein the concentration of indocyanine green in the aqueous composition is 0.1 to 50 mg / ml. (Aspect 7) An aqueous composition according to aspect 5 or 6, wherein the content of ICG (indocyanine green) in the composition before storage, as measured as the area percentage (%) at 240 nm by HPLC, is 90% or more. (Aspect 8) An indocyanine green composition according to any one of aspects 1 to 4, wherein the composition is in the form of a freeze-dried powder. (Aspect 9) An indocyanine green composition according to any one of aspects 1 to 8, wherein the indocyanine green composition is used as a pharmaceutical or diagnostic agent. (Aspect 10) At least (1) the composition described in Aspect 8, and 2) an aqueous diluent, A kit that provides these in separate compartments. (Aspect 11) A kit usable for preparing the composition according to any one aspect of aspects 5 to 7, comprising in separate compartments: (1) indocyanine green and (2) an aqueous solution containing at least ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, and sodium chloride.

Claims

1. 10-70% indocyanine green, 0.1-15% ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, 1-20% histidine, 20-80% sodium chloride, An indocyanine green composition containing at least (wherein the above percentage is a weight percentage relative to the total weight of the four compounds mentioned above).

2. In the indocyanine green composition according to claim 1, 10-70% indocyanine green, 0.1-15% of one or more salts of ethylenediaminetetraacetic acid, 1-20% histidine, 20-80% sodium chloride, An indocyanine green composition containing (wherein the above percentage is the weight percentage relative to the total weight of the four types of compounds).

3. An indocyanine green composition according to claim 1 or 2, wherein one or more salts of ethylenediaminetetraacetic acid are selected from disodium EDTA, calcium sodium EDTA, tetrasodium EDTA, dicalcium EDTA, or mixtures thereof.

4. The indocyanine green composition according to any one of claims 1 to 3, further, Sodium iodide in an amount of 5% by weight or less relative to the weight of indocyanine green. An indocyanine green composition containing the following:

5. An indocyanine green composition according to any one of claims 1 to 4, wherein the indocyanine green composition is an aqueous composition.

6. An indocyanine green composition according to claim 5, wherein the concentration of indocyanine green in the aqueous composition is 0.1 to 50 mg / ml.

7. An aqueous composition according to claim 5 or 6, wherein the content of ICG (indocyanine green) in the composition before storage, as measured as the area percentage (%) at 240 nm on an HPLC, is 90% or more.

8. An indocyanine green composition according to any one of claims 1 to 4, wherein the composition is in the form of a freeze-dried powder.

9. An indocyanine green composition according to any one of claims 1 to 8, wherein the indocyanine green composition is used as a pharmaceutical or diagnostic agent.

10. at least, (1) The composition according to claim 8, (2) Aqueous diluent and A kit that provides these in separate compartments.

11. at least, (1) Indocyanine green and, (2) an aqueous solution containing at least ethylenediaminetetraacetic acid (EDTA) and / or one or more salts thereof, histidine, and sodium chloride, A kit usable for preparing the composition according to any one of claims 5 to 7, comprising the components in separate compartments.

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