Compositions for near-infrared lymphatic imaging and uses and doses thereof

Abstract

Disclosed are imaging agents for near-infrared imaging of lymph nodes or lymphatic vessels, which can be used to selectively image primary lymph nodes relative to secondary and subsequent lymph nodes; and doses of the composition suitable for imaging lymph nodes or lymphatic vessels.

Description

Technical Field

[0001] The present disclosure relates to a composition for near infrared imaging of lymph nodes or lymphatic vessels, wherein primary lymph nodes can be selectively imaged relative to secondary and subsequent lymph nodes, and the present disclosure relates to the use and dosage of the composition suitable for imaging lymph nodes or lymphatic vessels. Background Art

[0002] The lymphatic system (along with the blood system) is an important circulatory system in the human body that transports fluids from peripheral tissues and forms part of the immune system. In the lymphatic system, lymph is produced from interstitial fluid derived from plasma components flowing into the capillary lymphatic vessels, and enters the blood system from the lymphatic vessels via the thoracic duct or lymph nodes. Lymph nodes play a filtering role in the lymphatic system and play the immune function of immune cells against non-self antigen targets such as foreign substances, pathogens, and cancer cells. Lymphatic system disorders can cause biological dysfunctions such as idiopathic or surgery-related secondary lymphedema. When cancer develops in the body and metastasizes to other organs, it metastasizes to distant sites through the main lymphatic system. The lymph nodes that pass first after the cancer site are called sentinel lymph nodes, and biopsy of sentinel lymph nodes to check whether systemic metastasis occurs via the lymphatic system has become one of the most important diagnostic methods in modern cancer treatment. Because it is difficult to examine the lymphatic system with the naked eye, various lymphatic system detection methods have been designed and put into practical use. Indigo carmine is a purplish blue pigment known as Blue No. 2 that has been widely used as a food additive for a long time. In medical applications, it is used for renal function tests by intravenous administration and as an imaging agent by intratissue administration. Indigo carmine is also used for sentinel lymph node biopsy, but identification can sometimes be difficult, and improving the identification rate is a challenge. The technology using the radioactive isotope technetium-99m has also become an important tool in sentinel lymph node biopsy, but the technology is hindered by the complexity of administering drugs at multiple sites of the patient the day before surgery, the imprecise location identification due to radioactive detection rather than visual detection, and the need to obtain nuclear licenses and prepare, handle and dispose of nuclear waste. In addition, exposure of patients and medical staff to radiation is a disadvantage.

[0003] In recent years, fluorescence imaging techniques using near-infrared wavelengths that easily pass through biological components have become popular, and the medical applications of such imaging have increased. Near-infrared wavelengths are on the longer wavelength side of the visible light wavelength range and cannot be visually perceived. However, because these wavelengths can be detected with high sensitivity using, for example, a CCD camera, they are an effective means of enhancing visual recognition during surgery. Indocyanine green is a known fluorescent agent using near-infrared wavelengths and is sold in Japan as an agent for liver / circulatory function testing, a fluorescent angiographic contrast agent, and a sentinel lymph node identification agent.

[0004] When administered around a tumor, indocyanine green tends to migrate to sentinel lymph nodes and then to lymph nodes further downstream. This migration can result in bright green lymph nodes that appear to be sentinel lymph nodes but are actually secondary and tertiary lymph nodes, and can result in very bright signals that are misidentified as lymph nodes when they are actually dilated lymphatic vessels. Therefore, the use of indocyanine green carries the risk of misidentifying and removing lymph nodes that do not need to be removed, as well as removing lymphatic vessels that are misidentified as lymph nodes. Currently, there are no fluorescent agents that use the near-infrared region to selectively and highly sensitively identify sentinel lymph nodes.

[0005] US2012 / 0302881 A1 mentions a cyclodextrin-bonded indocyanine compound represented by Chemical Formula 15, Chemical Formula 16, Chemical Formula 19 or Chemical Formula 20, including a compound represented by Formula (I) (Pudexacianinium), which is a fluorescent agent using a near-infrared wavelength. The diagnostic composition containing the compound can be applied to sentinel lymph node identification, lymphedema assessment, intraoperative cholangiography, tumor markers, coronary angiography, abdominal angiography (hepatic artery, abdominal aorta, gastrointestinal blood flow, etc.) of cancer (breast cancer, esophageal cancer, gastric cancer, colon cancer, prostate cancer, skin cancer, etc.), fundus angiography, cerebral circulation assessment, and intraoperative angiography in brain surgery.

