JP2024037356A - Pharmaceutical - Google Patents

Abstract

To provide a pharmaceutical that can improve the retention of therapeutics within lymph nodes.SOLUTION: The present invention provides a pharmaceutical for improving the retention of drugs within superficial lymph nodes. The pharmaceutical comprises an agent where an indocyanine green derivative binds to a therapeutic. The pharmaceutical is intradermally administered on the upstream side of the superficial lymph nodes.SELECTED DRAWING: None

Description

TECHNICAL FIELD The present invention relates to medicine.

According to an announcement by the Ministry of Health, Labor and Welfare, cancer has been the number one cause of death for Japanese people in Japan since 1981, and in recent years, more than 300,000 people die from cancer each year. Furthermore, it is estimated that one in two men and one in three women will develop cancer during their lifetime. Unlike benign tumors, cancer (malignant tumors) not only grows rapidly, but also tends to metastasize and grow in lymph nodes and other organs. For this reason, even if cancer cells are removed by surgery, cancer cells that could not be completely removed or cancer cells that had metastasized to lymph nodes or other organs may start growing again. For this reason, it is generally considered that the cancer has been cured only when it has not recurred for five years after the cancer has disappeared. As described above, the reality is that there are still many cancers for which effective treatments have not been established, and for which effective treatments for metastasis and recurrence have not been established.

Cancer treatment mainly includes surgery and drug therapy (anticancer drug treatment). Among these, in drug therapy (anticancer drug treatment), it has been reported that the therapeutic effect can be improved by intradermally administering a therapeutic agent through the accessed lymphatic structure (for example, Patent Document 1).

Special Publication No. 2007-503435

However, in the method of Patent Document 1, the therapeutic drug becomes undetectable from the lymph nodes within a relatively short period of time after administration, and the drug's efficacy cannot be maintained sufficiently.

Therefore, the present invention has been made in view of the above circumstances, and an object of the present invention is to provide a drug that can improve the retention of a therapeutic drug in lymph nodes.

In order to solve the above problem, the present inventors conducted intensive research and found that by intradermally administering a drug in which an indocyanine green derivative is bound to a therapeutic drug upstream of the target lymph node, The inventors have discovered that the above problems can be solved, and have completed the present invention.

That is, the above object is (1) a medicament for improving the retention of a drug in superficial lymph nodes, the medicament including an indocyanine green derivative bound to a therapeutic drug, and the medicament comprising: can be achieved by a medicament administered intradermally upstream of the superficial lymph node.
(2) In the medicament of (1) above, the therapeutic agent is preferably selected from antibodies, peptide agents, and protein preparations.
(3) Preferably, the medicament of (1) or (2) above is administered intradermally via an injection needle equipped with a needle tube having a protrusion length of 0.9 mm or more and 1.4 mm or less.
(4) The medicament according to any one of (1) to (3) above is preferably a medicament for treating breast cancer, skin cancer, or autoimmune disease.

According to the medicament of the present invention, retention of a therapeutic agent in superficial lymph nodes can be improved.

FIG. 1 is a perspective view of an administration device according to an embodiment. FIG. 2 is an exploded view of a needle hub according to an embodiment. FIG. 3 is a partial cross-sectional view of a needle hub and syringe according to an embodiment. FIG. 4 is a perspective view of a needle hub according to an embodiment. FIG. 5 is an enlarged cross-sectional view of a needle hub according to an embodiment. FIG. 6 is an enlarged plan view of the blade surface of the injection needle according to the embodiment. FIG. 7 is an enlarged perspective view of the blade surface of the injection needle according to the embodiment. 8(A) is a side view of the blade surface of the injection needle seen from the direction of arrow 8A shown in FIG. 6, and FIG. 8(B) is a perspective view of the blade surface of the injection needle seen from the direction of arrow 8B shown in FIG. FIG. 9(A) is a side view of the blade surface of the injection needle seen from the direction of arrow 9A shown in FIG. 6, and FIG. 9(B) is a perspective view of the blade surface of the injection needle seen from the direction of arrow 9B shown in FIG. FIG. FIG. 10 is a cross-sectional view schematically showing an example of use of the administration device. FIG. 11 is an enlarged cross-sectional view of the broken line portion 11A shown in FIG. FIG. 12 is a color photograph taken with the IVIS Imaging System of mice after a predetermined time had elapsed after intradermal, subcutaneous, or intravenous administration in Example 1, Comparative Example 1, and Comparative Example 2. FIG. 13 is a graph showing changes over time in fluorescence intensity after intradermal or subcutaneous administration in Example 1 and Comparative Example 1. FIG. 14 is a graph showing the amount of ICG-labeled antibody in the excised axillary lymph nodes 7 days after administration in Example 1 and Comparative Examples 1 and 2. FIG. 15 is a graph showing changes over time in "Anti-KLH mouse IgG1 antibody content per mg of lymph node (ng/1 mg Lymph Node)" in the reference example.

The present invention provides a medicament for improving the retention of a drug in superficial lymph nodes, the medicament comprising a drug in which an indocyanine green derivative is bound to a therapeutic drug, and the medicament includes a drug in which an indocyanine green derivative is bound to a therapeutic drug; A medicament is provided that is administered intradermally upstream of the node. According to this configuration, the drug (therapeutic drug) can be retained in the target superficial lymph node for a longer time than other administration routes (for example, subcutaneous administration or intravenous administration). Therefore, the medicament of the present invention can maintain its efficacy within the superficial lymph nodes for a long period of time.

In this specification, the indocyanine green derivative is also simply referred to as "ICG". Further, a drug formed by binding an indocyanine green derivative to a therapeutic drug is also simply referred to as a "drug" or "drug according to the present invention."

Embodiments of the present invention will be described below. Note that the present invention is not limited only to the following embodiments. Each drawing is exaggerated for convenience of explanation, and the dimensional ratio of each component in each drawing may differ from the actual size. Furthermore, when the embodiments of the present invention are described with reference to the drawings, the same elements are denoted by the same reference numerals in the description of the drawings, and redundant explanation will be omitted.

Furthermore, in this specification, the range "X to Y" includes X and Y, and means "more than or equal to X and less than or equal to Y." Further, unless otherwise specified, operations and measurements of physical properties, etc. are performed at room temperature (20 to 25°C)/relative humidity of 40 to 50%.

[Medicine]
The medicine according to the present invention essentially contains a drug (ICG-labeled drug) in which an indocyanine green derivative (ICG) is bound to a therapeutic drug. Furthermore, the medicament according to the present invention is administered intradermally upstream of a superficial lymph node. This configuration allows the drug (therapeutic agent) to remain in the target superficial lymph node for a longer period of time compared to other administration routes (e.g., subcutaneous administration or intravenous administration). (can improve drug retention in superficial lymph nodes).

The medicament according to the present invention may consist only of a drug formed by binding an indocyanine green derivative to a therapeutic agent, or may contain other components in addition to this. Here, other components include solvents (e.g., sterile water, medium-chain fatty acid triglycerides), stabilizers, buffers (e.g., PBS, physiological saline, phosphate buffer, citrate buffer, citrate phosphorus), acid buffer, histidine buffer, Tris-HCl buffer, acetate buffer, carbonate buffer, glycine-NaOH buffer), solubilizing agent (e.g., acetic acid), isotonic agent (e.g., sodium chloride), pH adjustment agents (e.g., bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, acids such as sulfuric acid, hydrochloric acid, phosphoric acid), soothing agents, reducing agents, antioxidants, solubilizing agents (e.g., polysorbates) 80) etc. The other components mentioned above may be used alone or in combination of two or more. Further, when the medicine contains other ingredients, the content of the other additive ingredients is not particularly limited, and the same amount as in known techniques is applied. The medicament according to the present invention is an intradermally administered drug. Therefore, the medicament according to the present invention preferably contains a buffer solution in addition to the drug, and is more preferably composed of the drug and the buffer solution.

The therapeutic agent constituting the drug is not particularly limited and is appropriately selected depending on the desired effect. Specifically, anticancer drugs, immunosuppressants, antibiotics, antirheumatic drugs, antithrombotic drugs, HMG-CoA reductase inhibitors, ACE inhibitors, calcium antagonists, antihyperlipidemic drugs, and integrin inhibitors. Medicines, antiallergic agents, antioxidants, GPIIbIIIa antagonists, retinoids, flavonoids, carotenoids, lipid improving agents, DNA synthesis inhibitors, tyrosine kinase inhibitors, antiplatelet agents, vascular smooth muscle growth inhibitors, anti-inflammatory agents, biological agents Examples include drugs (physiologically active substances) such as derived materials, interferon, and NO production promoting substances. Among these, antagonists such as anticancer drugs, immunosuppressants, and antibodies are preferred. Furthermore, from the viewpoint of ease of binding with ICG and high retention in superficial lymph nodes, the therapeutic agent is preferably an antibody (antibody drug), a peptide agent, or a protein preparation; ) is more preferable.

Here, anticancer drugs include, for example, alkylating drugs (e.g., Dacarbazine, Nimustine, Temozolomide, Fotemustine, Bendamustine, Cyclophosphamide, Ifosfamide, Carmustine, Chlorambucil, Procarbazine, etc.), platinum preparations (e.g., Cisplatin, Carboplatin, Nedaplatin, etc.) and Oxaliplatin, etc.), antimetabolites (e.g., folate antimetabolites (e.g., Pemetrexed, Leucovorin, and Methotrexate, etc.), pyridine metabolism inhibitors (e.g., TS-1®, 5-fluorouracil, UFT, Carmofur, Doxifluridine) , FdUrd, Cytarabine and Capecitabine etc.), purine metabolism inhibitors (e.g. Fludarabine, Cladribine and Nelarabine etc.), ribonucleotide reductase inhibitors, nucleotide analogues (e.g. Gemcitabine etc.)), topoisomerase inhibitors (e.g. Irinotecan, Nogitecan and Etoposide, etc.), microtubule polymerization inhibitors (e.g., Vinblastine, Vincristine, Vindesine, Vinorelbine and Eribulin, etc.), microtubule depolymerization inhibitors (e.g., Docetaxel and Paclitaxel, etc.), antineoplastic antibiotics (e.g., Bleomycin, Mitomycin, etc.) C, Doxorubicin, Daunorubicin, Idarubicin, Etoposide, Mitoxantrone, Vinblastine, Vincristine, Peplomycin, Amrubicin, Aclarubicin and Epirubicin, etc.), cytokine preparations (e.g. IFN-α2a, IFN-α2b, PEG-IFN-α2b, native IFN-β and Interleukin-2, etc.), antihormonal drugs (eg, Tamoxifen, Fulvestrant, Goserelin, Leuprorelin, Anastrozole, Letrozole, Exemestane, etc.), molecular target drugs, cancer immunotherapy drugs, and other antibody drugs. However, those skilled in the art will recognize other suitable anti-cancer agents.

