WO2022144764A1 - Cold kits based on psma ligands for the preparation of radiopharmaceuticals - Google Patents
Cold kits based on psma ligands for the preparation of radiopharmaceuticals Download PDFInfo
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- WO2022144764A1 WO2022144764A1 PCT/IB2021/062376 IB2021062376W WO2022144764A1 WO 2022144764 A1 WO2022144764 A1 WO 2022144764A1 IB 2021062376 W IB2021062376 W IB 2021062376W WO 2022144764 A1 WO2022144764 A1 WO 2022144764A1
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- Prior art keywords
- psma
- pharmaceutical formulation
- formulation according
- functionalized
- buffering system
- Prior art date
Links
- 239000012217 radiopharmaceutical Substances 0.000 title claims abstract description 26
- 229940121896 radiopharmaceutical Drugs 0.000 title claims abstract description 26
- 230000002799 radiopharmaceutical effect Effects 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims description 18
- 239000003446 ligand Substances 0.000 title abstract description 14
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 claims abstract description 43
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 claims abstract description 43
- 239000000203 mixture Substances 0.000 claims abstract description 32
- 239000002243 precursor Substances 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 230000003139 buffering effect Effects 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 16
- 235000010339 sodium tetraborate Nutrition 0.000 claims description 16
- 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 14
- CDMADVZSLOHIFP-UHFFFAOYSA-N disodium;3,7-dioxido-2,4,6,8,9-pentaoxa-1,3,5,7-tetraborabicyclo[3.3.1]nonane;decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].O1B([O-])OB2OB([O-])OB1O2 CDMADVZSLOHIFP-UHFFFAOYSA-N 0.000 claims description 14
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims description 12
- 239000004327 boric acid Substances 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 claims description 10
- 235000000346 sugar Nutrition 0.000 claims description 10
- 206010060862 Prostate cancer Diseases 0.000 claims description 9
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 9
- 235000010355 mannitol Nutrition 0.000 claims description 9
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 8
- 229910021538 borax Inorganic materials 0.000 claims description 6
- 229940107700 pyruvic acid Drugs 0.000 claims description 6
- 229940054269 sodium pyruvate Drugs 0.000 claims description 5
- 238000003745 diagnosis Methods 0.000 claims description 4
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- QJUIUFGOTBRHKP-LQJZCPKCSA-N (2s)-2-[[(1s)-1-carboxy-5-[6-[3-[3-[[2-[[5-(2-carboxyethyl)-2-hydroxyphenyl]methyl-(carboxymethyl)amino]ethyl-(carboxymethyl)amino]methyl]-4-hydroxyphenyl]propanoylamino]hexanoylamino]pentyl]carbamoylamino]pentanedioic acid Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)N[C@H](C(O)=O)CCCCNC(=O)CCCCCNC(=O)CCC1=CC=C(O)C(CN(CCN(CC(O)=O)CC=2C(=CC=C(CCC(O)=O)C=2)O)CC(O)=O)=C1 QJUIUFGOTBRHKP-LQJZCPKCSA-N 0.000 claims description 2
- UQGFMSUEHSUPRD-UHFFFAOYSA-N disodium;3,7-dioxido-2,4,6,8,9-pentaoxa-1,3,5,7-tetraborabicyclo[3.3.1]nonane Chemical compound [Na+].[Na+].O1B([O-])OB2OB([O-])OB1O2 UQGFMSUEHSUPRD-UHFFFAOYSA-N 0.000 claims description 2
- 239000004328 sodium tetraborate Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 9
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 claims 5
- 150000004691 decahydrates Chemical class 0.000 claims 1
- 238000009472 formulation Methods 0.000 abstract description 27
- 230000002285 radioactive effect Effects 0.000 abstract description 6
- 230000001225 therapeutic effect Effects 0.000 abstract description 5
- 239000000243 solution Substances 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 16
- 238000007792 addition Methods 0.000 description 13
- 239000003708 ampul Substances 0.000 description 13
- 238000000163 radioactive labelling Methods 0.000 description 12
- GYHNNYVSQQEPJS-YPZZEJLDSA-N Gallium-68 Chemical compound [68Ga] GYHNNYVSQQEPJS-YPZZEJLDSA-N 0.000 description 11
- 239000000546 pharmaceutical excipient Substances 0.000 description 11
- 229930195725 Mannitol Natural products 0.000 description 5
- 239000000594 mannitol Substances 0.000 description 5
- 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 description 4
- 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 description 4
- 102000007066 Prostate-Specific Antigen Human genes 0.000 description 4