[0006] (I)

[0007] According to Mol Imaging Biol (2021) (non-patent document 1), DOI:10.1007 / s11307-021-01613-0, published online on May 11, 2021, and Clinical Pharmacology in Drug Development, 2021, 10 (12) 1460-1468 (non-patent document 2), the compound represented by formula (I) is a compound used as a ureteral imaging agent during surgery. Summary of the invention

[0008] Provided herein are compositions for near infrared imaging of lymph nodes or lymphatic vessels. The compositions disclosed herein comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0009] (I)

[0010] And the composition is characterized by selectively imaging primary lymph nodes relative to secondary and subsequent lymph nodes.

[0011] Also provided is a composition for near-infrared imaging of lymph nodes or lymphatic vessels, the composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the composition is used so that the compound of formula (I) or a pharmaceutically acceptable salt thereof is topically administered in an amount of 0.005 to 10 mg / dose, based on the weight of the compound of formula (I) in free form.

[0012] Also provided herein is a method for imaging the primary lymph nodes of a patient, the method comprising administering to the patient an effective amount of a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and exposing the subject to near-infrared light to image the primary lymph nodes of the subject, wherein the primary lymph nodes are selectively imaged relative to the secondary lymph nodes and subsequent lymph nodes. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 Shown are near-infrared fluorescence images captured near the inguinal region 10 minutes (left), 20 minutes (middle), and 30 minutes (right) after subcutaneous administration of ICG (R: right) and compound (I) (pridisal chloride) (L: left) near the second nipple of a minipig.

[0014] Figure 2 Shown are near-infrared fluorescence images captured near the administration site within 10 seconds after 0.1 mL of an aqueous solution containing (1) 1 mg / mL, (2) 0.1 mg / mL, (3) 0.01 mg / mL, and (4) 0.001 mg / mL of compound (I) was subcutaneously administered to the abdomen of a miniature pig.

[0015] Figure 3 The diagram shows near-infrared fluorescence images captured near the inguinal region and after removal of the inguinal lymph nodes when the maximum trend was shown, after 0.1 mL of an aqueous solution containing 1 mg / mL ((1) - transdermal observation of inguinal lymph nodes; (2) - observation of inguinal lymph nodes at the time of removal), 0.1 mg / mL ((3) - transdermal observation of inguinal lymph nodes; (4) - observation of inguinal lymph nodes at the time of removal), and 0.01 mg / mL ((5) - transdermal observation of inguinal lymph nodes; (6) - observation of inguinal lymph nodes at the time of removal) of compound (I), and 5 mg / mL ((7) - transdermal observation of inguinal lymph nodes; (8) - observation of inguinal lymph nodes at the time of removal), and 2.5 mg / mL ((9) - transdermal observation of inguinal lymph nodes; (10) - observation of inguinal lymph nodes at the time of removal) of ICG was subcutaneously administered to miniature pigs.

[0016] Figure 4The near-infrared fluorescence image and bright-field image 10 minutes after the subcutaneous chest administration of compound (I) (1 mg / mL of ASP5354) and ICG (2.5 mg / mL) to beagle dogs, as well as the near-infrared fluorescence image and bright-field image of the exposed and removed axillary lymph nodes are shown. The observation in (1) is a transdermal observation of the thoracic lymphatic vessels. The observation of the axillary lymph nodes in (2) was obtained at the time of exposure and removal.

[0017] Figure 5 The near-infrared fluorescence images (1, 2) near the lymph nodes below the kneecap 20 minutes after subcutaneous administration of compound (1) and ICG to the interdigital part of the hind limb of a beagle dog, near-infrared fluorescence images (3, 4) near the internal iliac lymph nodes 90 to 100 minutes after subcutaneous administration, and photographs and near-infrared fluorescence images (5-12) after removal are shown. More specifically, Figure 5 The images show: (1) an in vivo near-infrared fluorescence image of the lymph nodes below the right kneecap 20 minutes after the administration of compound (I); (2) an in vivo near-infrared fluorescence image of the lymph nodes below the left kneecap 20 minutes after the administration of ICG; (3) an in vivo near-infrared fluorescence image of the right internal iliac lymph nodes 100 minutes after the administration of compound (I), wherein the arrow indicates the urethra and the dotted circle indicates the internal iliac lymph nodes; (4) an in vivo near-infrared fluorescence image of the left internal iliac lymph nodes 93 minutes after the administration of ICG, wherein the arrow indicates the urethra and the dotted circle indicates the internal iliac lymph nodes; (5) an in vivo near-infrared fluorescence image of the right iliac lymph nodes removed after the administration of compound (I). (10) an ex vivo near-infrared fluorescence image of the right internal iliac lymph node after administration of compound (I); (11) a photograph of the left internal iliac lymph node after administration of ICG; and (12) an ex vivo near-infrared fluorescence image of the left internal iliac lymph node after administration of ICG. DETAILED DESCRIPTION

[0018] The object of the present disclosure is to provide a composition for near infrared imaging of lymph nodes or lymphatic vessels, wherein primary lymph nodes can be selectively imaged relative to secondary and subsequent lymph nodes; and to establish uses and dosages for the composition suitable for imaging lymph nodes or lymphatic vessels. Sentinel lymph node (SLN) detection in patients with cancer (e.g., localized breast cancer, melanoma, cervical cancer, head and neck malignancies, or gastrointestinal malignancies) allows diagnosis of the presence of lymphatic spread and avoids complications associated with extended removal of lymph nodes. This is important because it has been shown that the extent of lymphatic complications is related to the number of lymph nodes removed.