Here, examples of molecular target drugs include ALK inhibitors (e.g., Crizotinib, Ceritinib, Ensartinib, Alectinib, and Lorlatinib, etc.), BCR-ABL inhibitors (e.g., Imatinib, Dasatinib, etc.), and EGFR inhibitors (e.g., Erlotinib, etc.). , EGF816, Afatinib, Osimertinib mesilate, Gefitinib and Rociletinib, etc.), B-RAF inhibitors (e.g. Sorafenib, Vemurafenib, TAK-580, Dabrafenib, Encorafenib, LXH254, Emurafenib and Zanubrutinib, etc.), VEGFR inhibitors (e.g. Bevacizumab, Apatinib, Lenvatinib, Aflibercept and Axitinib, etc.), FGFR inhibitors (e.g. AZD4547, Vofatmab, Roblitinib and Pemigatinib, etc.), c-MET inhibitors (e.g. Savolitinib, Merestinib, Capmatinib, Capmatinib and Glesatinib, etc.), AXL inhibitors (e.g. Savolitinib, Merestinib, Capmatinib, Capmatinib and Glesatinib, etc.) For example, ONO-7475 and Bemcentinib, etc.), MEK inhibitors (such as Cobimetinib, Binimetinib, Selumetinib and Trametinib, etc.), CDK inhibitors (such as Dinaciclib, Abemaciclib, Palbociclib and Trilaciclib, etc.), BTK inhibitors (such as Ibrutinib and Acalabrutinib, etc.), PI3K-δ/γ inhibitors (e.g., Umbralisib, Parsaclisib and IPI-549, etc.), JAK-1/2 inhibitors (e.g., Itacitinib and Ruxolitinib, etc.), ERK inhibitors (e.g., SCH 900353, etc.) , TGFbR1 inhibitors (e.g., Galunisertib, etc.), Cancer cell stemness kinase inhibitors (e.g., Amcasertib, etc.), FAK inhibitors (e.g., Defactinib, etc.), SYK/FLT3 dual inhibitors (e.g., Mivavotinib, etc.), ATR inhibitors (e.g., Ceralasertib, etc.), WEE1 kinase inhibitors (e.g., Adavosertib, etc.), multityrosine kinase inhibitors (e.g., Sunitinib, Pazopanib, Cabozantinib, Regorafenib, Nintedanib, Sitravatinib, and Midostaurin, etc.), mTOR inhibitors (e.g., Temsirolimus, Everolimus, Vistusertib and Irinotecan, etc.), HDAC inhibitors (e.g. Vorinostat, Romidepsin, Entinostat, Chidamide, Mocetinostat, Citarinostat, Panobinostat and Valproate, etc.), PARP inhibitors (e.g. Niraparib, Olaparib, Veliparib, Rucaparib and Beigene-290, etc.) ), aromatase inhibitors (e.g., Exemestane and Letrozole, etc.), EZH2 inhibitors (e.g., Tazemetostat, etc.), galectin-3 inhibitors (e.g., Belapectin, etc.), STAT3 inhibitors (e.g., Napabucasin, etc.), DNMT inhibitors ( BCL-2 inhibitors (e.g., Navitoclax and Venetoclax), SMO inhibitors (e.g., Vismodegib, etc.), HSP90 inhibitors (e.g., XL888, etc.), γ-tubulin-specific inhibitors (e.g., , Glaziovianin A and Plinabulin, etc.), HIF2α inhibitors (e.g., PT2385, etc.), glutaminase inhibitors (e.g., Telaglenastat, etc.), E3 ligase inhibitors (e.g., Avadomide, etc.), NRF2 activators (e.g., Omaveloxolone, etc.), Arginase inhibitors (e.g., CB-1158, etc.), cell cycle inhibitors (e.g., Trabectedin, etc.), Ephrin B4 inhibitors (e.g., sEphB4-HAS, etc.), IAP antagonists (e.g., Birinapant, etc.), anti-HER2 antibodies ( For example, Trastuzumab, Pertuzumab, Trastuzumab beta, Margetuximab, Trastuzumab deruxtecan, Disitamab, Disitamab vedotin, Trastuzumab emtansine, Gancotamab, Trastuzumab duocarmazine, Timigutuzumab, Zanidatamab, Zenocutuzumab, R48 and ZW33, etc.), anti-HER1 antibodies (e.g., Cetuximab, Cetuximab sarota) locan, Panitumumab, Necitumumab, Nimotuzumab, Depatuxizumab, Depatuxizumab mafodotin, Fu tuximab, Laprituximab, Laprituximab emtansine, Matuzumab, Modotuximab, Petosemtamab, Tomuzotuximab, Losatuxizumab, Losatuxizumab vedotin, Serclutamab, Serclutamab talirine, Imgatuzumab, Futuximab and Zalutumumab), anti-HER3 antibodies (e.g. , Duligotuzumab, Elgemtumab, Istiratumab, Lumretuzumab, Zenocutuzumab, Patritumab, Patritumab deruxtecan and Seribantumab, etc.), anti-CD40 antibodies (such as Bleselumab, Dacetuzumab, Iscalimab, Lucatumumab, Mitazalimab, Ravagalimab, Selicrelumab, Teneliximab, ABBV-428 and APX005M, etc.), Anti-CD70 antibodies (e.g. Cusatuzumab, Vorsetuzumab, Vorsetuzumab mafodotin and ARGX-110, etc.), anti-VEGF antibodies (e.g. Bevacizumab, Bevacizumab beta, Ranibizumab, Abicipar pegol, Aflibercept, Brolucizumab, Conbercept, Dilpacimab, Faricimab, Navicixizumab, Varisacumab and IMC -1C11, etc.), anti-VEGFR1 antibodies (e.g., Icrucumab, etc.), anti-VEGFR2 antibodies (e.g., Ramucirumab, Alacizumab, Alacizumab pegol, Olinvacimab, Pegdinetanib, and AMG596, etc.), anti-CD20 antibodies (e.g., Rituximab, Blontuvetmab, Epitumomab, Ibritumomab tiuxetan) , Ocaratuzumab, Ocrelizumab, Technetium (99mTc) nofetumomab merpentan, Tositumomab, Veltuzumab, Ofatumumab, Ublituximab, Obinutuzumab and Nofetumomab etc.), anti-CD30 antibodies (e.g. Brentuximab Vedotin and Iratumumab etc.), anti-CD38 antibodies (e.g. Daratumumab, Isatuximab, Mezagitamab etc.) . Cantuzumab, Cantuzumab ravtansine, Clivatuzumab, Clivatuzumab tetraxetan, Yttrium (90Y) clivatuzumab tetraxetan, Epitumomab, Epitumomab cituxetan, Sontuzumab, Gatipotuzumab, Nacolomab, Nacolomab tafenatox, 7F11C7, BrE-3, CMB-401, CTM01 and HMFG1, etc.), Anti-MUC5AC antibody (e.g., Ensituximab, etc.), anti-MUC16 antibodies (e.g., Oregovomab, Abagovomab, Igovomab, and Sofituzumab vedotin, etc.), anti-DLL4 antibodies (e.g., Demcizumab, Dilpacimab, Navicixizumab, and Enoticumab, etc.), anti-fucosyl GM1 antibodies (e.g., BMS-986012) etc.), anti-gpNMB antibodies (e.g., Glembatumumab vedotin, etc.), anti-Mesothelin antibodies (e.g., Amatuximab, Anetumab ravtansine, Anetumab corixetan, RG7784 and BMS-986148, etc.), anti-MMP9 antibodies (e.g., Andecaliximab, etc.), anti-GD2 antibodies ( Anti-MET antibodies (e.g. Emibetuzumab, Onartuzumab, Telisotuzumab and Telisotuzumab vedotin, etc.), anti-FOLR1 antibodies (e.g. Farletuzumab , Mirvetuximab and Mirvetuximab soravtansine, etc.), anti-CD79b antibodies (e.g., Iladatuzumab, Iladatuzumab vedotin, and Polatuzumab vedotin, etc.), anti-DLL3 antibodies (e.g., Rovalpituzumab and Rovalpituzumab Tesirine, etc.), anti-CD51 antibodies (e.g., Abituzumab, Etaracizumab, and Intetumumab, etc.) , anti-EPCAM antibodies (e.g. Adecatumumab, Catumaxomab, Edrecolomab, Oportuzumab monatox, Citatuzumab bogatox and Tucotuzumab celmoleukin, etc.), anti-CEACAM5 antibodies (e.g. Altumomab, Arcitumomab, Cergutuzumab amunaleukin, Labetuzumab, Labetuzumab govitecan, 90Y-cT84.66, AMG211, BW43) 1 /26, CE25/B7, COL-1 and T84.66 M5A), anti-CEACAM6 antibodies (e.g. Tinurilimab, etc.), anti-FGFR2 antibodies (e.g. Aprutumab, Aprutumab ixadotin and Bemarituzumab etc.), anti-CD44 antibodies (e.g. bivatuzumab) mertansine, etc.), anti-PSMA antibodies (e.g., Indium (111In) capromab pendetide, 177Lu-J591 and ES414, etc.), anti-Endoglin antibodies (e.g., Carotuximab, etc.), anti-IGF1R antibodies (e.g., Cixutumumab, Figitumumab, Ganitumab, Dalotuzumab, teprotumumab) and Robatumumab, etc.), anti-TNFSF11 antibodies (e.g., Denosumab, etc.), anti-GUCY2C (e.g., Indusatumab vedotin, etc.), anti-SLC39A6 antibodies (e.g., Ladiratuzumab vedotin, etc.), anti-SLC34A2 antibodies (e.g., Lifastuzumab vedotin, etc.), anti-NCAM1 antibodies (e.g., Lorvotuzumab mertansine and N901, etc.), anti-ganglioside GD3 antibodies (e.g., Ecromeximab and Mitumomab, etc.), anti-AMHR2 antibodies (e.g., Murlentamab, etc.), anti-CD37 antibodies (e.g., Lilotomab, Lutetium (177lu) lilotomab satetraxetan, Naratuximab, Naratuximab emtansine and Otlertuzumab, etc.), anti-IL1RAP antibodies (e.g., Nidanilimab, etc.), anti-PDGFR2 antibodies (e.g., Olaratumab and Tovetumab, etc.), anti-CD200 antibodies (e.g., Samalizumab, etc.), anti-TAG-72 antibodies (e.g., Anatumomab mafenatox, minretumomab, Indium (111In) satumomab pendetide, CC49, HCC49, M4, etc.), anti-SLITRK6 antibodies (e.g., Sirtratumab vedotin, etc.), anti-DPEP3 antibodies (e.g., Tamrintamab pamozirine, etc.), anti-CD19 antibodies (e.g., Axicabtagene ciloleucel, Coltuximab ravtansine) , Denintuzumab mafodotin, Inebilizumab, Loncastuximab, Loncastuximab tesirine, Obexelimab, Tafasitamab, Taplitumomab paptox, Taplitumomab paptox and huAnti-B4, etc.), anti-NOTCH2/3 antibodies (e.g., Tarextumab, etc.), anti-tenascin C antibodies (e.g., Tenatumomab, etc.), Anti-AXL antibodies (e.g., Enapotamab, Enapotamab vedotin, Tilvestamab, etc.), anti-STEAP1 antibodies (e.g., Vandortuzumab vedotin, etc.), anti-CTAA16 antibodies (e.g., technetium (99mTc) votumumab, etc.), CLDN18 antibodies (e.g., Zolbetuximab, etc.), GM3 antibodies (e.g., Racotumomab, FCGR1 and H22, etc.), anti-PSCA antibodies (e.g., MK-4721, etc.), anti-FN extra domain B antibodies (e.g., AS1409, etc.), anti-HAVCR1 antibodies (e.g., CDX-014, etc.) and Anti-TNFRSF4 antibodies (e.g., MEDI6383, etc.), anti-HER1-MET bispecific antibodies (e.g., Amivantamab, etc.), anti-EPCAM-CD3 bispecific antibodies (e.g., Solitomab and Catumaxomab, etc.), anti-Ang2-VEGF bispecific antibodies. Specific antibodies (e.g., Vanucizumab, etc.), anti-HER2-CD3 bispecific antibodies (e.g., Ertumaxomab, etc.), anti-HER3-IGF1R bispecific antibodies (e.g., Istiratumab, etc.), anti-PMSA-CD3 bispecific antibodies Antibodies (e.g., Pasotuxizumab, etc.), anti-HER1-LGR5 bispecific antibodies (e.g., Petosemtamab, etc.), anti-SSTR2-CD3 bispecific antibodies (e.g., Tidutamab, etc.), anti-CD30-CD16A bispecific antibodies ( For example, AFM13, etc.), anti-CEA-CD3 bispecific antibodies (for example, Cibisatamab and RO6958688, etc.), anti-CD3-CD19 bispecific antibodies (for example, Duvortuxizumab and Blinatumomab, etc.), IL3RA-CD3 bispecific antibodies (e.g., Flotetuzumab and Vibecotamab, etc.), anti-GPRC5D-CD3 bispecific antibodies (e.g., Talquetamab, etc.), anti-CD20-CD3 bispecific antibodies (e.g., Plamotamab, Odronextamab, Mosunetuzumab, Glofitamab, Epcoritamab, and REGN1979, etc.) , anti-TNFRSF17-CD3 bispecific antibody (e.g., Teclistamab, etc.), anti-CLEC12A-CD3 bispecific antibody (e.g., Tepoditamab, etc.), anti-HER2-HER3 bispecific antibody (e.g., Zenocutuzumab, etc.), Examples include FAP antibody/IL-2 fusion protein (eg, RO6874281, etc.) and anti-CEA antibody/IL-2 fusion protein (eg, Cergutuzumab amunaleukin, etc.).