- 108010072866 Prostate-Specific Antigen Proteins 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 230000009920 chelation Effects 0.000 description 4
- 238000010668 complexation reaction Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 150000002978 peroxides Chemical class 0.000 description 4
- 239000000600 sorbitol Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- -1 boric acid compound Chemical class 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 239000002738 chelating agent Substances 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000010979 pH adjustment Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 230000005526 G1 to G0 transition Effects 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- 102000018697 Membrane Proteins Human genes 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- PFURGBBHAOXLIO-UHFFFAOYSA-N cyclohexane-1,2-diol Chemical compound OC1CCCCC1O PFURGBBHAOXLIO-UHFFFAOYSA-N 0.000 description 2
- 150000002016 disaccharides Chemical class 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 238000012792 lyophilization process Methods 0.000 description 2
- 239000012931 lyophilized formulation Substances 0.000 description 2
- 150000002772 monosaccharides Chemical class 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 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 description 1
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 1
- MOILFCKRQFQVFS-BDNRQGISSA-N (1r,3s,4r,5r)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol Chemical compound C1[C@@H]2C(C)(C)[C@H]1C[C@H](O)[C@@]2(O)C MOILFCKRQFQVFS-BDNRQGISSA-N 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- GDTSJMKGXGJFGQ-UHFFFAOYSA-N 3,7-dioxido-2,4,6,8,9-pentaoxa-1,3,5,7-tetraborabicyclo[3.3.1]nonane Chemical compound O1B([O-])OB2OB([O-])OB1O2 GDTSJMKGXGJFGQ-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000012879 PET imaging Methods 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 206010051482 Prostatomegaly Diseases 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 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 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 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 description 1
- 239000003150 biochemical marker Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- BMRWNKZVCUKKSR-UHFFFAOYSA-N butane-1,2-diol Chemical compound CCC(O)CO BMRWNKZVCUKKSR-UHFFFAOYSA-N 0.000 description 1
- OWBTYPJTUOEWEK-UHFFFAOYSA-N butane-2,3-diol Chemical compound CC(O)C(C)O OWBTYPJTUOEWEK-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000013170 computed tomography imaging Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- PBVFROWIWWGIFK-KWCOIAHCSA-N fluoromethylcholine (18F) Chemical compound [18F]C[N+](C)(C)CCO PBVFROWIWWGIFK-KWCOIAHCSA-N 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 229910052733 gallium Inorganic materials 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- 238000012636 positron electron tomography Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229940076788 pyruvate Drugs 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
Definitions
- Sodium tetraborate decahydrate may be used in the present invention in an amount range between 80 and 100 mg, preferably between 85 and 88.5 mg.
- the amounts of boric acid/borate currently authorized for human use by EMA are capable of determining the buffering activity inside the formulation of the invention.
- the formulation of the invention comprises, for example, in addition to the boric acid/sodium borate pair, the addition of at least one compound having at least two hydroxyl groups separated by at least two atoms connected to each other in a chain or ring, said chain or ring containing carbon atoms, and optionally a heteroatom or heteroatoms such as N, S, or O.
- pyruvic acid may be replaced by another a-keto acid analogue, or salt thereof, which is capable of performing the same action.
- the solution is stirred by turning upside down the vial several times until the lyophilic product is completely solubilized.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Optics & Photonics (AREA)
- Physics & Mathematics (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Object of the present invention is a novel formulation, based on Prostate-Specific Membrane Antigen (PSMA) ligands, for use as radiopharmaceutical precursors (cold kits). The formulation of the invention is designed to allow the radiopharmaceutical to be prepared instantaneously and in a single step by direct addition of radioactive isotopes, to be used both for diagnostic and therapeutic purposes.