[0019] Indocyanine green, which has been used as a sentinel lymph node identification agent, tends to diffuse beyond the primary lymph nodes to reach the secondary and subsequent lymph nodes. This property may be due to the high hydrophobicity and tendency of indocyanine green to adsorb to lipids. Therefore, a compound represented by formula (I) (Pradixagin, sometimes referred to as "ASP5354" in this specification) was studied, which has a high water solubility.

[0020] (I)

[0021] The compound represented by formula (I) is an iodine-free indocyanine compound that exhibits hydrophilicity by conjugation with cyclodextrin while maintaining near-infrared fluorescence (NIR-F) properties. Due to its hydrophilic nature, the compound represented by formula (I) is almost completely excreted into urine through the kidneys after intravenous administration.

[0022] It is found that a composition containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof does not diffuse to secondary and subsequent lymph nodes like ICG, and can therefore be used to selectively image primary lymph nodes relative to secondary and subsequent lymph nodes. Non-clinical data of the compound also show that, due to its physical and chemical properties, it passes through lymphatic vessels and enters lymph nodes at a faster rate than ICG. It is also found that a composition containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, which is administered locally at a predetermined dose, is suitable for near-infrared imaging of lymphatic vessels and lymph nodes.

[0023] "Primary lymph nodes" refer to the lymph nodes that are first reached by the imaging agent via lymphatic vessels after local administration of an imaging agent (e.g., a compound of Formula (I)) near a lesion (e.g., a tumor). Sentinel lymph nodes are the lymph nodes that cancer cells first reach from the primary tumor of the cancer via lymphatic vessels. "Secondary and subsequent lymph nodes" refer to lymph nodes that are farther from the site of administration of the imaging agent via lymphatic vessels than the primary lymph nodes. The ability to "selectively" image the primary lymph nodes relative to the secondary and subsequent lymph nodes means that when exposed to near-infrared light (approximately 800 to 830 nm), the fluorescence emitted at the primary lymph nodes is identifiably stronger than the fluorescence emitted at the secondary and subsequent lymph nodes.

[0024] The composition containing the compound represented by formula (I) or its pharmaceutically acceptable salt as an active ingredient is effective as a composition for near-infrared imaging of lymph nodes or lymphatic vessels, which can selectively image primary lymph nodes relative to secondary and subsequent lymph nodes. Topically administered to a patient once or multiple times, if necessary, the compound represented by formula (I) or its pharmaceutically acceptable salt administered in an amount of 0.005 to 10 mg can be used for near-infrared imaging of lymph nodes or lymphatic vessels.

[0025] The compound represented by formula (I) may be a salt formed with an anion generated by releasing one or more protons from an acid. Specific examples include salts formed with anions generated by releasing protons from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid and glutamic acid. One embodiment of a pharmaceutically acceptable salt of a compound of formula (I) is a chloride (pridixakin chloride) of a compound of formula (I), which is a salt having a chloride anion (Cl-).

[0026] Combinations of these implementations may be used as long as they do not conflict.

[0027] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof can be produced using the production method described in Non-Patent Document 1, WO2011 / 093098 A1, or WO2021 / 105888 A1, or using a similar production method.

[0028] The compound represented by formula (I) and its pharmaceutically acceptable salt also include hydrates and solvates. The compound represented by formula (I) and its pharmaceutically acceptable salt may be amorphous or crystalline (including polymorphs). The amorphous compound represented by formula (I) and its pharmaceutically acceptable salt may be produced using the production method described in Journal of Biomedical Optics 21 (8), 086009 (August 2016) or a similar production method. The crystalline compound represented by formula (I) and its pharmaceutically acceptable salt may be produced using the method described in WO2021 / 105888 A1.

[0029] The compounds represented by formula (I) and pharmaceutically acceptable salts thereof also include compounds labeled with a radioactive or non-radioactive isotope.

[0030] The compound represented by formula (I) and its pharmaceutically acceptable salt may have tautomers. In the present specification, the compound represented by formula (I) and its pharmaceutically acceptable salt may be described in only one tautomeric form, but they may include other tautomers and isolated isomers or mixtures thereof.