Cancer immunotherapeutic drugs include, for example, anti-PD-1 antibodies (e.g., Nivolumab, Cemiplimab-rwlc, Pembrolizumab, Spartalizumab, Tislelizumab, Dostarlimab, Toripalimab, Camrelizumab, Genolimzumab, Sintilimab, Lodapolimab, Retifanlimab, Balstilimab, Serplulimab, Budigalimab, Prolgolimab, Sasanlimab, Cetrelimab, Zimberlimab, Geptanolimab, AMP-514, STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, CS1003, BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, Sym02 1, SSI-361 , JY034, HX008, ISU106 and CX-188), anti-PD-L1 antibodies (e.g. Atezolizumab, Avelumab, Durvalumab, Manelimab, Pacmilimab, Envafolimab, Cosibelimab, Sugemalimab, BMS-936559, STI-1014, HLX20, SHR-1316) , MSB2311, BGB-A333, KL-A167, AK106, AK104, ZKAB001, FAZ053, CBT-502 and JS003, etc.), PD-1 antagonists (e.g., AUNP-12, BMS-M1 to BMS-M10 compounds ( WO2014/151634, WO2016/039749, WO2016/057624, WO2016/077518, WO2016/100285, WO2016/100608, WO2016/126646, WO2016/149351, WO2017/151830 and WO2017/ 176608), BMS-1, BMS-2, BMS-3, BMS-8, BMS-37, BMS-200, BMS-202, BMS-230, BMS-242, BMS-1001 and BMS-1166 (WO2015/034820, WO2015/160641, WO2017/066227 and Oncotarget. 2017 Sep 22; 8(42): 72167-72181.), Incyte-1 to Incyte-6 compounds (WO2017/070089, WO2017/087777, WO2017/106634, WO2017/112730, WO2017/192961 and WO2017/205 464 ), CAMC-1 to CAMC-4 (see WO2017/202273, WO2017/202274, WO2017/202275 and WO2017/202276), RG_1 (see WO2017/118762) and DPPA-1 (Angew. Chem. Int. Ed. 2015 , 54, 11760-11764) etc.), PD-L1/VISTA antagonists (e.g. CA-170), PD-L1/TIM3 antagonists (e.g. CA-327), anti-PD-L2 antibodies, PD-L1 fusion proteins, PD-L2 fusion proteins (e.g. AMP-224 etc.), anti-CTLA-4 antibodies (e.g. Ipilimumab, Zalifrelimab, Nurulimab and Tremelimumab etc.), anti-LAG-3 antibodies (e.g. Relatlimab, Ieramilimab, Fianlimab, Encelimab etc.) and Mavezelimab, etc.), anti-TIM3 antibodies (e.g., MBG453 and Cobolimab, etc.), anti-KIR antibodies (e.g., Lirilumab, IPH2101, LY3321367, and MK-4280, etc.), anti-BTLA antibodies, anti-TIGIT antibodies (e.g., Tiragolumab, Etigilimab, Vibostolimab, etc.) and BMS-986207, etc.), anti-VISTA antibodies (e.g., Onvatilimab, etc.), anti-CD137 antibodies (e.g., Urelumab and Utomilumab, etc.), anti-CSF-1R antibodies/CSF-1R inhibitors (e.g., Cabiralizumab, Emactuzumab, LY3022855, Axatilimab) , MCS-110, IMC-CS4, AMG820, Pexidartinib, BLZ945 and ARRY-382, etc.), anti-OX40 antibodies (e.g., MEDI6469, Ivuxolimab, MEDI0562, MEDI6383, Efizonerimod, GSK3174998, BMS-986178 and MOXR0916, etc.), anti-HVEM antibodies , anti-CD27 antibodies (e.g., Varlilumab, etc.), anti-GITR antibodies/GITR fusion proteins (e.g., Efaprinermin alfa, Efgivanermin alfa, MK-4166, INCAGN01876, GWN323 and TRX-518, etc.), anti-CD28 antibodies, anti-CCR4 antibodies (e.g. , Mogamulizumab, etc.), anti-B7-H3 antibodies (e.g., Enoblituzumab, Mirzotamab, Mirzotamab clezutoclax and Omburtamab, etc.), anti-ICOS agonist antibodies (e.g., Vopratelimab and GSK3359609, etc.), anti-CD4 antibodies (e.g., Zanolimumab and IT1208, etc.), DEC-205 antibody/NY-ESO-1 fusion protein (e.g., CDX-1401), anti-SLAMF7 antibody (e.g., Azintuxizumab, Azintuxizumab vedotin, and Elotuzumab, etc.), anti-CD73 antibody (e.g., Oleclumab and BMS-986179, etc.), PEG IL-2 (e.g., Bempegaldesleukin, etc.), IDO inhibitors (e.g., Epacadostat, Indoximod, and Linrodostat, etc.), TLR agonists (e.g., Motolimod, CMP-001, G100, Tilsotolimod, SD-101, and MEDI9197, etc.), Adenosine A2A Receptor antagonists (e.g., Preladenant, AZD4635, Taminadenant, Ciforadenant, etc.), anti-NKG2A antibodies (e.g., Monalizumab, etc.), anti-CSF-1 antibodies (e.g., PD0360324, etc.), immune enhancers (e.g., PV-10, etc.) , IL-15 super agonists (e.g., ALT-803, etc.), soluble LAG3 (e.g., Eftilagimod alpha, etc.), anti-CD47 antibodies/CD47 antagonists (e.g., ALX148, etc.), and IL-12 antagonists (e.g., M9241, etc.) Examples include. Additionally, Nivolumab can be manufactured according to the method described in WO 2006/121168, Pembrolizumab can be manufactured according to the method described in WO 2008/156712, and BMS-936559 can be manufactured according to the method described in WO 2008/156712. Ipilimumab can be manufactured according to the method described in WO 2001/014424.

Other antibody drugs include, for example, anti-IL-1β antibodies (eg, Canakinumab, etc.) and anti-CCR2 antibodies (eg, Plozalizumab, etc.).

Immunosuppressants include, for example, statins; mTOR inhibitors such as rapamycin or rapamycin analogs; TGF-β signaling agents; TGF-β receptor agonists; histone deacetylase inhibitors such as trichostatin A; corticosteroids. ; inhibitors of mitochondrial function, such as rotenone; P38 inhibitors; NF-κβ inhibitors, such as 6Bio, dexamethasone, TCPA-1, IKK VII; adenosine receptor agonists; prostaglandin E2 agonists (PGE2), such as misoprostol; ); phosphodiesterase inhibitors such as phosphodiesterase 4 inhibitors (PDE4) such as rolipram; proteasome inhibitors; kinase inhibitors; G protein-coupled receptor agonists; G protein-coupled receptor antagonists; glucocorticoids; retinoids; cytokine inhibitors; Cytokine receptor inhibitors; cytokine receptor activators; peroxisome proliferator-activated receptor antagonists; peroxisome proliferator-activated receptor agonists; histone deacetylase inhibitors; calcineurin inhibitors; phosphatase inhibitors; TGX-221, etc. PI3KB inhibitors; autophagy inhibitors such as 3-methyladenine; aryl hydrocarbon receptor inhibitors; proteasome inhibitor I (PSI); and oxidized ATP such as P2X receptor blockers; IDO, vitamin D3, and cyclosporine. cyclosporine, aryl hydrocarbon receptor inhibitors, resveratrol, azathioprine (Aza), 6-mercaptopurine (6-MP), 6-thioguanine (6-TG), FK506, sanglifehrin A, salmeterol, mycophenolate mofetil (MMF), aspirin and other COX inhibitors, niflumic acid, estriol and triptolide; small molecule drugs, natural products, antibodies (e.g., antibodies against CD20, CD3, CD4), biologic-based drugs, Carbohydrate-based drugs, nanoparticles, liposomes, RNAi, antisense nucleic acids, aptamers, methotrexate, NSAIDs; fingolimod; natalizumab; alemtuzumab; anti-CD3; tacrolimus (FK506), and the like. However, those skilled in the art will recognize other suitable immunosuppressive agents.

According to the medicine of the present disclosure, it is possible for the medicine (therapeutic agent) to remain in the target superficial lymph node for a long time. Therefore, the medicament of the present disclosure can be applied to various uses such as cancer and autoimmune diseases. For example, breast cancer can metastasize to the axillary lymph node, which is one of the superficial lymph nodes, and then spread throughout the body (lymphatic metastasis). Skin cancers of epithelial origin, such as extramammary Paget's disease and Merkel cell carcinoma, can also metastasize to lymph nodes. When autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus, and Sjögren's syndrome are treated with immunosuppressants such as methotrexate, lymphadenopathy is observed. In this case, by using the medicament of the present disclosure, the drug (therapeutic drug) can be retained in the superficial lymph nodes for a long time to suppress/inhibit cancer metastasis or suppress/treat lymph node swelling. It is possible. Therefore, the medicament of the present disclosure can be suitably used for the treatment of breast cancer, skin cancer, or autoimmune disease.

The size of the therapeutic drug is not particularly limited, but if it is a low molecule, it will easily migrate into the blood. Therefore, from the viewpoint of further improving retention efficiency in superficial lymph nodes, the therapeutic agent usually has a molecular weight of 15 kDa or more, preferably 100 kDa or more. The upper limit of the size of the therapeutic agent is not particularly limited, but is usually 200 kDa or less, preferably 150 kDa or less.

The medicine according to the present invention essentially includes a drug (ICG-labeled drug) in which an indocyanine green derivative (ICG) is bound to a therapeutic drug, but the method of binding ICG to a therapeutic drug is not particularly limited and is known in the art. The method described above can be applied in the same manner or with appropriate modification. For example, when the therapeutic agent is an antibody, peptide agent, or protein preparation, indocyanine green, indocyanine green-N-hydroxysulfosuccinimide ester (ICG-Sulfo-OSu), indocyanine green-N-hydroxysulfosuccinimide ester ( ICG-OSu), ICG-Sulfo-EG8-OSu, ICG-Sulfo-EG4-OSu, ICG-PEG12-OSu, ICG-ATT(3-ICG-acyl-1,3-thiazolidine-2-thione) (all The indocyanine green derivative can be bound (labeled) to the therapeutic agent via the amino group of the therapeutic agent using AAT Bioquest, Inc.) or the like. Incidentally, indocyanine green, ICG-Sulfo-OSu, ICG-OSu, ICG-Sulfo-EG8-OSu, ICG-Sulfo-EG4-OSu, ICG-PEG12-OSu, and ICG-ATT have the following structures.

Alternatively, an indocyanine green derivative can be bound to a therapeutic agent using a kit or the like according to the instructions of the manufacturer (eg, Dojin Kagaku Co., Ltd.). Specifically, an appropriate amount of indocyanine green derivative solution is added to the therapeutic agent and stirred. Here, the mixing ratio of the therapeutic agent and the indocyanine green derivative (ICG) is not particularly limited, and is appropriately selected depending on the desired visibility (for example, brightness, fluorescence intensity). The mixing ratio of the therapeutic drug and the indocyanine green derivative (ICG) is, for example, a ratio of 1 to 10 molecules of ICG bound to one molecule of the therapeutic drug, preferably 1 to 5 molecules of ICG to one molecule of the therapeutic drug. It is a binding ratio, and more preferably a ratio of 1 to 3 molecules of ICG binding to 1 molecule of therapeutic drug.

