CN117797279A - Fluorescence-magnetic resonance bimodal contrast agent and preparation method thereof - Google Patents
Fluorescence-magnetic resonance bimodal contrast agent and preparation method thereof Download PDFInfo
- Publication number
- CN117797279A CN117797279A CN202311470414.6A CN202311470414A CN117797279A CN 117797279 A CN117797279 A CN 117797279A CN 202311470414 A CN202311470414 A CN 202311470414A CN 117797279 A CN117797279 A CN 117797279A
- Authority
- CN
- China
- Prior art keywords
- compound
- freeze
- injection
- formula
- contrast agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 239000002872 contrast media Substances 0.000 title claims abstract description 24
- 230000002902 bimodal effect Effects 0.000 title claims abstract description 22
- 239000003814 drug Substances 0.000 claims abstract description 94
- 150000001875 compounds Chemical class 0.000 claims abstract description 73
- 238000002347 injection Methods 0.000 claims abstract description 66
- 239000007924 injection Substances 0.000 claims abstract description 66
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 58
- 239000000843 powder Substances 0.000 claims abstract description 54
- 238000004108 freeze drying Methods 0.000 claims abstract description 52
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 29
- 239000003002 pH adjusting agent Substances 0.000 claims abstract description 5
- 239000007788 liquid Substances 0.000 claims description 80
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 75
- 239000000243 solution Substances 0.000 claims description 38
- 239000008215 water for injection Substances 0.000 claims description 36
- 229930006000 Sucrose Natural products 0.000 claims description 35
- 239000005720 sucrose Substances 0.000 claims description 35
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 33
- 238000003825 pressing Methods 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 25
- 229930182555 Penicillin Natural products 0.000 claims description 13
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 13
- 238000011049 filling Methods 0.000 claims description 13
- 229940049954 penicillin Drugs 0.000 claims description 13
- 230000001954 sterilising effect Effects 0.000 claims description 13
- -1 saccharide compound Chemical class 0.000 claims description 12
- 239000008176 lyophilized powder Substances 0.000 claims description 11
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 9
- 229930195725 Mannitol Natural products 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 239000000594 mannitol Substances 0.000 claims description 9
- 235000010355 mannitol Nutrition 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 8
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 8
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 8
- 239000008101 lactose Substances 0.000 claims description 8
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 3
- 229920002307 Dextran Polymers 0.000 claims description 3
- 239000004386 Erythritol Substances 0.000 claims description 3
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 claims description 3
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 3
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims description 3
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 3
- 235000019414 erythritol Nutrition 0.000 claims description 3
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 claims description 3
- 229940009714 erythritol Drugs 0.000 claims description 3
- 229960001031 glucose Drugs 0.000 claims description 3
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 3
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- 235000010356 sorbitol Nutrition 0.000 claims description 3
- 238000005303 weighing Methods 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims description 2
- 125000000185 sucrose group Chemical group 0.000 claims description 2
- 239000008186 active pharmaceutical agent Substances 0.000 abstract description 19
- 229940079593 drug Drugs 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 11
- 230000007774 longterm Effects 0.000 abstract description 7
- 238000003384 imaging method Methods 0.000 abstract description 6
- 238000003745 diagnosis Methods 0.000 abstract description 3
- 238000011160 research Methods 0.000 abstract description 3
- 230000007547 defect Effects 0.000 abstract description 2
- 238000011161 development Methods 0.000 abstract description 2
- 238000002601 radiography Methods 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 description 36
- 238000010438 heat treatment Methods 0.000 description 28
- 239000000203 mixture Substances 0.000 description 17
- 239000007864 aqueous solution Substances 0.000 description 14
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 13
- 229910052782 aluminium Inorganic materials 0.000 description 13
- 238000007710 freezing Methods 0.000 description 13
- 230000008014 freezing Effects 0.000 description 13
- 238000004806 packaging method and process Methods 0.000 description 13
- 238000007789 sealing Methods 0.000 description 13
- 229920005549 butyl rubber Polymers 0.000 description 11
- 238000001514 detection method Methods 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 230000001502 supplementing effect Effects 0.000 description 11
- 206010028980 Neoplasm Diseases 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 5
- 230000001133 acceleration Effects 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000002595 magnetic resonance imaging Methods 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- 239000002616 MRI contrast agent Substances 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000012632 fluorescent imaging Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 238000002271 resection Methods 0.000 description 2
- 239000011343 solid material Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000011281 clinical therapy Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 238000012792 lyophilization process Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000010882 preoperative diagnosis Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0032—Methine dyes, e.g. cyanine dyes
- A61K49/0034—Indocyanine green, i.e. ICG, cardiogreen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0052—Small organic molecules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- A61K49/0089—Particulate, powder, adsorbate, bead, sphere
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
- A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical & Material Sciences (AREA)
- Radiology & Medical Imaging (AREA)
- Nanotechnology (AREA)
- Medicinal Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to the field of medical diagnosis imaging, and particularly discloses a fluorescence-magnetic resonance bimodal contrast agent and a preparation method thereof, wherein the bimodal contrast agent is a freeze-dried powder injection and comprises a compound of the following formula (I):
Description
Technical Field
The invention relates to the field of medical diagnosis imaging, in particular to a freeze-dried powder injection fluorescent-magnetic resonance bimodal contrast agent and a preparation method thereof.
Background
Cancer is one of the major diseases that currently threatens human health. Surgery is still the preferred treatment, and primary tumor resection is the common surgical procedure. However, a large number of clinical pathologies confirm that a significant portion of early cancers fail to find distinct focal areas. And tumors tend to grow infiltratively, resulting in blurring of the boundaries with normal tissue and thus presenting great difficulties in surgical resection. Incomplete excision of tumors becomes a major cause of poor effect and high recurrence rate of the existing surgical treatment scheme. Thus, preoperative accurate localization of tumors is the most urgent need for current clinical therapies.