[0031] The composition for imaging disclosed herein can be prepared by methods commonly used in the art, using excipients, carriers and other additives commonly used in the art.

[0032] There is no particular limitation on how to administer the composition for imaging disclosed herein. Examples include parenteral administration, such as local administration injection.

[0033] "Topical administration" refers to the local application of a composition at the site where a biological effect is desired. "Topical administration" may also be described as "local administration" or "topically applied". Embodiments include intradermal, subcutaneous, intramuscular, interstitial, subdermal, and subareolar administration. Other embodiments include intradermal and subcutaneous administration. Another embodiment is intramuscular administration.

[0034] Injections can contain sterile aqueous or non-aqueous solutions, suspensions or emulsions. Aqueous solvents include, for example, distilled water for injection or saline. Non-aqueous solvents include alcohols, such as ethanol. These compositions can also include excipients, buffers, isotonic agents, antioxidants, surfactants, preservatives, wetting agents, emulsifiers, dispersants, stabilizers and solubilizers. These compositions can also be sterilized, for example, by filtering through a bacterial retention filter, or by sterilizing with a fungicide or radiation. These can also be obtained by producing a sterile solid composition and dissolving or suspending the composition in sterile water or a sterile injectable solvent before use. One embodiment of the dosage form of the composition for imaging disclosed herein is an aqueous solution. Examples of solid compositions that can be dissolved before use include freeze-dried preparations and spray-dried preparations. One embodiment is a freeze-dried preparation.

[0035] The compound represented by formula (I) or its pharmaceutically acceptable salt can be applied once, or if necessary, multiple times. In one embodiment, the number of applications is once. In another embodiment, the number of applications is twice. The compound represented by formula (I) or its pharmaceutically acceptable salt is applied before or during surgery. In one embodiment, it is applied before surgery. In another embodiment, it is applied during surgery. In one embodiment, it is first applied before surgery and then applied again during surgery. Application before surgery can be at most 24 hours before surgery, at most 18 hours before surgery, at most 12 hours before surgery, at most 10 hours before surgery, at most 8 hours before surgery, at most 6 hours before surgery, at most 4 hours before surgery, at most 3 hours before surgery, at most 2 hours before surgery, at most 1.5 hours before surgery, at most 1 hour before surgery, at most 45 minutes before surgery, at most 30 minutes before surgery, at most 15 minutes before surgery, or immediately before surgery (e.g., within 5 minutes).

[0036] The amount of the compound represented by formula (I) or its pharmaceutically acceptable salt administered per dose (based on the weight of formula (I) in free form) can be 0.005 to 10 mg, 0.01 to 10 mg, 0.03 to 10 mg, 0.05 to 10 mg, 0.05 to 5 mg, 0.05 to 4 mg, 0.05 mg to 2 mg, 0.05 to 1 mg or 0.1 to 1 mg. In one embodiment, it is 0.05, 0.2, 0.6, 1, 2 or 4 mg. In another embodiment, the dosage of multiple administrations is the same or different.

[0037] The site of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof can be any suitable site of a patient in need. In some cases, administration is around the areola. In some cases, administration is near the left breast of the patient. In some cases, administration is near the right breast of the patient. In various cases, after administration to the patient's breast, the patient's breast is massaged for about 5 minutes, which can help the compound migrate for imaging. In alternative cases, no massage is performed.

[0038] In aqueous solution, the concentration of the compound represented by formula (I) or its pharmaceutically acceptable salt in free form can be 0.1 to 5 mg / mL, 0.1 to 3 mg / mL, 0.3 to 3 mg / mL, 0.5 to 3 mg / mL or 1 to 3 mg / mL. In one embodiment, it is 0.1, 0.3, 0.5, 1, 2, 3 or 5 mg / mL. In another embodiment, it is 1, 2 or 3 mg / mL. In another embodiment, it is 1 mg / mL. In another embodiment, it is 3 mg / mL.

[0039] The total volume for topical application after single or multiple administration of a free form of a compound represented by formula (I) or an aqueous solution of a pharmaceutically acceptable salt thereof can be 0.05 mL to 5 mL. In some embodiments, the volume is 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.8, 1.0, 2.0, 3.0, 4.0 or 5.0 mL. In various embodiments, the volume is 0.05, 0.2, 0.6, 1.0, 2.0 or 4.0 mL. In some embodiments, the volume is 1.0 mL. In various embodiments, the volume is 2.0 mL.

[0040] Implementation

[0041] 1. A composition for near-infrared imaging of lymph nodes or lymphatic vessels, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0042] (I)

[0043] The composition is characterized by selectively imaging primary lymph nodes relative to secondary and subsequent lymph nodes.