The dosage of a medicine (drug, therapeutic agent) is determined by taking into consideration the therapeutically effective amount, but it also takes into consideration the nature of the subject's disease and side effects (e.g., degree of nausea, vomiting, migraine). The severity varies depending on the subject's size, weight, surface area, age, and sex; other drugs administered; and the judgment of the attending physician. In view of the differing efficacies of the various available agents, it is expected that the required dosage may vary widely. Variations in these dosage levels can be adjusted using standard empirical procedures for optimum known in the art. Moreover, the above-mentioned dosage may be divided into once a day or multiple times a day. Or, in some cases, may be administered less frequently (eg, weekly or monthly). Additionally, the dosage may vary even for the same subject depending on the subject's symptoms, severity, nature of treatment, etc.

As used herein, "therapeutically effective amount" means an amount of an active ingredient or drug that is effective to produce any desired suppressive effect, with a reasonable benefit/risk ratio applicable to any medical practice. do. For example, the dosage of the medicament according to the present invention varies depending on the target disease, administration target, etc. The dose can be appropriately selected by those skilled in the art since it can easily vary depending on conditions such as the body weight of the subject. In addition, the attending physician ultimately makes an appropriate selection, taking into consideration the subject's symptoms and severity. As used herein, "treatment" also refers to implementing a protocol that may include administering one or more drugs to a subject (e.g., a human) for the purpose of reducing or alleviating signs or symptoms of a disease. refers to doing. Relief can occur before signs or symptoms of the disease appear, as well as after their appearance. Therefore, "treatment" includes "preventing" a disease. Note that "prevention" refers to protective and/or prophylactic measures, and is intended here to prevent or suppress a target disease, pathological condition or disorder.

[Subject (patient)]
The subject (patient) to whom the medicament according to the present invention is administered can be a human or a non-human animal. Examples of non-human animals include, but are limited to, laboratory animals such as mice, rats, and hamsters; pets such as dogs, cats, and rabbits; livestock and poultry such as pigs, cows, goats, sheep, horses, and chickens. Not done. Preferably the subject is a human.

[Intradermal administration]
In the present disclosure, the medicament is administered intradermally upstream of said superficial lymph node. As used herein, the term "upstream side of a superficial lymph node" refers to the side of a capillary lymph vessel derived from a superficial lymph node where a drug resides. That is, the drug is administered intradermally, where there are lymph capillaries derived from superficial lymph nodes where the drug resides. The administration site can be determined based on the location of lymph vessels (lymph capillaries, collecting lymph vessels where lymph capillaries gather and merge) and lymph nodes confirmed by lymphoscintigraphy. In order to efficiently deliver the drug to the target superficial lymph node, it is preferable to administer the drug intradermally from a site appropriately spaced from the superficial lymph node where it should reside. Specifically, when the superficial lymph node is an axillary lymph node, the drug is administered intradermally from the upper body such as the upper limb or chest; when the superficial lymph node is an inguinal lymph node, the medicine is administered intradermally from the lower limb, chest, etc. Administer intradermally from the lower body such as the abdomen or buttocks; and if the superficial lymph nodes are cervical lymph nodes, administer intradermally from the neck or head.

In the present disclosure, the medicine is administered from the upstream side of the superficial lymph node, for example, via an injection needle. Here, the injection needle is appropriately selected depending on the subject. For example, when the administration target (subject) is a human, the skin includes an "epidermal layer" with a thickness of 50 μm to 200 μm from the skin surface, a "dermal layer" with a thickness of 0.5 to 3.5 mm continuing from the epidermal layer, It is composed of the subcutaneous tissue layer, which is deeper than the dermal layer. Further, for example, the thickness of the upper skin layer of human deltoid muscle, which consists of the epidermis layer and the dermis layer, is generally about 2 mm. Therefore, when the administration target (subject) is a human, the injection needle preferably includes a needle tube with a protrusion length of 0.9 mm or more and 1.4 mm or less. That is, in a preferred form of the present invention, the medicine is intradermally administered via an injection needle equipped with a needle tube having a protrusion length of 0.9 mm or more and 1.4 mm or less. Here, if the protrusion length is less than 0.9 mm or exceeds 1.4 mm, it may become difficult to reliably administer intradermally (the success rate of intradermal administration may decrease). From the viewpoint of the effects of the present invention (in particular, further improvement in the success rate of intradermal administration), the protruding length of the injection needle in this embodiment is preferably 1.0 mm or more and 1.3 mm or less. Alternatively, if the subject of administration (subject) is a small non-human animal such as a rodent (rat, mouse, rabbit, guinea pig, hamster, etc.), the injection needle should have a protrusion length of 0.1 mm or more and 0.6 mm. It is preferable to provide a needle tube with a protrusion length of 0.45 mm or more and 0.50 mm or less. In either case, it is important to set the protrusion length of the needle tube suitable for administering the medicine depending on the position in the depth direction of the dermal layer of the administration site.

The human epidermal layer is thin, and the thickness of the human epidermal layer depends on the age difference, gender difference, individual difference, medical history/treatment history, etc. of the subject (administration target). Therefore, when attempting intradermal administration using a drug administration device equipped with a needle used for conventional subcutaneous administration, it is not possible to unambiguously determine the depth of the administration site within the dermal layer, which is closer to the epidermis. It is not easy to properly position the tip of the injection needle within the dermal layer. Therefore, from the viewpoint of further improving the success rate of intradermal administration (when the administration target is a human, the protrusion length is set to 0.9 mm or more and 1.4 mm or less), published in Japanese Patent Publication No. 2012-503995 (WO 2010/038879) and Japanese Patent Application Publication No. 2010-172603 are preferably used.

In the following, preferred forms of the administration device 10 and needle assembly 100 having an injection needle with a needle tube will be described. Note that the present invention is not limited to the following form. Common members in each figure are given the same reference numerals.

[Administration device]
FIG. 1 is a perspective view schematically showing the overall configuration of the administration device 10. As shown in FIG.

The administration device 10 is used to administer a medicine to the dermal layer s2 of a subject (intradermal administration), as shown in FIGS. 10 and 11.

FIGS. 10 and 11 are schematic cross-sectional views of the epidermal layer s1, dermal layer s2, and subcutaneous tissue layer s3 of a subject to whom medicine is administered. In this specification, the epidermis layer s1 and the dermis layer s2 are collectively referred to as the upper skin layer s4.

As shown in FIG. 1, the administration device 10 includes a needle assembly 100 including a needle hub 120 holding an injection needle 110, and a syringe 200 connectable to the needle assembly 100.

As shown in FIG. 3, inside the syringe 200, a liquid chamber 240 that can accommodate a medicine (medical solution) is provided. A pusher 300 is inserted into the liquid chamber 240 of the syringe 200 to feed a medicine from the liquid chamber 240 to the inner cavity 111a of the needle tube 111 of the injection needle 110.

In this embodiment, the extending direction of the injection needle 110 and the extending direction of the syringe 200 are also referred to as the "axial direction." The needle tip 112 side of the injection needle 110 is referred to as the "distal end side", and the end side opposite to the distal end side is referred to as the "proximal end side".

The subject, the operator, etc. (hereinafter also referred to as the "user") move the pusher 300 toward the distal end of the syringe 200 with the needle tip 112 of the injection needle 110 placed within the dermal layer s2. Accordingly, the medicine can be intradermally administered to the subject through the tip opening 112a formed in the needle tip 112 (see FIG. 11). In this way, the simple operation of arranging the needle tip 112 of the injection needle 110 at the intended administration site and injecting the drug enables reliable intradermal administration. Further, the needle tip 112 is located within the guide portion 123 and is constructed so that it is not visible to the user during operation. Therefore, even subjects who are afraid of injections can administer the drug at home with little or no resistance.

The administration device 10 can be configured, for example, as a disposable device in which the liquid chamber 240 is filled with a medicine (medicine solution) during intradermal administration and the filled medicine is discarded every time the medicine is administered. Note that the administration device 10 can also be configured as a prefilled device in which the liquid chamber 240 is filled with a medicine in advance prior to intradermal administration. Further, the medicine (medicine to be administered intradermally) accommodated in the liquid chamber 240 is specifically as described in the above [Medicine].

As shown in FIG. 1, the syringe 200 includes a first cylindrical portion 210 having a locking mechanism 205 (see FIG. 3) to which the needle hub 120 can be connected, and a proximal end of the first cylindrical portion 210. and a second cylindrical portion 220 disposed at.

The first cylindrical portion 210 and the second cylindrical portion 220 have a substantially cylindrical outer shape. The second cylindrical portion 220 disposed on the base end side of the first cylindrical portion 210 has a larger outer diameter than the first cylindrical portion 210 .

When performing intradermal administration using the administration device 10, the user can grasp the second cylindrical portion 220 located on the proximal end side of the syringe 200. Since the second cylindrical portion 220 has a larger diameter than the first cylindrical portion 210, it is easier for the user to grip the second cylindrical portion 220, and the grip strength when gripping the second cylindrical portion 220 is also increased. Therefore, when a user performs intradermal administration using the administration device 10, it is difficult for the user to firmly pierce the needle tip 112 of the injection needle 110 protruding toward the distal side of the administration device 10 into the epidermal layer s1. It becomes possible.

The locking mechanism 205 shown in FIG. 3 can be composed of, for example, a member having a threaded groove on its inner surface. In this embodiment, the second member 127 of the needle hub 120 is provided with a connecting portion 128 that can be screwed into the thread groove of the locking mechanism 205 at the base end. The user inserts the proximal end of the needle hub 120 inside the locking mechanism 205, and then rotates and screws the needle hub 120 to removably connect the needle hub 120 to the syringe 200. be able to.

For example, the threads provided on the locking mechanism 205 may be configured with female threads, and the connecting portion 128 provided on the needle hub 120 may be configured with male threads. However, the thread groove on the locking mechanism 205 side may be configured with a male thread, and the thread groove on the connecting portion 128 side may be configured with a female thread. Further, there is no particular restriction on the specific mechanism for connecting the needle hub 120 and the syringe 200. For example, the distal end of the syringe 200 may be inserted inside the proximal end of the needle hub 120 and the two may be fitted together. It is also possible to adopt a similar mechanism. Further, the needle hub 120 may be fixed to the syringe 200 using an adhesive or the like so that it cannot be separated.

As shown in FIG. 3, the liquid chamber 240 of the syringe 200 is communicated with the lumen 111a of the injection needle 110 (see FIG. 6) when the needle hub 120 and the syringe 200 are connected. As will be discussed below, needle 110 is secured within needle hub 120 by adhesive 126.

[Needle assembly]
As shown in FIGS. 1, 2, and 3, the needle assembly 100 includes an injection needle 110 and a needle hub 120 in which the injection needle 110 is held.

An exploded view of needle assembly 100 is shown in FIG.

As shown in FIG. 3, the needle hub 120 includes a first member 121 disposed on the distal end side of the needle hub 120 and a second member 127 disposed on the proximal end side of the first member 121.

The injection needle 110 is fixed to the first member 121 by an adhesive 126 filled inside the first member 121. An elastic member 125 is arranged between the base end of the first member 121 and the distal end of the second member 127. The injection needle 110 is disposed inside the needle hub 120 with the proximal end 115 of the injection needle 110 aligned with the distal end of the liquid chamber 240.

As shown in FIGS. 3, 4, and 5, the first member 121 of the needle hub 120 is formed by exposing a certain range from the needle tip 112 of the needle tube 111 of the injection needle 110 toward the proximal end. An adjustment section 122 for adjusting the protrusion length L1 of the adjustment section 122 and the needle tube 111 are arranged so as to surround the portions of the adjustment section 122 and the needle tube 111 that are exposed from the adjustment section 122, and to leave a space 122a between the adjustment section 122 and the needle tube 111. It has a guide part 123.