Description
“COLD KITS BASED ON PSMA LIGANDS FOR THE PREPARATION OF RADIOPHARMACEUTICALS”
Summary of the invention
Object of the present invention is a novel formulation, based on Prostate-Specific Membrane Antigen (PSMA) ligands, for use as radiopharmaceutical precursors (cold kits). The formulation of the invention is designed to allow the radiopharmaceutical to be prepared instantaneously and in a single step by direct addition of radioactive isotopes, to be used both for diagnostic and therapeutic purposes.
Background art
In the recent years, as a direct consequence of the increase in the incidence of prostate cancer, the worldwide demand for diagnostic, therapeutic and theranostic radiopharmaceuticals with which to intervene has also intensified.
In particular, one of the greatest challenges in the prostate cancer is the possibility of identifying the biochemical marker that characterizes it at an early stage, so far identified in an increase in PSA (Prostate Specific Antigen) levels. However, PSA in the serum is present in small amounts and increases, sometimes very slightly, only in pathological cases, such as in the case of an enlarged prostate (benign prostatic hypertrophy) or, as mentioned, in the case of the prostate cancer. The current gold standard used for PET/CT imaging diagnosis of the prostate cancer is currently the [18F]Choline drug which, however, shows reduced sensitivity and specificity, especially in cases where PSA levels are very low.
The PSMA (Prostate-Specific Membrane Antigen) protein is a zinc membrane protein overexpressed in the prostate cancer cells. For this reason it could be a very interesting molecule both for obtaining good PET images of the prostate cancer and for its treatment. In fact, recent studies have shown that the radiopharmaceutical [68Ga]PSMA (Prostate-Specific Membrane Antigen) may represent a promising alternative in the early diagnosis and, for this reason, some methods have been developed that allow the radio-labeling of said specific antigen with radioisotopes, both for diagnostic and therapeutic purposes.
One of the disadvantages associated with the use of the [68Ga] isotope is its short
half-life (ti/2 = 68 minutes), which implies the need to set up the radio-labeled compound very quickly, preferably instantaneously.
W02016030103 describes a kit for radio-labeling several possible Gallium-68-based ligands comprising, in addition to the agent to be radio-labeled (functionalized with a radioactive-Gallium chelating agent), also an acetate salt or buffer and a co-chelating agent capable of inactivating any other metals present in the solution eluted by the Gallium-68 generator. The radio-labeling reaction takes place at room temperature, pH between 3 and 5 and following an incubation time of about 10 minutes with a yield >85% which varies depending on the type of ligand and chelator considered.
EP3064224 describes a method for radio-labeling a PSMA ligand with radioactive isotopes for the diagnosis and/or therapy of the prostate cancer. In particular, the method uses a sodium-based buffering agent and provides for the possible further correction of the pH by addition of NaOH to a value of 4-8. The incubation of the reaction is maintained for 5-10 minutes.
To date, there is still a need for a radioisotope labeling kit for PSMA that is easy to use, e.g., provides for the direct addition of the labeled isotope in any sterile acid solution, is applicable to different radionuclides, does not require pH adjustment or any incubation time, and allows for complexation yields and radiochemical purity greater than 95%.
Purposes of the invention
A purpose of the present invention is to provide a novel formulation based on Prostate-Specific Membrane Antigen (PSMA) ligands, for use as radiopharmaceutical precursors (cold kits), designed to allow the radiopharmaceutical to be prepared in a single step by direct addition of radioactive isotopes.
Another purpose of the present invention is to provide a formulation, based on PSMA ligands, which can be used for the preparation of radiopharmaceuticals to be used for diagnostic and/or therapeutic purposes following direct addition of the most appropriate radioisotope, without the need for pH adjustments of the reaction solution.
Another purpose of the present invention is to provide a process for manufacturing
the PSMA ligand-based formulation (cold kit) object of the present invention.
A further purpose of the present invention is to provide a method for preparing a radiopharmaceutical based on PSMA ligands in a single step, by direct addition of the appropriate radioactive isotope, without the need for pH adjustments of the reaction solution and with yields and radiochemical purity greater than 95%.