[0044] 2. The composition according to embodiment 1, wherein the composition is an aqueous solution having a concentration of 0.1 to 5 mg / mL of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the compound of formula (I) in free form.

[0045] 3. The composition according to embodiment 2, wherein the concentration of the compound of formula (I) or its pharmaceutically acceptable salt is 0.5 to 3 mg / mL based on the weight of the compound of formula (I) in free form.

[0046] 4. The composition according to embodiment 3, wherein the concentration of the compound of formula (I) or its pharmaceutically acceptable salt is 1 mg / mL based on the weight of the compound of formula (I) in free form.

[0047] 5. A composition according to any one of embodiments 1 to 3, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a chloride salt.

[0048] 6. A composition for near-infrared imaging of lymph nodes or lymphatic vessels, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0049] (I)

[0050] The composition is used so that the compound of formula (I) or a pharmaceutically acceptable salt thereof is topically applied in an amount of 0.005 to 10 mg / dose based on the weight of the compound of formula (I) in free form.

[0051] 7. A composition according to embodiment 6, wherein the composition is administered to the patient once.

[0052] 8. A composition according to embodiment 6, wherein the composition is administered to the patient multiple times.

[0053] 9. A composition according to any one of embodiments 6 to 8, wherein the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof administered per dose is 0.05 to 5 mg by weight of the compound of formula (I) in free form.

[0054] 10. The composition according to embodiment 9, wherein the amount of the compound of formula (I) or its pharmaceutically acceptable salt administered per dose is 0.05 to 4 mg, based on the weight of the compound of formula (I) in free form.

[0055] 11. A composition according to any one of embodiments 6 to 8, wherein the composition is an aqueous solution having a concentration of 0.1 to 5 mg / mL of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the compound of formula (I) in free form.

[0056] 12. The composition according to embodiment 11, wherein the concentration of the compound of formula (I) or its pharmaceutically acceptable salt is 0.5 to 3 mg / mL based on the weight of the compound of formula (I) in free form.

[0057] 13. The composition according to embodiment 12, wherein the concentration of the compound of formula (I) or its pharmaceutically acceptable salt is 1 mg / mL based on the weight of the compound of formula (I) in free form.

[0058] 14. The composition according to embodiment 10, wherein the concentration of the compound of formula (I) or its pharmaceutically acceptable salt is 1 mg / mL based on the weight of the compound of formula (I) in free form.

[0059] 15. A composition according to any one of embodiments 6 to 14, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a chloride salt.

[0060] 16. A composition according to any one of embodiments 6 to 15, wherein the composition selectively images primary lymph nodes relative to secondary lymph nodes and subsequent lymph nodes.

[0061] 17. The composition according to any one of embodiments 6 to 16, wherein the topical administration is intradermal, subcutaneous, intramuscular, interstitial, subdermal or subareolar administration.

[0062] 18. A method of imaging a first-level lymph node of a patient, the method comprising:

[0063] administering to the patient an effective amount of a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0064] (I); and

[0065] exposing the subject to near infrared light to image the subject's primary lymph nodes,

[0066] Wherein the primary lymph nodes are selectively imaged relative to secondary and subsequent lymph nodes.

[0067] 19. The method according to embodiment 18, wherein the composition is an aqueous solution having a concentration of 0.1 to 5 mg / mL of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the compound of formula (I) in free form.

[0068] 20. The method according to embodiment 19, wherein the concentration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 0.5 to 3 mg / mL based on the weight of the compound of formula (I) in free form.

[0069] 21. The method according to embodiment 20, wherein the concentration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 1 mg / mL based on the weight of the compound of formula (I) in free form.

[0070] 22. The method according to embodiment 18, wherein the composition is administered in an amount of 0.005 to 10 mg / dose based on the weight of the compound of formula (I) in free form.

[0071] 23. The method of any one of embodiments 18 to 22, wherein the administration is topical administration.

[0072] 24. The method of embodiment 23, wherein the topical administration is intradermal, subcutaneous, intramuscular, interstitial, subdermal, or subareolar administration.

[0073] 25. The method of any one of embodiments 18 to 24, wherein the composition is administered to the patient once.

[0074] 26. The method of any one of embodiments 18 to 24, wherein the composition is administered to the patient multiple times.

[0075] 27. The method of any one of embodiments 18 to 26, wherein the composition is administered to the patient prior to surgery.

[0076] 28. The method of any one of embodiments 18 to 27, wherein the composition is administered to the patient during surgery.

[0077] 29. The method according to any one of embodiments 18 to 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a chloride salt.

[0078] 30. The method of any one of embodiments 18 to 29, wherein the patient has localized breast cancer, melanoma, cervical cancer, head and neck malignancies, or gastrointestinal malignancies.