The adjustment portion 122 is provided at approximately the center position of the needle hub 120 in the plane direction. The adjustment portion 122 is configured with a hollow portion that exposes a portion of the needle tip 112 side of the injection needle 110. As shown in FIG. 5, the injection needle 110 is attached to the needle hub 120 with the adhesive 126 described above with a part of the needle tip 112 side exposed from the adjustment part 122 toward the tip side for a predetermined length L1. Fixed. Therefore, the needle hub 120 allows the injection needle 110 to move toward the proximal end side as the needle tip 112 of the injection needle 110 is pressed against the epidermal layer s1 of the subject when performing intradermal administration using the administration device 10. It is possible to prevent the protrusion length L1 from changing due to movement.

The guide section 123 is arranged concentrically with the adjustment section 122. Therefore, as shown in FIG. 4, a circular space 122a centered around the adjustment section 122 is formed around the adjustment section 122.

As shown in FIGS. 3 and 4, a flange portion 124 extending in a planar manner is disposed at a position further toward the outer circumference of the guide portion 123. As shown in FIGS. The flange portion 124, like the guide portion 123, is arranged concentrically with the adjustment portion 122. The flange portion 124 extends from near the base end of the guide portion 123 toward the outer circumference.

The elastic member 125 disposed near the proximal end 115 of the injection needle 110 increases liquid tightness at the connection between the liquid chamber 240 of the syringe 200 and the needle hub 120. Thereby, when the medicine is delivered from the liquid chamber 240 to the inner cavity 111a of the injection needle 110, it is possible to prevent the medicine from leaking near the proximal end of the injection needle 110.

The dispensing device 10 may include a cap member 130 as shown in FIG. Cap member 130 is configured to be connectable to first member 121 of needle hub 120 . The cap member 130 is disposed so as to cover the needle tip 112 of the injection needle 110 from the distal end side of the needle hub 120 while being connected to the needle hub 120 . By attaching the cap member 130 to the needle hub 120, the user can prevent the needle tip 112 of the injection needle 110 from being accidentally punctured.

Each part of the needle hub 120 shown in FIG. 5 can be formed, for example, with the following dimensions. However, the dimensions are not limited to the example dimensions shown below.

The distance T1 (corresponding to the horizontal width of the space 122a) from the outer circumferential edge of the adjustment part 122 to the inner circumferential edge of the guide part 123 can be set to, for example, 4.9 mm or more and 5.3 mm or less.

The distance T2 from the outer circumferential edge of the guide portion 123 to the outer circumferential edge of the flange portion 124 can be set to, for example, 2.9 mm or more and 3.1 mm or less.

The dimensional difference Hg between the adjustment part 122 and the guide part 123 in the protruding direction of the injection needle 110 can be set to, for example, 0.2 mm or more and 0.4 mm or less.

Each part of the needle hub 120 and the syringe 200 can be made of, for example, a known resin material or a known metal material. As an example, synthetic resins such as polycarbonate, polypropylene, and polyethylene, and metals such as stainless steel and aluminum can be used.

FIGS. 10 and 11 are schematic cross-sectional views when performing intradermal administration to a user using the injection needle 110.

As shown in FIG. 10, when the injection needle 110 perpendicularly punctures the epidermal layer s1, the adjustment part 122 comes into contact with the epidermal layer s1 and spreads the epidermal layer s1 around the injection needle 110. At this time, the skin layer s1 is spread flat within the space 122a provided between the adjustment section 122 and the guide section 123. By pressing the adjustment part 122 until the flange part 124 contacts the skin layer s1, the user can ensure that the force with which the adjustment part 122 and the needle tube 111 press against the skin layer s1 is equal to or higher than a predetermined value. The user inserts the injection needle 110, which is arranged so as to maintain a predetermined protrusion length L1, into the subject from the epidermal layer s1 side while pressing the adjustment part 122 and the flange part 124 against the epidermal layer s1. The needle tip 112 of the injection needle 110 can be appropriately guided into the dermal layer s2 without depending on variations in the state of the epidermal layer s1.

Note that the specific procedure of the intradermal administration method using the administration device 10 and the injection needle 110 according to the present embodiment will be explained in more detail through Examples described later.

6 to 9 show a portion of the distal end side (blade surface 113 side) of the injection needle 110 according to the present embodiment in an enlarged manner.

6 is a plan view of the front end opening 112a of the injection needle 110, and FIG. 7 is a perspective view of the injection needle 110. 8(A) is a side view (left side view) of the injection needle seen from the direction of arrow 8A shown in FIG. 6, and FIG. 8(B) is a perspective side view of the injection needle 110 seen from the direction of arrow 8B shown in FIG. It is. 9(A) is a side view (right side view) of the injection needle seen from the direction of arrow 9A shown in FIG. 6, and FIG. 9(B) is a perspective side view of the injection needle 110 seen from the direction of arrow 9B shown in FIG. It is.

As shown in FIG. 6, the injection needle 110 according to this embodiment includes a needle tube 111 in which a blade surface 113 is formed at the needle tip 112.

A straight line O1 shown in FIGS. 6 to 9 indicates a central axis along the extending direction of the injection needle 110 (needle tube 111).

A lumen 111a is formed inside the needle tube 111, through which a medicine to be administered intradermally can flow. A tip opening 112a is formed at the tip of the needle tip 112 and communicates with the inner cavity 111a.

In the administration device 10 described above, the injection needle 110 is arranged such that a certain range on the proximal end side of the injection needle 110 is housed inside the needle hub 120 (inside the first member 121 and the second member 127). Ru. A portion of the distal end of the injection needle 110 is arranged so as to protrude further toward the distal end than the adjustment portion 122 of the needle hub 120 .

A portion of the injection needle 110 that is closer to the proximal end of the needle tube 111 than the portion where the blade surface 113 is formed and is exposed from the adjustment portion 122 constitutes a needle body portion 114 .

The injection needle 110 can be configured with a "lancet needle" or a "semi-lancet needle", for example. However, there are no particular restrictions on the specific shape or structure of the injection needle 110. For example, the injection needle 110 may be configured not only as a straight needle but also as a tapered needle in which at least a portion thereof is tapered, or that the radial cross-sectional shape of the needle tube 111 is a polygon such as a triangle. may have been done.

The injection needle 110 can be configured with a metal needle made of metal, for example. As the metal constituting the injection needle 110, for example, stainless steel, aluminum, aluminum alloy, titanium, titanium alloy, and other metals can be used.

As shown in FIGS. 6 and 7, the blade surface 113 has a first blade surface 113a located on the proximal end side of the needle tube 111, and a boundary located on the needle tip 112 side (distal end side) from the first blade surface 113a. It has a second blade surface 113b and a third blade surface 113c forming a ridgeline at 116.

The second blade surface 113b and the third blade surface 113c are formed symmetrically with respect to the boundary line 116 in the plan view shown in FIG. Therefore, the second blade surface angle θ2 and the third blade surface angle θ3, which will be described later, are substantially the same, and the blade surface length L22 of the second blade surface 113b and the blade surface length L23 of the third blade surface 113c are also substantially the same. The second blade surface 113b and the third blade surface 113c have different shapes (for example, the second blade surface angle θ2 and the third blade surface angle θ3 and/or the blade surface length L22 of the second blade surface 113b and the third blade surface angle θ3). The blade surface length L23 of the surface 113c may be formed in a different shape.

The first blade surface angle θ1 shown in FIGS. 8(A) and 9(A) is the angle formed by the central axis O1 of the needle tube 111 and the first blade surface 113a. The straight line H1 shown in FIGS. 8(A) and 8(B) is a virtual straight line along the first blade surface 113a. That is, the first blade angle θ1 is an angle formed by the central axis O1 and the straight line H1.

The second blade surface angle θ2 shown in FIG. 9(B) is the angle formed between the central axis O1 of the needle tube 111 and the second blade surface 113b. A straight line H2 shown in FIG. 9(B) is a virtual straight line along the second blade surface 113b. That is, the second blade surface angle θ2 is an angle formed by the central axis O1 and the straight line H2.

The third blade surface angle θ3 shown in FIG. 8(B) is the angle formed between the central axis O1 of the needle tube 111 and the third blade surface 113c. A straight line H3 shown in FIG. 8(B) is a virtual straight line along the third blade surface 113c. That is, the third blade surface angle θ3 is an angle formed by the central axis O1 and the straight line H3.

The ridgeline angle α1 shown in FIGS. 8(A) and 9(A) is the angle formed by the central axis O1 and the ridgeline formed at the boundary 116. The straight line B1 shown in FIGS. 8(A) and 8(B) is a virtual straight line along the ridgeline. That is, the ridgeline angle α1 is the angle formed by the central axis O1 and the straight line B1.

The first blade angle θ1 and the ridgeline angle α1 can be formed to be acute angles, for example. Further, the first blade angle θ1 can be formed to be more acute than the ridgeline angle α1. Note that "the degree of the acute angle is large" means that the angle is smaller within the acute angle range.

The second blade angle θ2 and the third blade angle θ3 can be formed into acute angles, for example. Further, the first blade angle θ1 can be formed to be more acute than each of the second blade angle θ2 and the third blade angle θ3.

Since the relationship between the blade angles θ1, θ2, θ3 and the ridge angle α1 is defined as described above, the injection needle 110 has a relatively short blade length L2, so that the needle tip 112 can be Penetration into the epidermal layer s1 is improved.

Next, examples of preferred dimensions of each part of the injection needle 110 according to this embodiment will be described with reference to FIGS. 6 to 9.

The outer diameter D1 of the needle tube 111 shown in FIG. 6 can be formed to be 0.1 mm or more and 0.2 mm or less. Further, the outer diameter D1 of the needle tube 111 is more preferably 0.130 mm or more and 0.1845 mm or less from the viewpoint of enabling intradermal administration to a subject more reliably and easily.

The inner diameter Φ1 of the needle tube 111 shown in FIG. 6 can be formed to be 0.07 mm or more and 0.1 mm or less.

The protrusion length L1 of the needle tube 111 shown in FIG. 6 is 0.9 mm or more and 1.4 mm or less.

The protrusion length L1 of the needle tube 111 shown in FIG. 6 is a length suitable for intradermal administration of a medicine, and is appropriately selected depending on the subject to be administered. For example, when the administration target (subject) is a human, the protrusion length L1 of the needle tube 111 is preferably 0.9 mm or more and 1.4 mm or less. From the viewpoint of enabling intradermal administration to a subject more reliably and easily, the protrusion length L1 of the needle tube 111 is more preferably 1.0 mm or more and 1.3 mm or less. Further, for example, when the administration target (subject) is a small non-human animal such as a rodent (rat, mouse, rabbit, guinea pig, hamster, etc.), the protrusion length L1 of the needle tube 111 is 0.1 mm or more. The protrusion length L1 of the needle tube 111 is preferably 0.45 mm or more and 0.5 mm or less, from the viewpoint of enabling intradermal administration to the subject more reliably and easily. is more preferable.

The length (blade surface length) L2 of the blade surface 113 along the extending direction of the needle tube 111 (direction parallel to the central axis O1) shown in FIG. 6 can be formed to be less than 0.3 mm. Further, the length L2 of the blade surface 113 is more preferably 0.15 mm or more and 0.2 mm or less from the viewpoint of increasing the penetrating property of the subject's epidermal layer s1.

Note that the blade surface length L2 is the sum of the blade surface length L21 of the first blade surface 113a and the blade surface length L22 of the second blade surface 113b, or the blade surface length L21 of the first blade surface 113a and the third blade surface 113c. This is the total value of the blade surface length L23.

The needle barrel length L3 shown in FIG. 6 can be formed to be 0.05 mm or more and 0.5 mm or less. The needle barrel length L3 is more preferably 0.3 mm or more and 0.35 mm or less from the viewpoint of enabling intradermal administration to a subject more reliably and easily.

The wall thickness t1 of the needle tube 111 shown in FIG. 6 can be formed to be 0.01 mm or more and 0.06 mm or less. The wall thickness t1 of the needle tube 111 is set to be 0.0215 mm or more and 0.0505 mm or less, from the viewpoint of setting the injection pressure of the medicine by the injection needle 110 to an appropriate value in consideration of the outer diameter D1 of the needle tube 111 and the inner diameter Φ1 of the needle tube 111. It is more preferable that there be.