These and other purposes are achieved by the object of the present invention which provides a novel composition based on the PSMA ligands to be used as a kit for radiopharmaceutical preparations.
Brief description of the Figures
Figure 1 shows the image of the TLC plate on which the radiopharmaceutical preparation of Example 2.1 was run according to the conditions described in Example 2.2.1.
Figure 2 shows the chromatogram resulting from the HPLC analysis of the radiopharmaceutical preparation of Example 2.1, carried out according to the conditions described in Example 2.2.2.
Description of the invention
An object of the present invention is a Prostate-Specific Membrane Antigen (PSMA) ligand-based formulation for use as a kit for radiopharmaceutical preparations. Said formulation, also called "cold kit", is contained in a single vial containing the PSMA molecule functionalized with a chelating group of the radiopharmaceutical, in a quantity in the range between 10 and 30 pg, together with appropriate pharmaceutical excipients.
In the present invention, the PSMA molecule is present in a form characterized by the presence of a functionalization that allows its binding to the radionuclide; in the text it may therefore be referred to as "functionalized PSMA" for brevity. The skilled person in the art is fully aware of the different functionalized forms currently used of this membrane protein and will select the most appropriate one, depending on the type of radiopharmaceutical he intends to use.
In a preferred embodiment, the present invention involves the use of PSMA-11 having a HBED-CC chelating group capable of coordinating radioactive ions of interest, in particular Ga-68, Lu-177 and Ac-225, even at room temperature.
The formulation of the invention is, as mentioned, contained in a single vial/ampoule and is in the form of a white, sterile, apyrogenic lyophilic product.
This vial/ampoule is also the vessel in which the complexation and radio-labeling reaction takes place, without the need for the addition of other reagents or the need for any incubation or heating time.
In particular, in addition to the functionalized PSMA molecule, the formulation contains buffering excipients which, following the addition of concentrated hydrochloric acid in which the radioisotope is normally carried, are able to maintain the pH of the solution that is formed in a range between 3 and 6, more preferably between 5 and 6, considered optimal for the radio-labeling reaction.
In a preferred embodiment of the invention, excipients capable of protecting the functionalized PSMA molecule from degradation, by increasing its stability in the formulation itself and reducing the formation of peroxides and free radicals, as well as agents capable of assisting/coordinating chelation, are also present inside the vial/ampoule. In a preferred aspect said further excipients are multifunctional excipients capable of simultaneously performing more than one of the actions listed above.
In the present text the words "radio-labels", "radioisotopes" and "radionuclides" shall be considered synonymous.
The labeling of the functionalized PSMA molecule can be performed with different types of radioisotopes, particularly preferred are Ga-68, Lu-177 and Ac-225. Said radioisotopes are added directly to the reaction vial/ampoule containing the functionalized PSMA molecule and the other excipients. For example, Ga-68 is added in the form of sterile acid eluate coming from the radionuclide generator. By "eluate" is meant here to refer to the strongly acid solution produced by the machinery generating the radioisotopes and in which the radioisotopes are carried.
Said sterile acid eluate may have an HC1 concentration of, for example, 0.05 N, 0.1 N or 0.6 N and be directly introduced into the reaction vial in different volumes, for example from 1 mL to 5 mL.
As previously mentioned, in the present invention the buffering systems forming part of the formulation contained inside the reaction vial/ampoule allow the pH to be
stabilized within values in the desired range, i.e. between 3 and 6, preferably between 5 and 6, even following the introduction of the sterile acid eluate resulting from the radioisotope generator.
According to a preferred aspect of the present invention, said buffering systems are preferably characterized by at least one, preferably more than one, of the following aspects: they are suitable for the use in injectable pharmaceutical preparations, they are non-toxic and can be administered intravenously in humans; they possess a buffering capability able of achieving and maintaining a pH between 3 and 6 inside the reaction vial/ampoule, even after the addition of different volumes (in a range between 1 mL and 5 mL) of a concentrated HC1 solution, for example a 0.05 N, 0.1 N or 0.6 N solution, in the presence of functionalized PSMA and a radioisotope, preferably selected from Ga-68, Lu-177 and Ac-225; they are able to tolerate and compensate for small variations in volume and/or degree of acidity of the acid solution containing radionuclides (i.e. the eluate coming from the generator) caused, for example, by elutions and additions to the reaction vial/ampoule performed manually by the operator and not automatically by a machinery; they are able to determine high yields, over 95%, in the complexation reaction which occurs instantaneously and without the need for heating.