Magnetic Resonance Imaging (MRI) uses nuclear magnetic resonance phenomenon generated by exciting hydrogen atomic nuclei (protons) in human tissue with radio frequency pulse in magnetic field to generate magnetic resonance signals, and processing by electronic computer to reconstruct image of certain layer of human body. In clinical application, MRI has the advantages of non-invasive diagnosis, strong soft tissue imaging capability, no ionizing radiation, no detection angle limitation and the like, and is widely used in hospitals and research institutions all over the world; however, the low sensitivity and the short circulation time of the MRI contrast agent limit the imaging effect on tumors, and the imaging cannot be performed in real time in operation, so that the clinical practical application of the MRI contrast agent is greatly limited. The applicant successfully develops a brand new fluorescent-magnetic resonance bimodal contrast agent compound in 2021 (patent publication number: WO2022242437A 1), has the advantages of good magnetic resonance T1 weighted imaging contrast capability and in-vivo fluorescent imaging capability, high relaxation rate, good thermal stability, low toxic and side effects, good correspondence between fluorescence and magnetic resonance signals and the like, can be effectively applied to magnetic resonance imaging and fluorescent imaging of living cells and living bodies, can obviously enhance the magnetic resonance signals of livers and kidneys after 6 hours of administration, obviously improves the boundary resolution of organs, has higher correspondence between the magnetic resonance signal intensity and the fluorescence intensity, and has clinically required preoperative diagnosis and intra-operative navigation effects.
The contrast agent compound is generally prepared into injection solution or powder injection pharmaceutical preparations, and enters into tumor tissues through tumor vascular endothelial gaps in an intravenous injection mode so as to enhance the tumor image detection effect. The present inventors have found that when a contrast agent water injection is prepared using a contrast agent drug substance disclosed in patent WO2022242437A1 as an API component: although the contrast agent bulk drug disclosed in patent WO2022242437A1 has good water solubility, after being prepared into an injection, the long-term stability is not ideal, and especially the fluorescent groups in the API component are unstable in an aqueous solution and are easy to aggregate to cause fluorescence quenching, so that the fluorescence tracing effect is weakened or even fails in use. After the API component is directly dissolved in water for injection and then freeze-dried to prepare the freeze-dried powder injection, the content of unknown impurities (called as the impurity RRT1.03 in the application) at the position of about 1.03 of the relative retention time RRT after freeze-drying is found to be obviously higher than the content of the impurity RRT1.03 in the API component by the determination of an HPLC method, and the content of the impurity RRT1.03 has an ascending trend along with the extension of the storage time, so that the clinical medication risk of the freeze-dried powder injection is increased.
Disclosure of Invention
The impurity level in the medicine directly reflects the stability of the product quality, and lower impurity level means that the product has better stability and higher safety, and is more beneficial to the medication safety of patients.
The technical scheme of the invention is as follows: a fluorescence-magnetic resonance bimodal contrast agent which is a freeze-dried powder injection and comprises a compound of the following formula (I):
and a lyophilization excipient and optionally a pH adjuster.
The freeze-dried powder injection is dissolved into solution with the concentration of the compound of the formula (I) of 10-40 mg/ml and the pH value of 5.0-7.0 by using water for injection.
In the technical scheme, the freeze-dried powder injection comprises 30-180 parts by weight of freeze-dried excipient per 40 parts by weight of the compound of the formula (I).
In the technical scheme, the freeze-drying excipient is a sugar compound and/or a sugar alcohol compound; preferably, the saccharide compound is selected from one or more of dextran, anhydrous glucose, lactose, sucrose, trehalose and maltose, more preferably lactose, sucrose and trehalose, and even more preferably sucrose; the sugar alcohol compound is one or more selected from sorbitol, mannitol and erythritol.
The present inventors have studied the conditions of a freeze-drying process and the selection of auxiliary materials including a pH regulator, a freeze-drying excipient, etc. when preparing a freeze-dried powder injection using a compound of formula (I) as an API component, through a great deal of experimental exploration, it has been found that when a specific saccharide compound and/or a sugar alcohol compound is introduced as a freeze-drying excipient, the increase of impurity RRT1.03 in the process of obtaining the freeze-dried powder by freeze-drying can be significantly inhibited, and the quality stability and the clinical medication safety of the freeze-dried powder injection using the compound of formula (I) as an API component are effectively improved. These conventional freeze-dried excipients function in the art to impart a specific shape to the freeze-dried powder injection, but their technical effects exhibited in the present invention are completely independent of their conventional functions.
In the above technical solution, the pH adjustor is selected from NaOH, KOH, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or a combination thereof.
In the technical scheme, the solid content of the solution of the freeze-dried powder injection before freeze-drying is 2-12% (w/v), preferably 4-8% (w/v).
The term "solids content" means that the solid material (e.g. the active compound according to the invention and all excipients used, weight/g) is added to a solvent (e.g. water for injection) and dissolved to give a solution, the weight of the solid material divided by the percentage of the final solution volume (weight/volume percentage, e.g. g/100 ml).
The water content of the freeze-dried powder injection prepared by adopting the technical scheme is not more than 3 percent. The water content refers to the water content when the freeze-dried powder is obtained through a freeze-drying procedure, and the water content in the storage period of the freeze-dried powder injection is not more than 5%.
In the present invention, the symbol% may have a meaning easily understood by those skilled in the art according to the context in which it is used. For example, when referring to solids content, the symbol represents weight/volume percent (w/v, e.g., g/100 ml); also for example, when referring to "moisture content" in a lyophilized powder for injection, for example, the moisture content is below 3%, where the symbol% represents the weight/weight percent (w/w, g/100 g). In general,% represents weight/volume percent when solids are dispersed in a liquid; when the solid is dispersed in the solid or the liquid is dispersed in the solid (e.g., the water content of a lyophilized powder for injection), the% means weight/weight percentage. In other cases, the symbol% represents weight/weight percent unless otherwise indicated.