The ratio (L2/L22 and L2/L23) of the blade surface length L22 of the second blade surface 113b and the blade surface length L23 of the third blade surface 113c to the total length L2 of the blade surface 113 shown in FIG. 6 is 40% or more. 60% or less. The above-mentioned ratio is more preferably 47% or more and 56% or less from the viewpoint of improving the penetrating property of the epidermal layer s1 of the subject.

In addition, in the case where the blade surface length L2 is 0.15 mm or more and 0.2 mm or less, and the above ratio is 47% or more and 56% or less, the blade surface length L22 of the second blade surface 113b and the third blade surface 113c The blade surface length L23 can be, for example, 0.05 mm or more and 0.09 mm or less. In this case, the blade surface length L21 of the first blade surface 113a can be formed to be, for example, 0.09 mm or more and 0.17 mm or less.

The first blade angle θ1 shown in FIGS. 8(A) and 9(A) can be formed to be greater than or equal to 10° and less than or equal to 65°. The first blade angle θ1 is more preferably 23° or more and 40° or less from the viewpoint of improving the penetration ability of the needle tip 112 into the epidermal layer s1.

The second blade angle θ2 and the third blade angle θ3 shown in FIGS. 8(B) and 9(B) can be formed to be greater than or equal to 20° and less than or equal to 85°. The second blade angle θ2 and the third blade angle θ3 are more preferably 21° or more and 45° or less from the viewpoint of improving the penetration ability of the needle tip 112 into the epidermal layer s1.

The ridgeline angle α1 shown in FIGS. 8(A) and 9(A) can be formed to be greater than or equal to 15° and less than or equal to 70°. The ridge angle α1 is more preferably 28° or more and 44° or less from the viewpoint of improving the penetration ability of the needle tip 112 into the epidermal layer s1.

[Treatment method, drug delivery system]
As mentioned above, the disclosed medicament can be particularly suitably used for the treatment of breast cancer, skin cancer, and autoimmune diseases. That is, the present invention provides a method for treating breast cancer, which comprises intradermally administering a medicament containing an indocyanine green derivative bound to a therapeutic agent upstream of a superficial lymph node of a subject. The present invention provides a method for treating skin cancer, which comprises intradermally administering a medicament containing an indocyanine green derivative bound to a therapeutic agent upstream of a superficial lymph node of a subject. The present invention provides a method for treating autoimmune diseases, which comprises intradermally administering a medicament containing an indocyanine green derivative bound to a therapeutic agent upstream of a superficial lymph node of a subject.

As described above, the injection needle 110 and administration device 10 according to this embodiment have a configuration suitable for intradermal administration to a subject.

Therefore, in this embodiment, the needle assembly includes an injection needle including a needle tube with a protrusion length of 0.9 mm or more and 1.4 mm or less, and a needle hub that holds the injection needle, wherein the needle hub is , an adjustment part that adjusts the protrusion length of the needle tube by exposing a certain range from the needle tip of the needle tube toward the proximal end side; and a periphery of the adjustment part and the portion of the needle tube exposed from the adjustment part. a guide portion surrounding the adjustment portion and spaced between the adjustment portion and the needle tube; or a syringe connected to the needle hub. The syringe includes a first cylindrical portion disposed on the proximal side of the needle hub, and a first cylindrical portion disposed on the proximal side of the first cylindrical portion, the syringe having a larger outer diameter than the first cylindrical portion. After pressing the guide portion of the needle hub holding the injection needle against the administration site on the upstream side of the superficial lymph node of the subject using the administration device, the injection needle is Provided is a method for intradermal administration to a subject (particularly a human), which comprises intradermally administering a medicament containing an indocyanine green derivative bound to a therapeutic agent to the administration site by vertical puncture. Ru.

Further, in the present embodiment, a needle assembly includes an injection needle including a needle tube with a protrusion length of 0.9 mm or more and 1.4 mm or less, and a needle hub that holds the injection needle, wherein the needle hub is , an adjustment part that adjusts the protrusion length of the needle tube by exposing a certain range from the needle tip of the needle tube toward the proximal end side; and a periphery of the adjustment part and the portion of the needle tube exposed from the adjustment part. a guide portion surrounding the adjustment portion and spaced between the adjustment portion and the needle tube; or a syringe connected to the needle hub. The syringe includes a first cylindrical portion disposed on the proximal side of the needle hub, and a first cylindrical portion disposed on the proximal side of the first cylindrical portion, the syringe having a larger outer diameter than the first cylindrical portion. After pressing the guide portion of the needle hub holding the injection needle against the administration site on the upstream side of the superficial lymph node of the subject using the administration device, the injection needle is Provided is a method for treating breast cancer, skin cancer, or autoimmune disease, which comprises intradermally administering a drug containing an indocyanine green derivative bound to a therapeutic drug to the administration site by vertical puncture. Ru.

Further, in the present embodiment, a needle assembly includes an injection needle including a needle tube with a protrusion length of 0.9 mm or more and 1.4 mm or less, and a needle hub that holds the injection needle, wherein the needle hub is , an adjustment part that adjusts the protrusion length of the needle tube by exposing a certain range from the needle tip of the needle tube toward the proximal end side; and a periphery of the adjustment part and the portion of the needle tube exposed from the adjustment part. a guide portion surrounding the adjustment portion and spaced between the adjustment portion and the needle tube; or a syringe connected to the needle hub. The syringe includes a first cylindrical portion disposed on the proximal side of the needle hub, and a first cylindrical portion disposed on the proximal side of the first cylindrical portion, the syringe having a larger outer diameter than the first cylindrical portion. After pressing the guide portion of the needle hub holding the injection needle against the administration site on the upstream side of the superficial lymph node of the subject using the administration device, the injection needle is Provided is a method for improving the retention of a drug in a lymph node, which comprises intradermally administering a drug containing an indocyanine green derivative bound to a therapeutic drug to the administration site by vertical puncture.

The present embodiment also provides a drug delivery system for improving retention of a drug in superficial lymph nodes of a subject (particularly a human), wherein the drug delivery system has a protrusion length of 0.9 mm or more and 1.4 mm. A needle assembly comprising: an injection needle having a needle tube as follows; and a needle hub holding the injection needle, wherein the needle hub exposes a certain range from the needle tip of the needle tube toward the proximal end side. By doing so, the adjustment section for adjusting the protrusion length of the needle tube surrounds the adjustment section and the portion of the needle tube exposed from the adjustment section, and a space is left between the adjustment section and the needle tube. or a syringe connected to the needle hub, the syringe having a guide portion disposed proximally of the needle hub. a second cylindrical portion disposed proximally of the first cylindrical portion and having a larger outer diameter than the first cylindrical portion; The medicament includes an indocyanine green derivative bound to a therapeutic agent; after pressing the guide portion of the needle hub holding the injection needle against the administration site upstream of the superficial lymph node of the subject, the injection A drug delivery system is provided for intradermally administering the drug via a needle to the administration site by vertical puncture.

In one embodiment of the invention, the site of administration is the upper skin layer s4 upstream of the superficial lymph nodes having a dermal layer s2 less than 3.0 mm (preferably less than 2.0 mm) thick. Moreover, in this embodiment, the thickness of the administration site is measured by an ultrasound imaging apparatus.

Further, the protrusion length L1 of the injection needle 110 used for intradermal administration is preferably such that the ratio of the protrusion length L1 of the injection needle 110 to the thickness of the upper skin layer s4 of the subject is less than 0.9. , is more preferably less than 0.8, and particularly preferably 0.7 or less. Thereby, the needle tube 111 can be more reliably placed in the upper skin layer s4, and the success rate of intradermal administration can be further improved.

In place of or in addition to the above, when performing intradermal injection, it is preferable that the entire blade surface 113 of the injection needle 110 be buried in the upper skin layer s4 of the subject. Thereby, leakage of medicine from the needle tube 111 can be suppressed.

Specifically, the blade length L2 is smaller than the thickness of the upper skin layer s4 of the subject, and the ratio of the blade length L2 of the injection needle 110 to the thickness of the upper skin layer s4 of the subject is 0. It is preferably less than .60, more preferably less than 0.56, even more preferably less than 0.50, and particularly preferably less than 0.35. Thereby, the entire amount of the drug can be more reliably injected into the upper skin layer s4, and the success rate of intradermal administration can be further improved.

In the intradermal administration method, first confirm the administration site on the subject. Note that a support member (hereinafter also simply referred to as "support member") for stabilizing vertical puncture is placed below the administration site of the subject (on the epidermal layer side located on the opposite side to the insertion direction of the injection needle 110). ) may be placed. At this time, the support member is preferably formed from silicone resin or the like. Since such a support member has appropriate hardness, it is possible to stably fix the administration site.

Alternatively, any part of the subject's upper skin layer s4 may be stretched flat to serve as the administration site. At this time, after pressing the guide part 123 of the needle hub 120 against the administration site, the guide part 123 may be separated from the administration site by a predetermined distance (moved in the direction of lifting it from the epidermal layer s1). As a result, the injection pressure of the medicine (medicinal solution) is lowered, and intradermal administration can be performed satisfactorily. In this case, the distance between the guide portions 123 is preferably such that the injection pressure of the medicine is sufficiently lowered. Specifically, the distance is preferably such that the injection pressure during administration is 5 to 20N, and more preferably the distance is such that the injection pressure during administration is 10 to 15N. The above "injection pressure" is based on the feeling of the hand when administering to the subject, and measures the pressure when pressing the digital force gauge with the same force, and this pressure is taken as the injection pressure. It is measured by.

By using the above intradermal administration method and the puncture resistance of the injection needle, the medicine can be reliably and accurately delivered into the subject's skin (upper skin layer s4).

Conventionally, the Mantoux method is well known as a method for administering medicine into the dermal layer s2 of a subject. The Mantoux method is a method in which the injection needle 110 is inserted obliquely into the upper skin layer s4 having the dermis layer s2. Here, as described above, the skin is composed of an upper skin layer s4 consisting of an epidermal layer s1 and a dermal layer s2, and a subcutaneous tissue layer s3. The thickness of the upper skin layer of the human deltoid muscle is generally as thin as about 2 mm. For this reason, intradermal administration to the upper skin layer s4 is difficult, and depending on the procedure and the diameter of the injection needle used, there is a possibility that the drug may leak into the subcutaneous tissue layer s3 or onto the skin surface. Furthermore, whether or not intradermal administration is successful may vary depending on the skill of the operator performing the injection. In contrast, according to the intradermal administration method according to the present embodiment (particularly the intradermal administration method using the administration device of the present disclosure), a predetermined amount of the drug can be reliably administered intradermally. In addition, since vertical puncture is used, the procedure is easy and variations among surgeons can be suppressed. Furthermore, leakage of medicine can be suppressed. Therefore, according to the intradermal administration method of the present embodiment, a predetermined amount of a drug can be reliably and accurately delivered intradermally to a subject, and a predetermined amount of a drug (drug, therapeutic drug) can be delivered more reliably and accurately. It can stay in the target superficial lymph nodes accurately and for a long period of time. Therefore, it can be expected that even if the amount of the drug (therapeutic drug) is smaller than before, the drug will be effective. Additionally, since there are fewer nerves in the intradermal tissue than in the subcutaneous tissue, pain during administration can be reduced and alleviated.

The effects of the present invention will be explained using the following examples and comparative examples. However, the technical scope of the present invention is not limited only to the following examples. In addition, in the following examples, unless otherwise specified, operations were performed at room temperature (25° C.). Furthermore, unless otherwise specified, "%" and "parts" mean "% by mass" and "parts by mass", respectively.

[Experiment 1: Confirmation of effects by administration route]
In this experiment, each material was prepared as follows.

(Animals used)
Mice (strain: BALB/cAjcl, female, age: 6 weeks, purchased from CLEA Japan Co., Ltd.) were subjected to a 7-day quarantine and acclimatization period, and all mice showed no abnormalities in health and weight loss. After confirming that there was no Mice were allowed free access to food and water in a breeding environment with 12 hours of light, temperature of 20-26°C, and humidity of 30-70%. The experiment was conducted in accordance with Terumo Corporation's guidelines for animal experiments.