In the present invention, by the term "buffering system" is meant to denote the excipients allowing to bring and maintain the pH of the solution in the range of values most suitable for the complexation reaction between the functionalized PSMA molecule and the radionuclide, both when present as a single acid/base pair and when said pair is accompanied by other excipients assisting the buffering activity, the chelation reaction and/or having stabilizing activity for the formulation itself.
In particular, the present invention uses as a basic buffering system the boric acid/sodium borate pair obtained in situ in aqueous solution by using sodium tetraborate in the anhydrous or hydrated form, preferably in the decahydrated form. Other inorganic or organic salts of the tetraborate may be used. Alternatively, the boric acid/sodium borate pair can also be obtained in situ from any other suitable
analogous precursor. The boric acid compound has also already been used in formulations for intravenous drug administration in humans.
Sodium tetraborate decahydrate may be used in the present invention in an amount range between 80 and 100 mg, preferably between 85 and 88.5 mg. However, the amounts of boric acid/borate currently authorized for human use by EMA are capable of determining the buffering activity inside the formulation of the invention.
To said acid/base pair capable of buffering the solution of the reaction environment other excipients can be added, as previously mentioned, which will implement, on the one hand, the buffering capability of the acid/base pair, and on the other hand improve the coordination capability between the functionalized PSMA molecule and the radio-labels, that is, assisting the chelation and increasing the yield and radiochemical purity of the final compound.
In one of its configurations, the formulation of the invention comprises, for example, in addition to the boric acid/sodium borate pair, the addition of at least one sugar or mixture of sugars, the sugar preferably being a monosaccharide or disaccharide. Non-limiting examples of suitable sugars include glucose, sucrose, fructose, trehalose, mannitol and sorbitol. In some preferred embodiments, the sugar is a reduced sugar, more preferably mannitol or sorbitol. Preferably, the mannitol or sorbitol have the D-configuration, although the L-configuration may also be used.
In another of its configurations, the formulation of the invention comprises, for example, in addition to the boric acid/sodium borate pair, the addition of at least one compound having at least two hydroxyl groups separated by at least two atoms connected to each other in a chain or ring, said chain or ring containing carbon atoms, and optionally a heteroatom or heteroatoms such as N, S, or O. Said compounds having at least two hydroxyl groups may be, for example but not limited to, pinanediol, pinacol, ethylene glycol, di ethylene glycol, catechol, 1,2- cyclohexanediol, 1,3-propanediol, 2,3 -butanediol, 1,2-butanediol, glycerol and diethanolamine. For the purposes of the present invention, the compound having two hydroxyl groups is preferably a pharmaceutically acceptable compound and is preferably soluble or miscible with water.
In a preferred aspect of the invention said compound having the two hydroxyl groups
is a sugar, as described above, preferably a monosaccharide or a disaccharide, more preferably a reduced sugar, and even more preferably mannitol or sorbitol. In some particularly preferred embodiments, said compound is mannitol, more preferably D- mannitol.
Said compound having two hydroxyl groups, or a mixture of several compounds, preferably two compounds, having two hydroxyl groups, and the sodium tetraborate decahydrate may be introduced into the formulation in a mixture in a molar ratio with the sodium tetraborate decahydrate in a range from about 0.5:1 to 100: 1, more preferably between 0.5: 1 and 50: 1. In the preferred embodiments, the compound having the two hydroxyl groups and the sodium tetraborate decahydrate are present in a ratio between 1 : 1 and 10: 1, preferably between 1 : 1 and 5: 1, even more preferably between 1 : 1 and 4: 1.