In the above technical scheme, sucrose is selected as the freeze-drying excipient, and the weight ratio of the compound of formula (I) to the freeze-drying excipient is 1 (0.75-4), preferably 1 (1-4), and more preferably 1:4.
The inventor finds through a large number of experiments that when preparing the freeze-dried powder injection taking the compound of the formula (I) as an API component, sucrose is introduced as a freeze-drying excipient, the dosage proportion of the compound of the formula (I) and the sucrose is regulated, the increase of the impurity RRT1.03 in the process of obtaining the freeze-dried powder through freeze drying can be more effectively inhibited, the content of the impurity RRT1.03 in the prepared freeze-dried powder injection is not more than 1 percent, the content of the impurity RRT1.03 in the bulk drug of the compound of the formula (I) is obviously lower than that of the impurity RRT1.03 in the bulk drug of the compound of the formula (I), the quality stability of the drug and the clinical medication safety of the freeze-dried powder injection taking the compound of the formula (I) as the API component are ensured, and the prepared freeze-dried powder injection is more fluffy.
The inventor further discovers through a large number of experiments that when sucrose is selected as a freeze-drying excipient, the pH value of the liquid medicine before freeze-drying is regulated to 5.5-6.7, the increase of the impurity RRT1.03 in the process of obtaining the freeze-dried powder through freeze-drying can be further inhibited, the content of the impurity RRT1.03 in the prepared freeze-dried powder injection can be reduced to 0.32%, the content of the impurity RRT1.03 in the raw material medicine of the compound in the formula (I) is far lower than that of the impurity RRT1.03, and after the compound is stored for 6 months under the conditions of 25 ℃ +/-2 ℃ and 60% +/-5% RH, the content of the impurity RRT1.03 is basically stabilized at a smaller value, and the clinical medication safety of the freeze-dried powder injection taking the compound in the formula (I) as an API component is greatly improved.
The freeze-dried powder injection prepared by adopting the technical scheme is dissolved into solution with the concentration of the compound of the formula (I) of 10mg/ml by using water for injection, and the pH value of the solution is measured to be 5.3-6.7 according to the method of the four-part rule 0631 of the year 2020 edition of Chinese pharmacopoeia.
In the technical scheme, the water content of the freeze-dried powder injection is not more than 2%. The water content herein also refers to the water content when the lyophilized powder is obtained by the lyophilization process.
Another object of the present invention is to provide a method for preparing the fluorescent-magnetic resonance bimodal contrast agent, comprising the following steps:
(a) Weighing excipient with prescription amount, placing in a preparation tank, adding appropriate amount of water for injection, stirring to dissolve;
(b) Adding a prescribed amount of a compound of formula (I) into a preparation tank, and stirring to dissolve the compound;
(c) Adding water for injection into a preparation tank until the weight of the water for injection reaches the prescription weight, uniformly stirring, measuring the pH value of the solution, and adjusting the pH value to 5-7 by using a pH regulator if necessary;
(d) Sterilizing the liquid medicine, filling into penicillin bottles according to the prescription amount, freeze-drying to remove water, and pressing to obtain the final product.
Preferably, the mass part ratio of the compound of the formula (I) to the excipient is 1 (0.75-4.5). The freeze-drying excipient is sucrose, and the weight ratio of the compound of the formula (I) to the freeze-drying excipient in the freeze-drying powder injection is 1 (0.75-4), preferably 1 (1-4), and more preferably 1:4.
Preferably, the freeze-drying excipient is a sugar compound and/or a sugar alcohol compound; the saccharide compound is selected from one or more of dextran, anhydrous glucose, lactose, sucrose, trehalose and maltose, preferably lactose, sucrose and trehalose, more preferably sucrose; the sugar alcohol compound is one or more selected from sorbitol, mannitol and erythritol.
Preferably, the pH adjustor is selected from NaOH, KOH, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or a combination thereof; further preferably, the pH adjustor is an aqueous NaOH solution, and the concentration of the aqueous NaOH solution is 0.002 to 0.05mol/L, preferably 0.005 to 0.02mol/L.
When NaOH aqueous solution is selected for adjusting the pH value of the liquid medicine before freeze drying, the condition that the pH value exceeds the range occurs, and hydrochloric acid solution is preferably used for callback.
Preferably, the fluorescence-magnetic resonance bimodal contrast agent is freeze-dried powder injection.
Preferably, the solid content of the solution of the freeze-dried powder injection before freeze-drying is 2-12% (w/v), preferably 4-8% (w/v).
Preferably, the water content of the freeze-dried powder injection is not more than 3%, and more preferably, the water content of the freeze-dried powder injection is not more than 2%.
Preferably, the freeze-dried powder injection is dissolved into solution with the concentration of the compound of the formula (I) of 10mg/ml by using water for injection, and the pH value of the solution is measured to be 5.3-6.7 according to the method of the fourth edition rule 0631 of the Chinese pharmacopoeia 2020.
Preferably, in the step (d), the step of freeze drying to remove the water comprises pre-freezing the sterilized and filled liquid medicine below-40 ℃, and maintaining for 0.5-4 hours when the liquid medicine temperature is below-40 ℃; heating to above-20 ℃ within 1-4 hours, maintaining for 5-40 hours, wherein the vacuum degree is less than 0.5mbar; heating to more than 10 ℃ within 1-6 hours, maintaining for 1-20 hours, heating to more than 40 ℃ within 0.5-5 hours, maintaining for 2-10 hours, pressing, locking an aluminum cover, sealing and packaging.