(Preparation of test substance)
According to the manufacturer's instructions, Anti-KLH (Anti-Keyhole Limpet Hemocyanin) mouse IgG1 antibody [Purified Mouse Monoclonal IgG, Clone#11711] (manufactured by R&D Systems, Cat. No. MAB002, Lot. No. IX2417011) (molecular weight = 150 kDa) (IgG Isotype Control), ICG-Sulfo-OSu (manufactured by Dojin Kagaku Co., Ltd., Cat. No. I254) as a fluorescent dye, ICG-Sulfo-OSu:Antibody (IgG Isotype Control) = 30:1 A PBS solution containing an ICG-labeled antibody (antibody concentration = 0.497 mg/mL) in which two ICG molecules were bound to one antibody molecule was prepared (Lot. No. 2D-022, buffer: PBS, pH=7.4).

The PBS solution containing the ICG-labeled antibody obtained above was diluted with PBS (manufactured by ThermoFisher Scientific, Cat. No. 10010-023, Lot. No. 2081860, pH 7.4) to a concentration of 0.280 mg/mL. , an antibody solution for intradermal and subcutaneous administration was prepared (ICG-labeled antibody solution for intradermal/subcutaneous administration).

In addition, the PBS solution containing the ICG-labeled antibody obtained above was adjusted to a concentration of 0.014 mg/mL with PBS (manufactured by ThermoFisher Scientific, Cat. No. 10010-023, Lot. No. 2081860, pH 7.4). It was diluted to prepare an antibody solution for intravenous administration (ICG-labeled antibody solution for intravenous administration).

(Administration device)
For intradermal administration, a syringe (capacity: 50 μL) is attached to an injection needle (needle tube outer diameter: 0.30 mm (31 G), needle length: 20 mm, blade angle: 18°, needle tip shape: lancet). (intradermal administration device).

For subcutaneous administration, use an injection needle (manufactured by Terumo Corporation, code number: NN-2719S) (outer diameter of needle tube: 0.40 mm (27G), needle length: 19 mm, needle tip shape: short bevel, blade angle: A device with a syringe (volume: 50 μL) attached was prepared (subcutaneous administration device).

For intravenous administration, use a syringe needle (manufactured by Terumo Corporation, code number: NN-2719S) (outer diameter of needle tube: 0.40 mm (27G), needle length: 19 mm, needle tip shape: short bevel, blade angle: A device with a syringe (capacity: 1 mL) attached was prepared (intravenous administration device).

(Equipment/appliances used)
IVIS Imaging System: Manufactured by Perkin Elmer, model number: Lumina Series III (hereinafter simply referred to as "IVIS")
IVIS Software: Manufactured by Perkin Elmer, Model Number: Living Image(R) Software 4.7.3.

Example 1: Intradermal administration Each mouse (3 mice) was given isoflurane (isoflurane inhalation anesthetic solution "Pfizer", manufactured by Mylan Pharmaceutical Co., Ltd.) using an anesthesia machine (manufactured by Natsume Seisakusho Co., Ltd., model number: KN-1071). , sold by Pfizer Inc.) (induction anesthesia: 2.0-3.0%, maintenance anesthesia: 2.0-3.0%, carrier gas: air). Under anesthesia, 10 μL of an ICG-labeled antibody solution for intradermal/subcutaneous administration (2.8 μg of ICG-labeled antibody) was administered intradermally into the forelimbs of the above mice by the Mantoux method using an intradermal administration device (administration to mice). Dose: 2.8 μg/head). After administration, the intradermal administration site of each mouse was visually confirmed. As a result, in all mice, there was no leakage of the injection solution (drug solution) and a bulge was formed, so it was judged that the intradermal administration was successful.

Next, the fluorescence of the axillary lymph nodes of each mouse was observed and photographed using IVIS (day 0). After imaging, mice were allowed to wake up. Furthermore, 1 day, 2 days, and 7 days after administration, the fluorescence of the axillary lymph nodes of each mouse was observed and photographed using the IVIS Imaging System. At this time, photography was performed under the conditions of "Excitation Filter; 760nm, Emission Filter; 845nm, Exposure Time; Auto, Binning; Medium, F/Stop; 2". The results are shown in FIG. In FIG. 12, areas where red color is observed indicate the presence of ICG-labeled antibodies. FIG. 12 confirms that the ICG-labeled antibody remains in the axillary lymph node for at least 7 days after intradermal administration. Furthermore, after imaging, the fluorescence intensity (Phtons/sec) in the axillary lymph nodes was analyzed using IVIS software. The results are shown in FIG.

Furthermore, after the final photograph on the 7th day after administration, axillary lymph nodes were collected from the mice, and one tissue per well was placed in a 96-well plate. Thereafter, the amount of residual ICG-labeled antibody in the lymph node tissue (Total lymph node flux) (unit: photons/sec) was measured using IVIS. At this time, the measurement was performed under the conditions of "Excitation Filter; 760nm, Emission Filter; 845nm, Exposure Time; Auto, Binning; Medium, F/Stop; 2".

After measurement with IVIS, fluorescence intensity (Phtons/sec) was measured using IVIS software. The results are shown in FIG. 14 (I.D. in FIG. 14). In addition, in the results showing axillary lymph nodes, the intradermal administration group (I.D. group; I.D. in FIG. 14), the subcutaneous administration group (S.C. group: S.C. in FIG. 14) and the intravenous administration group (I.V. group: The purpose of this study was to verify whether there was a significant difference in lymph node migration between the I.D. group and the I.D. group. Difference tests were performed.

Comparative Example 1: Subcutaneous administration Each mouse (4 mice) was given isoflurane (isoflurane inhalation anesthetic solution "Pfizer", manufactured by Mylan Pharmaceutical Co., Ltd., using an anesthesia machine (manufactured by Natsume Seisakusho Co., Ltd., model number: KN-1071). (Sales: Pfizer Inc.) (induction anesthesia: 2.0-3.0%, maintenance anesthesia: 2.0-3.0%, carrier gas: air). Under anesthesia, 10 μL of an ICG-labeled antibody solution for intradermal/subcutaneous administration (2.8 μg of ICG-labeled antibody) was administered subcutaneously to the forelimbs of the above mice using a subcutaneous administration device (dose to mouse: 2.8 μg/ head). At this time, insert the injection needle along the body axis while pinching the injection site. After confirming that the needle tip moves easily and is inserted subcutaneously, insert the injection needle into the skin and into the skin. The ICG-labeled antibody solution for subcutaneous administration was administered subcutaneously to the upper limb. After administration, the needle was gently removed and it was confirmed that the administered solution did not leak.

Next, the fluorescence of the axillary lymph nodes of each mouse was observed and photographed using IVIS (day 0). After imaging, mice were allowed to wake up. Furthermore, 1 day, 2 days, and 7 days after administration, the fluorescence of the axillary lymph nodes of each mouse was observed and photographed using the IVIS Imaging System. The results are shown in FIG. From Figure 12, a red area (i.e., the presence of ICG-labeled antibody) was confirmed until about the second day after administration, but after that, the red area became significantly smaller, and by the seventh day, almost no fluorescence was observed. It wasn't done. Furthermore, after imaging, the fluorescence intensity (Phtons/sec) in the axillary lymph nodes was analyzed using IVIS software. The results are shown in FIG. FIG. 13 also shows that the antibody can be retained for a longer period of time when administered intradermally than when administered subcutaneously.

In addition, after the final imaging on the 7th day after administration, the amount of residual ICG-labeled antibody (Total lymph node flux) (unit: photons/sec) in the mouse axillary lymph node tissue was measured in the same manner as in Example 1. Analyzed. The results are shown in FIG. 14 (S.C. in FIG. 14).

Comparative Example 2: Intravenous Administration Each mouse (3 mice) was placed in a mouse retainer while awake. 200 μL of an ICG-labeled antibody solution for intravenous administration (2.8 μg of ICG-labeled antibody) was administered into the tail vein of each mouse using an intravenous administration device (dose administered to mice: 2.8 μg/head).

Immediately after administration (day 0) and 1 day, 2 days, and 7 days after administration, the fluorescence of the axillary lymph nodes of each mouse was observed and photographed using the IVIS Imaging System. The results are shown in FIG. As a result, a red area (ie, presence of ICG-labeled antibody) was observed only in the abdomen (liver) immediately after administration, and was not observed in the axillary lymph nodes. Further, no red area (ie, presence of ICG-labeled antibody) could be observed after 7 days. This is thought to be due to the ICG-labeled antibody being metabolized in the liver.

In addition, after the final imaging on the 7th day after administration, the amount of residual ICG-labeled antibody (Total lymph node flux) (unit: photons/sec) in the mouse axillary lymph node tissue was measured in the same manner as in Example 1. was determined and analyzed. The results are shown in FIG. 14 (I.V. in FIG. 14).

From the results in Figure 14, the intradermal administration group (I.D. group; I.D. in Figure 14), the subcutaneous administration group (S.C. group: S.C. in Figure 14) and the intravenous administration group (I.V. group: I.V. in Figure 14) In comparison, it can be seen that the ICG-labeled antibody significantly migrates and remains in the axillary lymph nodes. Although the above effects are due to intradermal administration using the Mantoux method, it is thought that similar effects can be obtained by other intradermal administration methods. Furthermore, although the above effects were observed in mice, it is thought that similar effects would be observed when administered intradermally to humans. Further, although the above effect was confirmed using ICG-labeled Anti-KLH mouse IgG1 antibody, it is thought that similar effects would be observed with other ICG-labeled drugs.

[Experiment 2: Confirmation of the effect of ICG labeling]
In this experiment, each material was prepared as follows.

(Animals used)
Rats (strain: Crl: CD (SD), sex: female, age: 6 weeks, purchased from Jackson Laboratory Japan Co., Ltd. (formerly Charles River Japan Co., Ltd.)) were quarantined and acclimatized for 7 days. After a certain period of time, it was confirmed that all the animals were in good health and had no weight loss before being subjected to the test. The rats were kept in a breeding environment with 12 hours of light, a temperature of 20 to 26°C, and a humidity of 30 to 70%, and were allowed free access to food and water. The experiment was conducted in accordance with Terumo Corporation's guidelines for animal experiments.

(reagent)
Information regarding the reagents used in this experiment is shown in Table 1 below.

(Administration device)
For intradermal administration, a syringe (capacity: 50 μL) is attached to an injection needle (needle tube outer diameter: 0.30 mm (31 G), needle length: 20 mm, blade angle: 18°, needle tip shape: lancet). (intradermal administration device).

For subcutaneous administration, an injection needle (injection needle manufactured by Terumo Corporation, code number: NN-2719S) (outer diameter of needle tube: 0.40 mm (27G), needle length: 19 mm, needle tip shape: short bevel, blade surface) A device with a syringe (capacity: 100 μL) attached to a syringe (capacity: 100 μL) was prepared (subcutaneous administration device).

(Equipment/appliances used)
Information regarding the equipment used in this experiment is as follows:
・Balance: Manufactured by Sartorius, model number: CP224S
・Freeze-fracture tube: Manufactured by Yasui Kikai Co., Ltd., model number: ST-0320PCF
・Metal beads (metal cone): Manufactured by Yasui Kikai Co., Ltd., model number: MC-0316 (S)
・Homogenizer: Yasui Kikai Co., Ltd., model number: ST-0320PCF
・Centrifuge (for plate): Manufactured by Kubota Seisakusho Co., Ltd., model number: KUBOTA-5220
・Centrifuge (for tube): Manufactured by Kubota Seisakusho Co., Ltd., model number: KUBOTA-3780
・Plate shaker: Manufactured by Nisshin Rika Co., Ltd., model number: N-704
・Incubator: Manufactured by Sanyo Electric Biomedica Co., Ltd., model number: MCO-20AIC
・Plate reader: Manufactured by Molecular Devices, model number: VERSA max microplate reader
・Plate reader analysis software: Manufactured by Molecular Devices, model number: SoftMax Pro 7.0.3
・Medical cooler: Manufactured by PHC Holdings Co., Ltd. (formerly Panasonic Healthcare Co., Ltd.), model number: MPR-414FS-PJ
・Deep freezer: Manufactured by PHC Holdings Co., Ltd. (formerly Panasonic Healthcare Co., Ltd.), model number: MDF-C8V1-PJ.