[0079] 31. Use of a composition in the manufacture of an agent for near infrared imaging of primary lymph nodes of a patient,

[0080] The composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0081] (I)

[0082] And the near infrared imaging results in selective imaging of primary lymph nodes relative to secondary and subsequent lymph nodes in a patient.

[0083] 32. The use according to embodiment 31, wherein the composition is an aqueous solution having a concentration of 0.1 to 5 mg / mL of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the compound of formula (I) in free form.

[0084] 33. The use according to embodiment 32, wherein the concentration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 0.5 to 3 mg / mL, based on the weight of the compound of formula (I) in free form.

[0085] 34. The use according to embodiment 33, wherein the concentration of the compound of formula (I) or its pharmaceutically acceptable salt is 1 mg / mL based on the weight of the compound of formula (I) in free form.

[0086] 35. The use according to embodiment 31, wherein the composition is administered in an amount of 0.005 to 10 mg / dose, based on the weight of the compound of formula (I) in free form.

[0087] 36. The use according to any one of embodiments 31 to 34, wherein the composition is for topical administration to the patient.

[0088] 37. The use according to embodiment 36, wherein the topical administration is intradermal, subcutaneous, intramuscular, interstitial, subdermal or subareolar administration.

[0089] 38. The use according to any one of embodiments 31 to 37, wherein the composition is for administration to the patient once.

[0090] 39. The use according to any one of embodiments 31 to 37, wherein the composition is for multiple administrations to the patient.

[0091] 40. The use according to any one of embodiments 31 to 39, wherein the composition is for administration to the patient prior to surgery.

[0092] 41. The use according to any one of embodiments 31 to 40, wherein the composition is for administration to the patient during surgery.

[0093] 42. The use according to any one of embodiments 31 to 41, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a chloride salt.

[0094] 43. The use according to any one of embodiments 31 to 42, wherein the patient suffers from localized breast cancer, melanoma, cervical cancer, head and neck malignancies, or gastrointestinal malignancies.

[0095] 44. A method of imaging lymph nodes or lymphatic vessels of a patient, the method comprising:

[0096] (a) topically administering to the patient a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of 0.005 to 10 mg / dose,

[0097]

[0098] wherein the amounts are based on the weight of the compound of formula (I) in free form; and

[0099] (b) exposing the patient to near infrared light to image the patient's lymph nodes or lymphatic vessels.

[0100] 45. Use of a composition in the manufacture of an agent for near infrared imaging of lymph nodes or lymphatic vessels of a patient,

[0101] The composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0102]

[0103] And the composition is used for topical application in an amount of 0.005 to 10 mg / dose based on the weight of the compound of formula (I) in free form.

[0104] Example

[0105] The present disclosure will now be described in more detail with reference to examples. However, these examples do not limit the scope of the present disclosure.

[0106] Example 1: Lymphatic imaging test (minipigs)

[0107] Compound (I) and ICG were subcutaneously administered to the chest and abdomen of miniature pigs (Göttingen or NIBS), and near-infrared fluorescence images were captured using a near-infrared fluorescence imaging device (PDE-Neo from Hamamatsu Photonics or Fluobeam from Fluoptics). 1 mg / mL of ICG was subcutaneously administered near the right second nipple of NIBS miniature pigs (weight 19.74 to 23.13 kg), and 1 mg / mL of compound (I) was subcutaneously administered near the left second nipple, and near-infrared fluorescence was observed using a near-infrared fluorescence imaging device after 10, 20, and 30 minutes. Figure 1 To verify the concentration dependence of compound (I), 0.001, 0.01, 0.1 and 1 mg / mL of compound (I) were subcutaneously administered to the abdomen of Göttingen miniature pigs (weight 6.12 kg) in a volume of 0.1 mL, and near-infrared fluorescence observation was performed immediately after administration using a near-infrared fluorescence imaging device to observe the process of the compound moving from the administration site to the lymphatic vessels ( Figure 2 In addition, 0.01, 0.1 and 1 mg / mL of compound (I) and 2.5 and 5 mg / mL of ICG (whose intralymphatic migration has been demonstrated) were subcutaneously administered near the second nipple of Göttingen miniature pigs (13.7-16.4 kg in weight), and near-infrared fluorescence observation was performed for two hours immediately after administration using a near-infrared fluorescence imaging device ( Figure 3 After administration at concentrations of 0.1 and 1 mg / mL, the fluorescent signal of compound (I) rapidly migrated from the administration site to the inguinal lymph nodes, and the lymph nodes could be confirmed transdermally ( Figure 3 -(1) and Figure 3 -(3)). Fluorescence signals in the inguinal lymph nodes were confirmed by transdermal administration of 0.01 mg / mL of compound (I), but these signals were weak ( Figure 3 -(5)). Similarly, in the case of ICG, the fluorescent signal migrates from the administration site to the inguinal lymph nodes, and the lymph nodes can be confirmed transdermally ( Figure 3 -(7), Figure 3 -(9)). At the end of the experiment, the inguinal lymph nodes were removed, and near-infrared fluorescence was observed using a near-infrared fluorescence imaging device when removed. When compound (I) was administered at concentrations of 0.1 and 1 mg / mL, strong fluorescence signals were easily observed on the head side (afferent lymphatic vessel side) of the excised lymphatic tissue, and weak fluorescence signals were easily observed on the tail side (efferent lymphatic vessel side) ( Figure 3 -(2) and Figure 3 -(4)). At a concentration of 0.01 mg / mL of compound (I), the fluorescence signal in the lymphoid tissue disappeared upon excision ( Figure 3 -(6)). In the case of ICG, strong fluorescence signals were observed throughout the excised lymphoid tissue ( Figure 3 -(8), Figure 3 -(10)).