Preferably, in the step (d), the step of freeze drying to remove the water comprises the steps of pre-freezing the sterilized and filled liquid medicine at the temperature of-45 ℃ and maintaining for 1 to 4 hours when the temperature of the liquid medicine reaches the temperature of-45 ℃; heating to-15 ℃ within 1-4 hours, maintaining for 10-40 hours, and keeping the vacuum degree less than 0.5mbar; heating to 20 ℃ within 1-6 hours, maintaining for 1-20 hours, heating to more than 40 ℃ within 1-5 hours, maintaining for 5-10 hours, pressing, locking an aluminum cover, sealing and packaging to obtain the product.
The invention has the beneficial effects that:
(1) The invention prepares the water injection taking the compound of the formula (I) as the API component into the freeze-dried powder injection, avoids the technical defect that the water injection taking the compound of the formula (I) as the API component has poor long-term stability so as to weaken or even lose the fluorescence tracing effect, and ensures the fluorescence-magnetic resonance bimodal radiography effect of the API component.
(2) According to the invention, a specific freeze-drying excipient is selected, the dosage ratio of the freeze-drying excipient to the API component and the pH value of the system are regulated, so that the risk of increasing the content of the impurity RRT1.03 brought by the freeze-drying process of obtaining the freeze-dried powder is avoided, the lower content of the impurity RRT1.03 is provided for the freeze-dried powder injection, the prepared freeze-dried powder has the advantages of full and uniform appearance, low moisture content and high medicine stability, the prepared freeze-dried powder is placed for 6 months under the RH condition of 25+/-2 ℃/60+/-5% or placed for 30 days under the RH condition of 40 ℃/75%, and the content of the impurity RRT1.03 in the freeze-dried powder injection is basically maintained at the same level and only has slight fluctuation.
(3) The freeze-dried powder injection provided by the invention can effectively solve the problems of obvious increase of impurity RRT1.03 in the process of freeze-drying and poor stability of the freeze-dried product, and the freeze-dried powder injection has short re-dissolution time and extremely small insoluble particle amount after re-dissolution, thus greatly improving the clinical medication safety and further promoting the development of the clinical application research of the follow-up compound medicament of formula (I).
Drawings
Fig. 1 is an HPLC profile of the impurity RRT1.03 content in the lyophilized powder for injection prepared in example 13.
Fig. 2 is an HPLC profile of the impurity RRT1.03 content of the lyophilized powder for injection prepared in example 13 after 12 months.
Fig. 3 is an HPLC profile of the impurity RRT1.03 content in the lyophilized powder for injection prepared in example 18.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It should be apparent to those skilled in the art that the examples are provided only to aid in understanding the present invention and should not be construed as limiting the invention in any way.
In the examples below, the starting materials, reagents and the like are commercially available products and are commercially available, except that the compound of formula (I) used is self-made by the applicant of the present invention according to the synthesis method described in WO2022242437A 1. The specific techniques or conditions not identified in the examples are all carried out in the manner described by conventional means in the art or in accordance with the product specifications.
Example 1
Prescription composition (1000 pieces): 40g of a compound of formula (I), 40g of mannitol;
the preparation method comprises the following steps: a) Dissolving mannitol in a proper amount of water for injection, adding a compound shown in formula (I) after stirring and dissolving, continuously stirring to dissolve, adjusting the pH value of the liquid medicine to 5.50 by using 0.01mol/L NaOH aqueous solution, and then supplementing the rest amount of water for injection until the total volume of the liquid medicine is 1L; filtering the liquid medicine, sterilizing, filling the liquid medicine into a penicillin bottle according to the dosage of 1 ml/branch, half-pressing a butyl rubber plug, and sending the liquid medicine into a freeze dryer for freeze drying: pre-freezing the filled liquid medicine at-50deg.C, and maintaining for 2 hr when the liquid medicine temperature reaches-50deg.C; raising the temperature to-10 ℃ in 2.5 hours and maintaining for 35 hours, wherein the vacuum degree is less than 0.5mbar; then heating to 20 ℃ for 3 hours within 4 hours, heating to 40 ℃ for 5 hours within 2 hours, pressing, locking an aluminum cover, sealing and packaging.
Example 2
Prescription composition (1000 pieces): 40g of a compound of formula (I), 80g of mannitol;
the preparation method comprises the following steps: a) Dissolving mannitol in a proper amount of water for injection, adding a compound shown in formula (I) after stirring and dissolving, continuously stirring to dissolve, adjusting the pH value of the liquid medicine to 5.50 by using 0.01mol/L NaOH aqueous solution, and then supplementing the rest amount of water for injection until the total volume of the liquid medicine is 1L; filtering the liquid medicine, sterilizing, filling the liquid medicine into a penicillin bottle according to the dosage of 1 ml/branch, half-pressing a butyl rubber plug, and sending the liquid medicine into a freeze dryer for freeze drying: pre-freezing the filled liquid medicine at-50deg.C, and maintaining for 2 hr when the liquid medicine temperature reaches-50deg.C; raising the temperature to-10 ℃ in 2.5 hours and maintaining for 35 hours, wherein the vacuum degree is less than 0.5mbar; then heating to 20 ℃ for 3 hours within 4 hours, heating to 40 ℃ for 6 hours within 2 hours, pressing, locking an aluminum cover, sealing and packaging.