(Preparation of test substance)
Anti-KLH (Anti-Keyhole Limpet Hemocyanin) mouse IgG1 antibody [Purified Mouse Monoclonal IgG, Clone#11711] (manufactured by R&D Systems, Cat. No. MAB002, Lot. No. IX2417011) (Molecular weight = 150 kDa) (IgG Isotype Control) An antibody solution for intradermal administration was prepared by diluting 15 μg with 10 μL of PBS (manufactured by ThermoFisher Scientific, Cat. No. 10010-023, Lot. No. 2081860, pH 7.4) (unlabeled antibody for intradermal administration). solution).

Anti-KLH (Anti-Keyhole Limpet Hemocyanin) mouse IgG1 antibody [Purified Mouse Monoclonal IgG, Clone#11711] (manufactured by R&D Systems, Cat. No. MAB002, Lot. No. IX2417011) (Molecular weight = 150 kDa) (IgG Isotype Control) 15 μg was diluted with 100 μL of PBS (manufactured by ThermoFisher Scientific, Cat. No. 10010-023, Lot. No. 2081860, pH 7.4) to prepare an antibody solution for subcutaneous administration (unlabeled antibody solution for subcutaneous administration). .

Reference example Each rat (nine rats) was treated with isoflurane (isoflurane inhalation anesthetic solution "Pfizer", manufactured by Mylan Pharmaceutical Co., Ltd., sold by Pfizer Inc.) using an anesthesia machine (manufactured by Natsume Manufacturing Co., Ltd., model number: KN-1071). (Induction anesthesia: 2.0-3.0%, maintenance anesthesia: 2.0-3.0%, carrier gas: air). Under anesthesia, 10 μL of an unlabeled antibody solution for intradermal administration (Anti-KLH mouse IgG1 15 μg in PBS 10 μL) was administered intradermally into the forelimbs of rats using an intradermal administration device (dose for rats: 15 μg/ head). After administration, the intradermal administration site of each rat was visually confirmed, and then the rats were allowed to wake up. As a result, in all mice, there was no leakage of the injection solution (drug solution) and a bulge was formed, so it was judged that the intradermal administration was successful.

Each rat (nine rats) was treated with isoflurane (isoflurane inhalation anesthetic solution "Pfizer", manufactured by Mylan Pharmaceutical Co., Ltd., sold by Pfizer Inc.) using an anesthesia machine (manufactured by Natsume Seisakusho Co., Ltd., model number: KN-1071). (induction anesthesia: 2.0-3.0%, maintenance anesthesia: 2.0-3.0%, carrier gas: air). Under anesthesia, 100 μL of an unlabeled antibody solution for subcutaneous administration (Anti-KLH mouse IgG1 15 μg in PBS 100 μL) was administered subcutaneously to the forearm of the rat using a subcutaneous administration device (dosage administered to rats: 15 μg/head). After administration, the animals were allowed to wake up.

Table 2 below summarizes the composition of each administration group.

After the time period shown in Table 2 above had elapsed after each administration, the rats were euthanized by exsanguination. For each rat, the axillary lymph node located in the armpit of the forelimb to which the drug was administered was sampled. Axillary lymph nodes of untreated rats (4 rats) were collected using the same method and used as blank samples. After measuring the weight of the sampled axillary lymph node, it was placed in a freeze-fracture tube and stored frozen at -80°C.

(Preparation of axillary lymph node homogenate)
Metal beads (metal cones) for cryo-fracture were placed in axillary lymph nodes that were cryopreserved at -80°C and immersed in liquid nitrogen. Freeze-fracture was performed using a homogenizer at 2,500 rpm and room temperature (25° C.) for 10 seconds. After crushing, RIPA Buffer was added so that the dilution ratio was 40 times, and the mixture was crushed again at 2,500 rpm and room temperature (25° C.) for 10 seconds.

The crushed sample was sonicated for 3 minutes using an ultrasonic crusher, and after collecting the metal cone, the homogenate was transferred to a 2 mL tube and centrifuged at 12,000 rpm, 4°C, and 5 minutes using a centrifuge (KUBOTA-3780). I did it.

After centrifugation, the fat layer was removed and the supernatant was collected into a 1.5 mL tube and stored frozen at -80°C until the day of ELISA measurement (lymph node homogenate).

(Antibody concentration measurement (ELISA))
The antibody concentration of the lymph node homogenate prepared above was measured using the following method.

1. Reagent preparation/adjustment <Antigen (KLH Stock)>
2 mL of distilled water was added to 20 mg/vial of Hemocyanin from Megathura crenulata [keyhole limpet] (hereinafter referred to as KLH) to adjust the concentration to 10 mg/mL, dispensed in 100 μL portions, and stored at -20°C or below. .

<Standard>
1 mL of distilled water was added to 0.5 mg/vial of IgG Isotype Control (Purified Mouse Monoclonal IgG, Clone11711) to adjust the concentration to 0.5 mg/mL, and the mixture was stored at 4°C.

<Coating Buffer>
Carbonate-Bicarbonate Buffer Capsule 100 mL of distilled water was added to 1 capsule to prepare 0.05 M Carbonate-Bicarbonate Buffer (pH 9.4) (at this time, only the contents of the capsule were used and the capsule was dissolved). ).

<Wash Buffer>
Pierce ^TM 20X PBS Tween ^TM 20 Buffer was diluted 20 times with distilled water and stored at room temperature.

<Blocking Buffer>
On the day of use, Blocking One was diluted 5 times with distilled water.

2. ELISA
A frozen 10 mg/mL KLH stock was thawed and centrifuged at 15,000 rpm at 4°C for 5 minutes using a centrifuge (KUBOTA-3780) to adjust the concentration to 20 μg/mL (KLH solution). 50 μL of the prepared KLH solution was added to each well of Nunc-Immuno ^™ Plate I, and centrifuged at 1000 rpm and room temperature (25° C.) for 5 minutes using a centrifuge (KUBOTA-5220). After centrifugation, each well was coated with a KLH solution by standing at 4° C. overnight (KLH coated plate).

The KLH solution in the KLH-coated plate was removed, and 200 μL of Wash Buffer was added to each well and then removed. This operation was repeated a total of 4 times to wash the plate. Thereafter, 200 μL of the prepared Blocking Buffer was added to each well, mixed gently with a plate shaker, and incubated at 37° C. for 1 hour.

During the blocking reaction, the lymph node homogenate was prepared with Can Get Signal (registered trademark) Solution 1 (manufactured by Toyobo Co., Ltd.) so as to be diluted 8000 times. In addition, Standard was prepared with Can Get Signal (registered trademark) Solution 1 (manufactured by Toyobo Co., Ltd.) to a concentration in the range of 0.006859 to 15 ng/mL, and these were used as standard samples.

After the Blocking reaction was completed, the Blocking buffer was removed, and 200 μL of Wash Buffer was added to each well and then removed. This operation was repeated a total of 4 times to wash the plate. After that, the blank (the standard blank was Can Get Signal (registered trademark) Solution 1, and the homogenate blank was a lymph node homogenate of an untreated rat), the prepared standard, and the prepared diluted sample were each set using "duplicate". 50 μL each was added to each well, mixed gently with a plate shaker, and incubated at 37° C. for 1 hour.

During the sample reaction, secondary antibody (Goat anti-Mouse IgG1 HRP Conjugated (MinX hu & rt)) was prepared at a concentration of 50 ng/mL using Can Get Signal (registered trademark) Solution 2 (manufactured by Toyobo Co., Ltd.). did.

After the Sample reaction was completed, the Sample was removed, and 200 μL of Wash Buffer was added to each well and then removed. This operation was repeated a total of 4 times to wash the plate. Thereafter, 50 μL of the prepared secondary antibody was added to each well, mixed gently with a plate shaker, and incubated at 37° C. for 1 hour.

After the secondary antibody reaction was completed, the secondary antibody was removed, and 200 μL of Wash Buffer was added to each well, and then removed. This operation was repeated a total of 5 times to wash the plate. Immediately after washing, TMB Peroxidase Substrate and TMB Peroxidase Substrate Solution B were mixed at a ratio of 1:1, and 50 μL of the prepared TMB solution was added to each well. After gently mixing with a plate shaker, the mixture was incubated at room temperature (25°C). ) for 10 to 20 minutes. After confirming the blue staining reaction, 50 μL of 1 mol/L sulfuric acid (2N) was added to each well at an appropriate timing, and the mixture was gently mixed using a plate shaker.

Immediately after the reaction was stopped with sulfuric acid, measurements were taken at wavelengths of 450 nm and 540 nm using a plate reader (VERSA max microplate reader), and the value obtained by subtracting the "OD value at 540 nm" from the "OD value at 450 nm" was calculated as the "measurement after correction." "value" and further corrected with Blank (measured value after re-correction). Standard Curve fit was “4-Parameter Logistic”.

From the measured results (measured values after re-correction), the usable range of the Standard Curve under each condition was determined, and the lower and upper limits were determined. Note that the concentration was calculated using SoftMax Pro 7.0.3.

The "Anti-KLH mouse IgG1 antibody content per 1 mg of lymph node" was calculated using the following formula from the concentration calculated from the Standard Curve described above, the lymph node weight, and the added amount of Total. volume (RIPA Buffer + lymph node volume). .

Figure 15 shows the change over time in the Anti-KLH mouse IgG1 antibody content per 1 mg of lymph node (ng/1 mg Lymph Node). The results in FIG. 15 show that for antibodies not labeled with ICG, the antibody amount decreases significantly within 7 hours after administration for both intradermal and subcutaneous administration, and becomes almost undetectable after 24 hours. In contrast, as shown in Example 1, antibodies labeled (bound) with ICG can significantly prolong retention in lymph nodes.

Although the present invention has been described above based on the embodiments and examples, the present invention is not limited to the content described in this specification, and may be modified as appropriate based on the description of the claims. It is possible.

10 Administration device 100 Needle assembly 110 Injection needle 111 Needle tube 111a Inner lumen of needle tube 112 Needle tip 112a Tip opening 113 Blade surface 113a First blade surface 113b Second blade surface 113c Third blade surface 114 Needle body 115 Proximal end 116 Boundary 120 Needle hub 121 First member 122 Adjustment part 122a Space 123 Guide part 124 Flange part 127 Second member 130 Cap member 200 Syringe 210 First cylinder part 220 Second cylinder part 240 Liquid chamber D1 Outer diameter Hg of needle tube Adjustment part Dimension difference L1 in the protruding direction of the guide portion and the protruding length of the needle tube L2 Total length of the blade surface L21 Length of the first blade surface L22 Length of the second blade surface L23 Length of the third blade surface L3 Needle barrel length O1 Central axis of the needle T1 Distance between the adjustment part and the guide part T2 Distance between the guide part and the flange part s1 Epidermal layer s2 Dermal layer s3 Subcutaneous tissue layer s4 Upper skin layer t1 Thickness of the needle Φ1 Inner diameter of the needle α1 Ridge angle θ1 1st blade angle θ2 2nd blade angle θ3 3rd blade angle

Claims (4)

A drug for improving retention of a drug in superficial lymph nodes,
The drug includes a drug in which an indocyanine green derivative is bound to a therapeutic drug,
The medicament is administered intradermally upstream of the superficial lymph node. The medicament according to claim 1, wherein the therapeutic agent is selected from antibodies, peptide agents, and protein preparations. The medicament according to claim 1, wherein the medicament is intradermally administered via an injection needle having a needle tube with a protrusion length of 0.9 mm or more and 1.4 mm or less. The medicament according to claim 1, for the treatment of breast cancer, skin cancer or autoimmune diseases.