The introduction, in the formulation of the invention, of at least one compound having at least two hydroxyl groups may be desired and/or advantageous since their concomitant presence with boric acid leads to the formation of esters thereof. The boric acid ester is an acid stronger than the corresponding unesterified acid (characterized by a lower acid/base equilibrium constant pKa) and thus a better buffering capability of the solution is obtained, i.e. it makes it easier to reach the desired pH values for the solution contained in the reaction vial once the sterile acid eluate from the radioisotope generator is added.
If desired, pyruvic acid may be added to the sodium tetraborate decahydrate of the formulation of the invention, either alone or together with the sugar or compound having two hydroxyl groups, as an acid species or in a salified form thereof, preferably sodium pyruvate, in an amount between about 1 mg and about 50 mg, preferably between 10 mg and 50 mg. The pyruvic acid is an a-keto acid naturally present in living organisms, including humans, and involved in several cellular processes, the safety of which via intravenous route is proven in the literature. In solution with the other components of the invention, the pyruvic acid/pyruvate pair will tend to be created, which will contribute to the buffering activity of the buffering system of which it is part, by bringing and maintaining the pH of the solution in the range of desired values between 3 and 6, preferably between 5 and 6.
The pyruvic acid also has antioxidant properties thanks to its ability to neutralize the peroxides; said molecules could form during the preparation and storage of the lyophilized product as well as during the radio-labeling step. Thus, this compound is able to act not only as an adjuvant in maintaining the pH within the predetermined range but also as a stabilizer of the formulation thus preventing the degradation of the functionalized PSMA molecule by the peroxides.
Alternatively, pyruvic acid may be replaced by another a-keto acid analogue, or salt thereof, which is capable of performing the same action.
A further aspect of the present invention provides for the presence of sodium hydroxide, which allows the buffer pair to respond more efficiently to the possible variations/differences in acidity and/or volume of the acid solution containing the radionuclide, while maintaining the pH of the radio-labeling solution within the desired range. Said sodium hydroxide may be present in an amount in the range between 0 mg and 50 mg, preferably between 1 mg and 30 mg, more preferably between about 1 and 15 mg.
In a preferred embodiment of the invention, the formulation comprises sodium tetraborate decahydrate, D-mannitol, sodium pyruvate and sodium hydroxide in relative ratios expressed as a weight/weight percentage of about 28%, 52%, 16%, 4% respectively, preferably 27.7%, 52.3%, 15.8%, 4.2% respectively.
The formulation of the invention, contained, as mentioned above, inside a single vial/ampoule, is prepared by subjecting to a lyophilization process between 2 and 5 mL of a solution containing the functionalized PSMA molecule in an amount between 10 and 30 pg, the sodium tetraborate decahydrate in an amount between 80 and 100 mg and possibly other desired or necessary excipients. Said lyophilization process may take place, for example, in a LIO5Pascal lyophilizer, for a time of 48 hours, at a temperature of -50°C and a pressure of 0.06 mbar.
The present invention describes the formulation for a "cold kit" for radio-labeling PSMA ligands containing a specific buffering system capable of maintaining the pH of the solution, in which the radio-labeling takes place, in a range between 3 and 6 following the direct addition of the acid eluate resulting from the radioisotope generator.
Said buffering system included in the formulation of the invention is constituted by an appropriate acid/base pair, in particular the boric acid/borate pair, and possibly other pharmaceutical excipients that contribute to improve the buffering capability of the acid/base pair as well as to assist the chelation reaction and stabilize/protect the functionalized PSMA molecule from possible degradation caused, for example, by the possible presence of peroxides.
The formulation of the invention causes that the radio-labeling reaction to take place instantaneously, without the need for heating, with a yield between 95 and 99% and a radiochemical purity between 95 and 99%.
The present invention further describes a process for radio-labeling the PSMA molecule with Ga-68, Lu-177 or Ac-225, which provides for the use of the "cold kit" for the diagnosis and therapy of the prostate cancer.
The invention will now be exemplified, in a non-limiting manner, by the following experimental section.