Example 3
Prescription composition (1000 pieces): 40g of a compound of formula (I), 80g of trehalose;
the preparation method comprises the following steps: a) Dissolving trehalose in a proper amount of water for injection, adding a compound shown in formula (I) after stirring and dissolving, continuously stirring to dissolve, adjusting the pH value of the liquid medicine to 5.50 by using 0.01mol/L NaOH aqueous solution, and then supplementing the rest amount of water for injection to 1L of total volume of the liquid medicine; filtering the liquid medicine, sterilizing, filling the liquid medicine into a penicillin bottle according to the dosage of 1 ml/branch, half-pressing a butyl rubber plug, and sending the liquid medicine into a freeze dryer for freeze drying: pre-freezing the filled liquid medicine at-40deg.C, and maintaining for 3 hr when the liquid medicine temperature reaches-40deg.C; raising the temperature to-15 ℃ in 2 hours and maintaining for 40 hours, wherein the vacuum degree is less than 0.5mbar; then heating to 20 ℃ for 3 hours within 4 hours, heating to 40 ℃ for 6 hours within 2 hours, pressing, locking an aluminum cover, sealing and packaging.
Example 4
Prescription composition (1000 pieces): 40g of a compound of formula (I), 40g of lactose;
the preparation method comprises the following steps: a) Dissolving lactose in a proper amount of water for injection, adding a compound shown in a formula (I) after stirring and dissolving, continuously stirring to dissolve, adjusting the pH value of the liquid medicine to 5.50 by using 0.005mol/L NaOH aqueous solution, and then supplementing the rest to 4L by using the water for injection; filtering the liquid medicine, sterilizing, filling the liquid medicine into a penicillin bottle according to the dosage of 4 ml/branch, half-pressing a butyl rubber plug, and sending the liquid medicine into a freeze dryer for freeze drying: pre-freezing the filled liquid medicine at-45 ℃, and maintaining for 3 hours when the temperature of the liquid medicine reaches-45 ℃; raising the temperature to-15 ℃ in 2 hours and maintaining for 30 hours, wherein the vacuum degree is less than 0.3mbar; then heating to 20 ℃ in 4 hours and maintaining for 4 hours, heating to 40 ℃ in 2 hours and maintaining for 8 hours, pressing, locking an aluminum cover, sealing and packaging to obtain the product.
Example 5
Prescription composition (1000 pieces): 40g of a compound of formula (I), 40g of sucrose;
the preparation method comprises the following steps: a) Dissolving sucrose in a proper amount of water for injection, adding a compound shown in formula (I) after stirring and dissolving, continuously stirring to dissolve, adjusting the pH value of the liquid medicine to 5.50 by using 0.005mol/L NaOH aqueous solution, and then supplementing the rest to 4L by using the water for injection; filtering the liquid medicine, sterilizing, filling the liquid medicine into a penicillin bottle according to the dosage of 4 ml/branch, half-pressing a butyl rubber plug, and sending the liquid medicine into a freeze dryer for freeze drying: pre-freezing the filled liquid medicine at-45 ℃, and maintaining for 2.5 hours when the temperature of the liquid medicine reaches-45 ℃; raising the temperature to-15 ℃ in 2 hours and maintaining for 30 hours, wherein the vacuum degree is less than 0.5mbar; then heating to 20 ℃ for 4 hours and maintaining for 4 hours, heating to 40 ℃ for 8 hours and maintaining for 2 hours, pressing the plug, locking the aluminum cover for sealing, and packaging.
Example 6
Prescription composition (1000 pieces): 40g of a compound of formula (I), 80g of sucrose;
the preparation method is the same as in example 5.
Example 7
Prescription composition (1000 pieces): 40g of a compound of formula (I), 120g of sucrose;
the preparation method is the same as in example 5.
Example 8
Prescription composition (1000 pieces): 40g of a compound of formula (I), 160g of sucrose;
the preparation method is the same as in example 5.
Example 9
Prescription composition (1000 pieces): 40g of a compound of formula (I), 180g of sucrose;
the preparation method is the same as in example 5.
Examples 10 to 16
The prescription composition (1000 pieces) is as follows: 40g of a compound of formula (I), 160g of sucrose;
the preparation method was the same as in example 8, except that the pH of the solution before lyophilization in example 10 was adjusted to 5.00, the pH of the solution in example 11 was adjusted to 5.3, the pH of the solution in example 12 was adjusted to 6.00, the pH of the solution in example 13 was adjusted to 6.50, the pH of the solution in example 14 was adjusted to 7.00, the pH of the solution in example 15 was adjusted to 6.70, and the pH of the solution in example 16 was adjusted to 7.20.
Example 17
Prescription composition (1000 pieces): 40g of a compound of formula (I), 120g of sucrose and 40g of mannitol;
the preparation method comprises the following steps: a) Dissolving sucrose and mannitol in a proper amount of water for injection, stirring and dissolving, adding a compound shown in formula (I), continuously stirring and dissolving, regulating the pH value of the liquid medicine to 6.50 by using 0.05mol/L NaOH aqueous solution, and then supplementing the rest amount of water for injection until the total volume of the liquid medicine is 4L; filtering the liquid medicine, sterilizing, filling the liquid medicine into a penicillin bottle according to the dosage of 4 ml/branch, half-pressing a butyl rubber plug, and sending the liquid medicine into a freeze dryer for freeze drying: pre-freezing the filled liquid medicine at-45 ℃, and maintaining for 2.5 hours when the temperature of the liquid medicine reaches-45 ℃; raising the temperature to-15 ℃ in 2 hours and maintaining for 30 hours, wherein the vacuum degree is less than 0.5mbar; then heating to 20 ℃ in 4 hours and maintaining for 4 hours, heating to 40 ℃ in 2 hours and maintaining for 8 hours, pressing, locking an aluminum cover, sealing and packaging to obtain the product.