[0108] Example 2: Lymphatic Imaging Test (Dog)

[0109] 2.5 mg / mL of ICG was subcutaneously administered near the left second nipple of beagle dogs (weight 7.90 kg) in a volume of 0.1 mL, and 1 mg / mL of compound (I) was subcutaneously administered near the right second nipple, and near-infrared fluorescence observation was performed using a near-infrared fluorescence imaging device (Fluobeam from Fluoptics) 10 minutes later ( Figure 4 -(1)). When the axillary lymph nodes were exposed and after the axillary lymph nodes were removed, near-infrared fluorescence imaging was also used to observe the lymph nodes by near-infrared fluorescence ( Figure 4 -(2)).

[0110] Example 3: Canine Lymphatic Imaging Test (Dog, Hind Leg)

[0111] First, 1 mg / mL of compound (I) (right hind limb) and 2.5 mg / mL of ICG (left hind limb) were applied to the subcutaneous tissue in the interdigital area of ​​the hind limb of a beagle dog (male, 7 months old, weighing 12.6 kg) in a volume of 0.1 mL, and 20 minutes later, the area around the gastrocnemius muscle and near the lymph nodes below the kneecap was imaged using a near-infrared fluorescence imaging device (Fluobeam from Fluoptics) ( Figure 5 -(1) and Figure 5 -(2)). After opening the abdomen and exposing the internal iliac lymph nodes, the same device was used to image the vicinity of the internal iliac lymph nodes ( Figure 5 -(3) and Figure 5 -(4)). After euthanasia approximately 2.5 hours later, the lymph nodes below the kneecap and internal iliac lymph nodes were removed, and near-infrared fluorescence images were captured using the same setup ( Figure 5 -(5) to Figure 5 -(12)).

Claims

1. A composition for near-infrared imaging of lymph nodes or lymphatic vessels, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, (I) The composition is characterized by selectively imaging primary lymph nodes relative to secondary and subsequent lymph nodes.

2. The composition according to claim 1, wherein the composition is an aqueous solution having a concentration of 0.1 to 5 mg / mL of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the compound of formula (I) in free form.

3. The composition according to claim 2, wherein the concentration of the compound of formula (I) or its pharmaceutically acceptable salt is 0.5 to 3 mg / mL based on the weight of the compound of formula (I) in free form.

4. The composition according to claim 3, wherein the concentration of the compound of formula (I) or its pharmaceutically acceptable salt is 1 mg / mL based on the weight of the compound of formula (I) in free form.

5. The composition according to any one of claims 1 to 3, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a chloride salt.

6. A composition for near-infrared imaging of lymph nodes or lymphatic vessels, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, (I)， The composition is used so that the compound of formula (I) or a pharmaceutically acceptable salt thereof is topically applied in an amount of 0.005 to 10 mg / dose based on the weight of the compound of formula (I) in free form.

7. The composition of claim 6, wherein the composition is administered to a patient once.

8. The composition of claim 6, wherein the composition is administered to a patient multiple times.

9. The composition according to any one of claims 6 to 8, wherein the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof administered per dose is 0.05 to 5 mg by weight of the compound of formula (I) in free form.

10. The composition according to claim 9, wherein the amount of the compound of formula (I) or its pharmaceutically acceptable salt administered per dose is 0.05 to 4 mg based on the weight of the compound of formula (I) in free form.

11. The composition according to any one of claims 6 to 8, wherein the composition is an aqueous solution having a concentration of 0.1 to 5 mg / mL of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the compound of formula (I) in free form.

12. The composition according to claim 11, wherein the concentration of the compound of formula (I) or its pharmaceutically acceptable salt is 0.5 to 3 mg / mL based on the weight of the compound of formula (I) in free form.