Experimental section
Example 1
Preparation of a lyophilized formulation containing the functionalized PSMA molecule, sodium tetraborate decahydrate, D-mannitol, sodium pyruvate and sodium hydroxide
Inside a single vial/ampoule, 2 mL of a solution containing 30 pg of the functionalized PSMA molecule, 88 mg of sodium tetraborate decahydrate, 166 mg of D-mannitol, 50 mg of sodium pyruvate and 325 pL of a 1 M NaOH solution are transferred. Such solution is stored in a chill room at -20°C until completely frozen. The vial/ampoule was then placed in a lyophilizer at a temperature between about - 40°C and -50°C and pressure of 0.06 mbar, for a time of about 42 hours, until the ice completely disappeared. In a second step of the lyophilization cycle, the temperature of the vial/ampoule was gradually increased from about -40°C to about 25°C over a period of about 2 hours. The secondary drying process of the sample contained in the vial/ampoule was carried out for about 4 hours at a temperature of 25°C. The sample was subsequently sealed with rubber stopper under nitrogen stream and removed from the lyophilizer.
Example 2
Radiopharmaceutical preparation 68Ga-PSMA-l 1
2.1 - SETTING UP THE RADIOPHARMACEUTICAL PREPARATION 68Ga- PSMA-11
Inside the single vial/ampoule containing the lyophilized formulation derived from Example 1, 5 mL of 68GaC13 eluate coming from the 68Ge/68Ga generator eluted with a 0.1N HC1 solution is transferred.
The solution is stirred by turning upside down the vial several times until the lyophilic product is completely solubilized.
The necessary quantities are taken immediately from the prepared radiopharmaceutical preparation to verify the radiochemical purity by analytical methods in TLC and HPLC.
2.2 - QUALITY CONTROLS ON THE RADIOPHARMACEUTICAL PREPARATION 68Ga-PSMA-ll
2.2.1 TLC method:
Stationary phase: chromatographic paper iTLC SG (10 cm)
Mobile phase: Ammonium acetate 77 g/L in water / Methanol (50:50 volume/volume)
Sample to be tested: 1.5 pL
Retention factors: o [68Ga]gallium in colloidal form: 0.0 - 0.1 o [68Ga]PSMA-l l : 0.8 - 1.0.
As can be observed from the numerical results in Table 1, which lists the data obtained by means of the TLC plate shown in Figure 1, the Gallium-68 present in the radiopharmaceutical preparation is almost exclusively in the form bound to the functionalized PSMA molecule (higher retention times, evident spot at the top of the plate) compared to a much lower percentage of Gallium-68 in colloidal form (much smaller spot at the base of the plate).
Table 1 : Numerical results deriving from the TLC analysis of the radiopharmaceutical preparation 68Ga-PSMA-l l
2.2.2 HPLC method
Stationary phase: Deactivated Cl 8 silica gel column
Mobile phase: [A] Trifluoroacetic Acid/Water 0.1 :99.9 (volume/volume); [B] Trifluoroacetic Acid / Acetonitrile 0.1 :99.9 (volume/volume) - Sample to be tested: 5 pL
Retention times: o [68Ga]PSMA-l 1 : between 6.5 and 7.5 minutes o Relative retention time free [68Ga]Gallium(III) ion: 0.3 minutes
As can be observed from the numerical data listed in Table 2, derived from the analysis of the chromatogram shown in Figure 2, in the sample analyzed there is no presence of free Gallium-68 ions but only of the form bound to the functionalized PSMA molecule, in the two respective stereoisomeric forms.
Table 2: Numerical results from HPLC analysis of the radiopharmaceutical preparation 68Ga-PSMA-l 1
Claims
1. A pharmaceutical formulation based on functionalized PSMA for the preparation of radiopharmaceutical precursors (cold kits), comprising a buffering system, said buffering system comprising the boric acid/borate pair.
2. The pharmaceutical formulation according to claim 1 characterized in that said buffering system is generated from anhydrous or hydrated, preferably decahydrate, sodium tetraborate.
3. The pharmaceutical formulation according to claim 1 or 2 characterized in that said buffering system further comprises at least one sugar or at least one compound containing at least two hydroxyl groups separated by two atoms connected to each other in a chain or ring, or a mixture thereof.