Example 18
Prescription composition (1000 pieces): 40g of a compound of formula (I), naOH solution and water for injection;
the preparation method comprises the following steps: a) Dissolving a compound shown in a formula (I) in a proper amount of water for injection, stirring to dissolve the compound, regulating the pH value of the liquid medicine to 6.50 by using 0.05mol/L NaOH aqueous solution, and then supplementing the rest amount to 4L by using the water for injection; filtering the liquid medicine, sterilizing, filling the liquid medicine into a penicillin bottle according to the dosage of 4 ml/branch, half-pressing a butyl rubber plug, and sending the liquid medicine into a freeze dryer for freeze drying: pre-freezing the filled liquid medicine at-45 ℃, and maintaining for 2.5 hours when the temperature of the liquid medicine reaches-45 ℃; raising the temperature to-15 ℃ in 2 hours and maintaining for 30 hours, wherein the vacuum degree is less than 0.5mbar; then heating to 20 ℃ for 4 hours and maintaining for 4 hours, heating to 40 ℃ for 8 hours and maintaining for 2 hours, pressing the plug, locking the aluminum cover for sealing, and packaging.
Example 19
Prescription composition (1000 pieces): 40g of a compound of formula (I) and 160g of sucrose;
the preparation method comprises the following steps: a) Dissolving sucrose in a proper amount of water for injection, adding a compound shown in formula (I) after stirring and dissolving, continuously stirring to dissolve, adjusting the pH value of the liquid medicine to 6.50 by using 0.05mol/L NaOH aqueous solution, and then supplementing the rest to 4L by using the water for injection; filtering the liquid medicine, sterilizing, filling the liquid medicine into a penicillin bottle according to the dosage of 4 ml/branch, half-pressing a butyl rubber plug, and sending the liquid medicine into a freeze dryer for freeze drying: pre-freezing the filled liquid medicine at-45 ℃, and maintaining for 2.5 hours when the temperature of the liquid medicine reaches-45 ℃; raising the temperature to-15 ℃ in 2 hours and maintaining for 30 hours, wherein the vacuum degree is less than 0.5mbar; then heating to 20 ℃ for 3 hours within 4.5 hours, heating to 40 ℃ for 4 hours within 2 hours, pressing, locking an aluminum cover, sealing and packaging.
Example 20
Prescription composition (1000 pieces): 40g of a compound of formula (I) and 30g of sucrose;
the preparation method comprises the following steps: a) Dissolving sucrose in a proper amount of water for injection, adding a compound shown in formula (I) after stirring and dissolving, regulating the pH value of the liquid medicine to 6.50 by using 0.05mol/L NaOH aqueous solution, and then supplementing the rest to 4L by using the water for injection; filtering the liquid medicine, sterilizing, filling the liquid medicine into a penicillin bottle according to the dosage of 4 ml/branch, half-pressing a butyl rubber plug, and sending the liquid medicine into a freeze dryer for freeze drying: pre-freezing the filled liquid medicine at-45 ℃, and maintaining for 2.5 hours when the temperature of the liquid medicine reaches-45 ℃; raising the temperature to-15 ℃ in 2 hours and maintaining for 30 hours, wherein the vacuum degree is less than 0.5mbar; then heating to 20 ℃ for 4 hours and maintaining for 4 hours, heating to 40 ℃ for 8 hours and maintaining for 2 hours, pressing the plug, locking the aluminum cover for sealing, and packaging.
Example 21
Prescription composition (1000 pieces): 40g of a compound of formula (I) and 25g of sucrose;
the preparation method comprises the following steps: a) Dissolving sucrose in a proper amount of water for injection, adding a compound shown in formula (I) after stirring and dissolving, continuously stirring to dissolve, adjusting the pH value of the liquid medicine to 6.50 by using 0.05mol/L NaOH aqueous solution, and then supplementing the rest to 4L by using the water for injection; filtering the liquid medicine, sterilizing, filling the liquid medicine into a penicillin bottle according to the dosage of 4 ml/branch, half-pressing a butyl rubber plug, and sending the liquid medicine into a freeze dryer for freeze drying: pre-freezing the filled liquid medicine at-45 ℃, and maintaining for 2.5 hours when the temperature of the liquid medicine reaches-45 ℃; raising the temperature to-15 ℃ in 2 hours and maintaining for 30 hours, wherein the vacuum degree is less than 0.5mbar; then heating to 20 ℃ for 4 hours and maintaining for 4 hours, heating to 40 ℃ for 8 hours and maintaining for 2 hours, pressing the plug, locking the aluminum cover for sealing, and packaging.
Example 22
Prescription composition (1000 pieces): 40g of a compound of formula (I) and 20g of sucrose;
the preparation method comprises the following steps: a) Dissolving sucrose in a proper amount of water for injection, adding a compound shown in formula (I) after stirring and dissolving, continuously stirring to dissolve, adjusting the pH value of the liquid medicine to 6.50 by using 0.05mol/L NaOH aqueous solution, and then supplementing the rest to 4L by using the water for injection; filtering the liquid medicine, sterilizing, filling the liquid medicine into a penicillin bottle according to the dosage of 4 ml/branch, half-pressing a butyl rubber plug, and sending the liquid medicine into a freeze dryer for freeze drying: pre-freezing the filled liquid medicine at-45 ℃, and maintaining for 2.5 hours when the temperature of the liquid medicine reaches-45 ℃; raising the temperature to-15 ℃ in 2 hours and maintaining for 30 hours, wherein the vacuum degree is less than 0.5mbar; then heating to 20 ℃ for 4 hours and maintaining for 4 hours, heating to 40 ℃ for 8 hours and maintaining for 2 hours, pressing the plug, locking the aluminum cover for sealing, and packaging.
Examples 23 to 28
The prescription composition (1000 pieces) is as follows: 40g of a compound of formula (I), 160g of sucrose;
the preparation method was the same as in example 13, except that the pH adjustor was used in a different concentration, example 23 was conducted by adjusting the pH of the chemical to 6.50 with an aqueous NaOH solution having a concentration of 0.01mol/L, example 24 was conducted by adjusting the pH of the chemical to 6.50 with an aqueous NaOH solution having a concentration of 0.02mol/L, example 25 was conducted by adjusting the pH of the chemical to 6.50 with an aqueous NaOH solution having a concentration of 0.025mol/L, example 26 was conducted by adjusting the pH of the chemical to 6.50 with an aqueous NaOH solution having a concentration of 0.03mol/L, and example 27 was conducted by adjusting the pH of the chemical to 6.50 with an aqueous NaOH solution having a concentration of 0.1 mol/L. Example 28 the pH of the liquor was adjusted to 6.50 using NaOH solution at a concentration of 0.15 mol/L.