13. The composition according to claim 12, wherein the concentration of the compound of formula (I) or its pharmaceutically acceptable salt is 1 mg / mL based on the weight of the compound of formula (I) in free form.

14. The composition according to claim 10, wherein the concentration of the compound of formula (I) or its pharmaceutically acceptable salt is 1 mg / mL based on the weight of the compound of formula (I) in free form.

15. A composition according to any one of claims 6 to 14, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a chloride salt.

16. The composition of any one of claims 6 to 15, wherein the composition selectively images primary lymph nodes relative to secondary and subsequent lymph nodes.

17. The composition according to any one of claims 6 to 16, wherein the topical administration is intradermal, subcutaneous, intramuscular, interstitial, subdermal or subareolar administration.

18. A method of imaging a first-level lymph node of a patient, the method comprising: administering to the patient an effective amount of a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, (I) exposing the patient to near infrared light to image the patient's first-order lymph nodes, Wherein the primary lymph nodes are selectively imaged relative to secondary and subsequent lymph nodes.

19. The method according to claim 18, wherein the composition is an aqueous solution having a concentration of 0.1 to 5 mg / mL of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the compound of formula (I) in free form.

20. The method of claim 19, wherein the concentration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 0.5 to 3 mg / mL based on the weight of the compound of formula (I) in free form.

21. The method of claim 20, wherein the concentration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 1 mg / mL based on the weight of the compound of formula (I) in free form.

22. The method of claim 18, wherein the composition is administered in an amount of 0.005 to 10 mg / dose based on the weight of the compound of formula (I) in free form.

23. The method according to any one of claims 18 to 22, wherein the administration is topical administration.

24. The method of claim 23, wherein the topical administration is intradermal, subcutaneous, intramuscular, interstitial, subdermal, or subareolar administration.

25. The method of any one of claims 18 to 24, wherein the composition is administered to the patient once.

26. The method of any one of claims 18 to 24, wherein the composition is administered to the patient multiple times.

27. The method of any one of claims 18 to 26, wherein the composition is administered to the patient prior to surgery.

28. The method of any one of claims 18 to 27, wherein the composition is administered to the patient during surgery.

29. The method according to any one of claims 18 to 28, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a chloride salt.

30. The method of any one of claims 18 to 29, wherein the patient has localized breast cancer, melanoma, cervical cancer, head and neck malignancies, or gastrointestinal malignancies.

31. Use of a composition in the manufacture of an agent for near infrared imaging of a primary lymph node of a patient, The composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, (I) And the near infrared imaging results in selective imaging of primary lymph nodes relative to secondary and subsequent lymph nodes in a patient.

32. The use according to claim 31, wherein the composition is an aqueous solution having a concentration of 0.1 to 5 mg / mL of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the weight of the compound of formula (I) in free form.

33. The use according to claim 32, wherein the concentration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 0.5 to 3 mg / mL based on the weight of the compound of formula (I) in free form.

34. The use according to claim 33, wherein the concentration of the compound of formula (I) or its pharmaceutically acceptable salt is 1 mg / mL based on the weight of the compound of formula (I) in free form.

35. The use according to claim 31, wherein the composition is administered in an amount of 0.005 to 10 mg / dose based on the weight of the compound of formula (I) in free form.

36. The use according to any one of claims 31 to 34, wherein the composition is for topical administration to the patient.

37. The use according to claim 36, wherein the topical administration is intradermal, subcutaneous, intramuscular, interstitial, subdermal or subareolar administration.

38. The use according to any one of claims 31 to 37, wherein the composition is for administration to the patient once.

39. The use according to any one of claims 31 to 37, wherein the composition is for multiple administration to the patient.

40. The use according to any one of claims 31 to 39, wherein the composition is for administration to the patient prior to surgery.

41. The use according to any one of claims 31 to 40, wherein the composition is for administration to the patient during surgery.

42. The use according to any one of claims 31 to 41, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a chloride salt.

43. The use according to any one of claims 31 to 42, wherein the patient suffers from localized breast cancer, melanoma, cervical cancer, head and neck malignancies, or gastrointestinal malignancies.

44. A method of imaging lymph nodes or lymphatic vessels of a patient, the method comprising: (a) topically administering to the patient a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of 0.005 to 10 mg / dose, wherein the amounts are based on the weight of the compound of formula (I) in free form; and (b) exposing the patient to near infrared light to image the patient's lymph nodes or lymphatic vessels.

45. Use of a composition in the manufacture of an agent for near infrared imaging of lymph nodes or lymphatic vessels of a patient, The composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, And the composition is used for topical application in an amount of 0.005 to 10 mg / dose based on the weight of the compound of formula (I) in free form.

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