4. The pharmaceutical formulation according to any one of the preceding claims characterized in that said buffering system comprises an a-keto acid, preferably pyruvic acid, or a salt thereof.
5. The pharmaceutical formulation according to any one of the preceding claims characterized in that said buffering system comprises sodium hydroxide.
6. The pharmaceutical formulation according to any one of the preceding claims characterized in that said buffering system comprises sodium tetraborate decahydrate, D-mannitol, sodium pyruvate and sodium hydroxide in a relative w/w % ratio of about 28%, 52%, 16%, 4% respectively, preferably 27.7%, 52.3%, 15.8%, 4.2% respectively.
7. The pharmaceutical formulation according to any one of the preceding claims characterized in that said functionalized PSMA is a PSMA-11 comprising a HBED- CC chelating group.
8. Use of the pharmaceutical formulation according to any one of the preceding claims for obtaining a radio-labeled form of the PSMA molecule functionalized with a radionuclide, said radionuclide preferably being selected from Ga-68, Lu-177, Ac- 225.
9. A method for the preparation of a radio-labeled form of the functionalized PSMA molecule, comprising directly adding a sterile acid solution containing a radionuclide to the pharmaceutical formulation according to any one of claims 1-7,
said radionuclide preferably being selected from Ga-68, Lu- 177, Ac-225.
10. A radio-labeled form of the functionalized PSMA molecule according to the method of claim 9 for its use in the diagnosis or therapy of prostate cancer.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT102020000032603A IT202000032603A1 (en) | 2020-12-29 | 2020-12-29 | COLD KITS BASED ON PSMA LIGANDS FOR THE PREPARATION OF RADIO-PHARMACEUTICALS. |
| IT102020000032603 | 2020-12-29 |
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| WO2022144764A1 true WO2022144764A1 (en) | 2022-07-07 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3064224A1 (en) * | 2015-03-03 | 2016-09-07 | Isotopia Molecular Imaging Ltd | Method for labeling a prostate-specific membrane antigen ligand with a radioactive isotope |
| WO2016142702A1 (en) * | 2015-03-10 | 2016-09-15 | Theragnostics Limited | Methods and kits for preparing radionuclide complexes |
| EP3375787A1 (en) * | 2015-11-09 | 2018-09-19 | Cellbion Co., Ltd. | Peptide thiourea derivative, radioisotope labeled compound containing same, and pharmaceutical composition containing same as active ingredient for treating or diagnosing prostate cancer |
| US20180267050A1 (en) * | 2014-08-29 | 2018-09-20 | Anmi S.A. | Kit for radiolabelling |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE1021191B1 (en) | 2014-08-29 | 2015-10-27 | Anmi S.A. | KIT FOR RADIOMARKING. |
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2020
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2021
- 2021-12-28 WO PCT/IB2021/062376 patent/WO2022144764A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180267050A1 (en) * | 2014-08-29 | 2018-09-20 | Anmi S.A. | Kit for radiolabelling |
| EP3064224A1 (en) * | 2015-03-03 | 2016-09-07 | Isotopia Molecular Imaging Ltd | Method for labeling a prostate-specific membrane antigen ligand with a radioactive isotope |
| WO2016142702A1 (en) * | 2015-03-10 | 2016-09-15 | Theragnostics Limited | Methods and kits for preparing radionuclide complexes |
| EP3375787A1 (en) * | 2015-11-09 | 2018-09-19 | Cellbion Co., Ltd. | Peptide thiourea derivative, radioisotope labeled compound containing same, and pharmaceutical composition containing same as active ingredient for treating or diagnosing prostate cancer |
Non-Patent Citations (1)
| Title |
|---|
| CALDERONI LETIZIA ET AL: "Evaluation of an Automated Module Synthesis and a Sterile Cold Kit-Based Preparation of 68 Ga-PSMA-11 in Patients with Prostate Cancer", THE JOURNAL OF NUCLEAR MEDICINE, vol. 61, no. 5, 1 May 2020 (2020-05-01), US, pages 716 - 722, XP055838503, ISSN: 0161-5505, DOI: 10.2967/jnumed.119.231605 * |
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