The detection and analysis method comprises the following steps:
quality detection of freeze-dried powder injection
For each of the batches of lyophilized powder injections obtained in examples 1 to 22, quality/property indexes such as moisture content, API content, pH value and impurity RRT1.03 content were examined as follows.
1) Measurement of API content: taking 1 sample each, and adopting an HPLC method to carry out detection analysis, wherein the method comprises the following steps: the flow rate is 0.9ml/min, the sample injection amount is 10 μl, the detection wavelength is 230nm, the chromatographic column Phenomenex Gemini NX-C18.6X10mm×3μm, 35mM ammonium acetate is used as mobile phase A, methanol/acetonitrile (3:7) is used as mobile phase B, and the gradient of the mobile phase is as follows:
the detection results of the corresponding products of the examples are shown in Table 1.
2) Impurity RRT1.03 content determination: taking 1 sample each, and detecting by adopting an HPLC method, wherein the method comprises the following steps: the flow rate is 0.8mL/min, the sample injection amount is 10 mu L, the detection wavelength is 254nm, the chromatographic column Xtimate C18 Welch is 250 multiplied by 4.6mM multiplied by 3 mu m, the eluent A is 120mM ammonium acetate+5 mM citric acid solution (pH 6.0), the eluent B is acetonitrile, the diluent is methanol, and the mobile phase gradient is as follows:
by the above method, the measured value of the impurity content of RRT1.03 in the self-made compound of formula (I) used in examples was 1.80%, and the detection results of the corresponding products of each example are shown in table 1.
3) pH value: taking 1 sample each, preparing a solution with the concentration of the compound of the formula (I) of 40mg/ml by using water in examples 1-3 and preparing a solution with the concentration of the compound of the formula (I) of 10mg/ml by using water in examples 4-22, and measuring according to the method of the general rule 0631 of the fourth edition of the Chinese pharmacopoeia 2020, wherein the detection results are shown in Table 1 in detail.
4) Moisture content: and (3) taking a proper amount of the test sample, precisely weighing, drying the test sample to constant weight at the temperature of 105 ℃, and calculating the moisture content (%) in the test sample according to the weight loss. The detection results are shown in Table 1.
5) Insoluble particles: taking 1 sample each, and detecting according to the third general rule 0903 of Chinese pharmacopoeia 2020 edition and the second microscopic counting method of insoluble particle inspection method.
(II) acceleration experiment
The freeze-dried powder injection prepared in examples 1 to 22 is placed in an acceleration experiment box, sampled for a certain time, and the RRT1.03 impurity content is detected according to an HPLC method. Wherein, the acceleration experiment parameters are as follows: temperature 40+ -2deg.C, humidity RH75% + -5%, investigation time: 0. the experimental results are shown in Table 1 for 5, 10 and 30 days.
(III) Long-term stability test
The freeze-dried powder injection prepared in examples 1 to 22 is placed in a long-term sample box, sampled for a certain time, and the content of the impurity RRT1.03 is detected according to an HPLC method. Wherein, the temperature of stay appearance case is 25 ± 2 ℃, and humidity is 60% ± 10% of RH, and the investigation time: 0.1, 2, 3, 6 and 12 months, and the experimental results are shown in table 1.
TABLE 1
As apparent from the experimental data in table 1, the content of the impurity RRT1.03 in the freeze-dried powder injection added with the freeze-dried excipient is obviously lower than the content of the impurity RRT1.03 in the freeze-dried powder injection without the freeze-dried excipient, whether the impurity RRT1.03 content is the impurity RRT1.03 content after the freeze-drying process or the impurity RRT1.03 content is subjected to the accelerated experiment or the long-term stability experiment (example 18); the content of the impurity RRT1.03 in the freeze-dried powder injection prepared by taking sucrose as a freeze-drying excipient is obviously lower than the content of the impurity RRT1.03 in the freeze-dried powder injection prepared by taking other auxiliary materials as the freeze-drying excipient, and the impurity RRT1.03 in the freeze-dried powder injection is found to have only slight fluctuation along with the cycle extension of an acceleration experiment and a long-term stability experiment and finally is in a low-content stable state.
The results of the test of insoluble particles in the water-soluble foaming conditions and the compound solutions for injection prepared in examples 1 to 22 are shown in tables 2 and 3.
TABLE 2
TABLE 3 Table 3
The inventors have also unexpectedly found that when sucrose is selected as the excipient, the concentration of the aqueous solution of pH regulator-NaOH has a great influence on the re-solubility of the prepared freeze-dried powder injection, and the specific results are shown in Table 4.
TABLE 4 Table 4
Claims (10)
1. The fluorescent-magnetic resonance bimodal contrast agent is characterized in that the bimodal contrast agent is a freeze-dried powder injection and comprises a compound of the following formula (I):
and a lyophilization excipient and optionally a pH adjuster.
2. The fluorescence-magnetic resonance bimodal contrast agent according to claim 1, wherein the lyophilized powder for injection is dissolved with water for injection to a solution having a compound of formula (I) concentration of 10-40 mg/ml at a pH value of 5.0-7.0.
3. The fluorescence-magnetic resonance bimodal contrast agent according to claim 1, wherein the lyophilized powder for injection comprises a material in an amount of 30-180 parts by weight per 40 parts by weight of the compound of formula (I).
4. A fluorescent-magnetic resonance bimodal contrast agent according to claim 3, characterized in that the lyophilization excipient is a saccharide compound, and/or a sugar alcohol compound; the saccharide compound is selected from one or more of dextran, anhydrous glucose, lactose, sucrose, trehalose and maltose, preferably lactose, sucrose and trehalose, more preferably sucrose; the sugar alcohol compound is one or more selected from sorbitol, mannitol and erythritol.
5. The fluorescence-magnetic resonance bimodal contrast agent according to claim 1, wherein the pH adjusting agent is selected from NaOH, KOH, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or a combination thereof.
6. A fluorescent-magnetic resonance bimodal contrast agent according to claim 3, characterized in that the solid content of the solution of the lyophilized powder for injection before lyophilization is 2-12% (w/v), preferably 4-8% (w/v).
7. The fluorescent-magnetic resonance bimodal contrast agent according to claim 4, wherein the lyophilization excipient is sucrose, and the weight ratio of the compound of formula (I) to the lyophilization excipient contained in the lyophilization powder injection is 1 (0.75-4), preferably 1 (1-4), more preferably 1:4.
8. The fluorescence-magnetic resonance bimodal contrast agent according to claim 2, wherein the lyophilized powder for injection is dissolved with water for injection to form a solution with a concentration of the compound of formula (I) of 10mg/ml, and the pH value thereof is measured according to the method 0631 of the fourth edition of chinese pharmacopoeia 2020.
9. The fluorescence-magnetic resonance bimodal contrast agent according to claim 8, wherein the pH adjusting agent is an aqueous NaOH solution, the concentration of which is 0.002-0.05 mol/L, preferably 0.005-0.02 mol/L.
10. A method of preparing a fluorescent-magnetic resonance bimodal contrast agent according to any one of claims 1 to 9, comprising the steps of:
(a) Weighing excipient with prescription amount, placing in a preparation tank, adding appropriate amount of water for injection, stirring to dissolve;
(b) Adding a prescribed amount of a compound of formula (I) into a preparation tank, and stirring to dissolve the compound;
(c) Adding water for injection into a preparation tank until the weight of the water for injection reaches the prescription weight, uniformly stirring, measuring the pH value of the solution, and adjusting the pH value to 5-7 by using a pH regulator if necessary;
(d) Sterilizing the liquid medicine, filling into penicillin bottles according to the prescription amount, freeze-drying to remove water, and pressing to obtain the final product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311470414.6A CN117797279A (en) | 2023-11-07 | 2023-11-07 | Fluorescence-magnetic resonance bimodal contrast agent and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311470414.6A CN117797279A (en) | 2023-11-07 | 2023-11-07 | Fluorescence-magnetic resonance bimodal contrast agent and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117797279A true CN117797279A (en) | 2024-04-02 |
Family
ID=90434056
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311470414.6A Pending CN117797279A (en) | 2023-11-07 | 2023-11-07 | Fluorescence-magnetic resonance bimodal contrast agent and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117797279A (en) |
-
2023
- 2023-11-07 CN CN202311470414.6A patent/CN117797279A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2643762C2 (en) | Lyophilized preparations of melphalan flufenamide | |
| US20100087392A1 (en) | Complexes of ibuprofen, cyclodextrins and ternary agents and the use thereof in pharmaceutics | |
| Zhang et al. | A sensitive and rapid radiolabelling method for the in vivo pharmacokinetic study of lentinan | |
| EP3040067A1 (en) | Chlorogenic acid powder-injection and preparation method thereof | |
| CN107028897B (en) | Immune regulator thymopentin powder injection medicine composition and quality control method | |
| CN117797279A (en) | Fluorescence-magnetic resonance bimodal contrast agent and preparation method thereof | |
| TWI660729B (en) | Formulation | |
| CN110478379B (en) | Selaginella chinensis total biflavone precursor liposome and preparation method thereof | |
| CN103980279B (en) | A kind of methotrexate compound and methotrexate for injection | |
| US11071737B2 (en) | Drug inclusion complex, preparation thereof, and preparation method thereof | |
| CN104800172A (en) | Carbazochrome sodium sulfonate powder injection for injection and preparation method thereof | |
| CN104814959A (en) | Magnetic sodium cantharidinate vitamin B6 compound preparation and preparation method thereof | |
| JP4896401B2 (en) | Ursolic acid-soybean lecithin freeze-dried nanoparticle injection and method for producing the same | |
| CN109010290A (en) | A kind of preparation method of ulinastatin freeze-dried powder preparation | |
| CN103159710B (en) | Antiviral decalin derivate | |
| CN103565747B (en) | Esomeprazole composition and preparation method thereof | |
| EP3395346B1 (en) | Oral preparation and preparation method therefor | |
| EP3856151B1 (en) | Lyophilisate of treosulfan | |
| NISHIOKA et al. | A Study of Embolizing Materials for Chemo-embolization Therapy of Hepatocellular Carcinoma: Effects of Particle Size and Dose on Chitin-Containing cis-Diamminedichloroplatinum (II) Albumin Microsphere Antitumor Activity in VX2Hepatic Tumor Model Rabbits | |
| CN112557547B (en) | Method for determining in vivo behavior of aminomethylbenzoic acid lyophilized preparation | |
| CN105663060A (en) | Dianhydrodulcitol lipidosome freeze-dried powder injection and preparation method thereof | |
| CN112595795B (en) | Aminomethylbenzoic acid lyophilized preparation | |
| CN105541946A (en) | Adenosine cyclophosphate crystalline compound | |
| CN101658498B (en) | Freeze-drying manufactured product of cytidine triphosphate disodium and arginine and preparation method thereof | |
| Yan et al. | Preparation of Simvastatin Loaded Nanostructured Lipid Carriers and Its Therapeutic Effect on Patients with Severe Acute Lung Injury |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |