NZ714737B2 - Pharmaceutical preparation - Google Patents
Pharmaceutical preparation Download PDFInfo
- Publication number
- NZ714737B2 NZ714737B2 NZ714737A NZ71473714A NZ714737B2 NZ 714737 B2 NZ714737 B2 NZ 714737B2 NZ 714737 A NZ714737 A NZ 714737A NZ 71473714 A NZ71473714 A NZ 71473714A NZ 714737 B2 NZ714737 B2 NZ 714737B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- solution
- alpha
- selective binder
- isotope
- kit
- Prior art date
Links
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 37
- 239000011230 binding agent Substances 0.000 claims abstract description 89
- 230000027455 binding Effects 0.000 claims description 79
- 229910052776 Thorium Inorganic materials 0.000 claims description 45
- 239000003446 ligand Substances 0.000 claims description 44
- ZSLUVFAKFWKJRC-UHFFFAOYSA-N thorium Chemical compound [Th] ZSLUVFAKFWKJRC-UHFFFAOYSA-N 0.000 claims description 43
- 229910052588 hydroxylapatite Inorganic materials 0.000 claims description 29
- 239000000919 ceramic Substances 0.000 claims description 28
- 108090001123 antibodies Proteins 0.000 claims description 20
- 102000004965 antibodies Human genes 0.000 claims description 20
- 239000003729 cation exchange resin Substances 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- 230000015572 biosynthetic process Effects 0.000 claims description 19
- 238000005755 formation reaction Methods 0.000 claims description 19
- 229910052705 radium Inorganic materials 0.000 claims description 18
- HCWPIIXVSYCSAN-UHFFFAOYSA-N radium Chemical compound [Ra] HCWPIIXVSYCSAN-UHFFFAOYSA-N 0.000 claims description 17
- 229940023913 cation exchange resins Drugs 0.000 claims description 14
- 229940102223 Injectable Solution Drugs 0.000 claims description 13
- 239000002502 liposome Substances 0.000 claims description 13
- 239000011780 sodium chloride Substances 0.000 claims description 13
- 239000011324 bead Substances 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 10
- 238000010668 complexation reaction Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 239000011148 porous material Substances 0.000 claims description 8
- 239000012528 membrane Substances 0.000 claims description 7
- 239000002105 nanoparticle Substances 0.000 claims description 7
- 238000011146 sterile filtration Methods 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 6
- 230000021615 conjugation Effects 0.000 claims description 4
- 229920000642 polymer Polymers 0.000 claims description 4
- 239000000499 gel Substances 0.000 claims description 3
- 239000011859 microparticle Substances 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 239000012508 resin bead Substances 0.000 claims description 3
- 238000007792 addition Methods 0.000 claims description 2
- 125000003473 lipid group Chemical group 0.000 claims 4
- 239000000243 solution Substances 0.000 description 100
- 239000000463 material Substances 0.000 description 41
- HCWPIIXVSYCSAN-OIOBTWANSA-N radium-223 Chemical compound [223Ra] HCWPIIXVSYCSAN-OIOBTWANSA-N 0.000 description 32
- 239000000203 mixture Substances 0.000 description 28
- 238000002360 preparation method Methods 0.000 description 20
- ZSLUVFAKFWKJRC-FTXFMUIASA-N thorium-227 Chemical compound [227Th] ZSLUVFAKFWKJRC-FTXFMUIASA-N 0.000 description 20
- 238000003860 storage Methods 0.000 description 17
- 230000005258 radioactive decay Effects 0.000 description 14
- 239000000047 product Substances 0.000 description 12
- 238000003608 radiolysis reaction Methods 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 238000002560 therapeutic procedure Methods 0.000 description 12
- 238000000746 purification Methods 0.000 description 11
- 230000002285 radioactive Effects 0.000 description 11
- 239000011347 resin Substances 0.000 description 11
- 229920005989 resin Polymers 0.000 description 11
- 238000009472 formulation Methods 0.000 description 10
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 210000004027 cells Anatomy 0.000 description 8
- 150000002500 ions Chemical class 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 235000010443 alginic acid Nutrition 0.000 description 7
- 229920000615 alginic acid Polymers 0.000 description 7
- 201000011510 cancer Diseases 0.000 description 7
- 239000000969 carrier Substances 0.000 description 7
- 239000002738 chelating agent Substances 0.000 description 7
- 230000005484 gravity Effects 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 230000014759 maintenance of location Effects 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 239000012217 radiopharmaceutical Substances 0.000 description 7
- 230000002799 radiopharmaceutical Effects 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 239000002245 particle Substances 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 210000001519 tissues Anatomy 0.000 description 6
- 230000036499 Half live Effects 0.000 description 5
- 229940072056 alginate Drugs 0.000 description 5
- 239000008139 complexing agent Substances 0.000 description 5
- 229910052742 iron Inorganic materials 0.000 description 5
- 150000002632 lipids Chemical group 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- 239000011368 organic material Substances 0.000 description 5
- 239000008363 phosphate buffer Substances 0.000 description 5
- 235000002949 phytic acid Nutrition 0.000 description 5
- 239000007790 solid phase Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 230000001225 therapeutic Effects 0.000 description 5
- LBDSXVIYZYSRII-IGMARMGPSA-N α-particle Chemical compound [4He+2] LBDSXVIYZYSRII-IGMARMGPSA-N 0.000 description 5
- 102000008857 Ferritin Human genes 0.000 description 4
- 108050000784 Ferritin Proteins 0.000 description 4
- 238000008416 Ferritin Methods 0.000 description 4
- 108090000437 Peroxidases Proteins 0.000 description 4
- 102000003992 Peroxidases Human genes 0.000 description 4
- 229940067631 Phospholipids Drugs 0.000 description 4
- 239000000648 calcium alginate Substances 0.000 description 4
- 235000010410 calcium alginate Nutrition 0.000 description 4
- 229960002681 calcium alginate Drugs 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 150000003904 phospholipids Chemical class 0.000 description 4
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 4
- -1 silica Chemical class 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- SXVBHNXTPNLOKR-FCLWLKJISA-L Calcium alginate Chemical compound [Ca+2].O1[C@@H](C([O-])=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C([O-])=O)O[C@@H](O)[C@@H](O)[C@H]1O SXVBHNXTPNLOKR-FCLWLKJISA-L 0.000 description 3
- 101710040861 DCN Proteins 0.000 description 3
- 230000035693 Fab Effects 0.000 description 3
- 229950002499 Fytic acid Drugs 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- IMQLKJBTEOYOSI-GPIVLXJGSA-N Inositol-hexakisphosphate Chemical compound OP(O)(=O)O[C@H]1[C@H](OP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@@H]1OP(O)(O)=O IMQLKJBTEOYOSI-GPIVLXJGSA-N 0.000 description 3
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 229960003330 Pentetic Acid Drugs 0.000 description 3
- 229940072417 Peroxidase Drugs 0.000 description 3
- 229940068041 Phytic Acid Drugs 0.000 description 3
- 231100000494 adverse effect Toxicity 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000007979 citrate buffer Substances 0.000 description 3
- 230000000875 corresponding Effects 0.000 description 3
- 238000009792 diffusion process Methods 0.000 description 3
- FVJZSBGHRPJMMA-UHFFFAOYSA-N distearoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCCCC FVJZSBGHRPJMMA-UHFFFAOYSA-N 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 229910001385 heavy metal Inorganic materials 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000002808 molecular sieve Substances 0.000 description 3
- 239000000467 phytic acid Substances 0.000 description 3
- 230000003439 radiotherapeutic Effects 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 3
- 229910052712 strontium Inorganic materials 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000004642 transportation engineering Methods 0.000 description 3
- 239000010457 zeolite Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- GGOZGYRTNQBSSA-UHFFFAOYSA-N 3-hydroxy-1H-pyridin-2-one Chemical group OC1=CC=CN=C1O GGOZGYRTNQBSSA-UHFFFAOYSA-N 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N AI2O3 Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 102100001249 ALB Human genes 0.000 description 2
- 101710027066 ALB Proteins 0.000 description 2
- 102000000546 Apoferritins Human genes 0.000 description 2
- 108010002084 Apoferritins Proteins 0.000 description 2
- ABLZXFCXXLZCGV-UHFFFAOYSA-L CHEBI:8154 Chemical class [O-]P([O-])=O ABLZXFCXXLZCGV-UHFFFAOYSA-L 0.000 description 2
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N Cyclic guanosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- IMQLKJBTEOYOSI-UHFFFAOYSA-N Diphosphoinositol tetrakisphosphate Chemical compound OP(O)(=O)OC1C(OP(O)(O)=O)C(OP(O)(O)=O)C(OP(O)(O)=O)C(OP(O)(O)=O)C1OP(O)(O)=O IMQLKJBTEOYOSI-UHFFFAOYSA-N 0.000 description 2
- 101700025368 ERBB2 Proteins 0.000 description 2
- 102100016662 ERBB2 Human genes 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 2
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 2
- 239000000232 Lipid Bilayer Substances 0.000 description 2
- 102000004895 Lipoproteins Human genes 0.000 description 2
- 108090001030 Lipoproteins Proteins 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 210000004940 Nucleus Anatomy 0.000 description 2
- 101710037934 QRSL1 Proteins 0.000 description 2
- 102000005632 Single-Chain Antibodies Human genes 0.000 description 2
- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 description 2
- 102000004338 Transferrin Human genes 0.000 description 2
- 108090000901 Transferrin Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000000259 anti-tumor Effects 0.000 description 2
- 229910052789 astatine Inorganic materials 0.000 description 2
- 229920001222 biopolymer Polymers 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 238000000975 co-precipitation Methods 0.000 description 2
- 230000000536 complexating Effects 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000002390 hyperplastic Effects 0.000 description 2
- 229910052745 lead Inorganic materials 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229910044991 metal oxide Inorganic materials 0.000 description 2
- 150000004706 metal oxides Chemical class 0.000 description 2
- 108010045030 monoclonal antibodies Proteins 0.000 description 2
- 102000005614 monoclonal antibodies Human genes 0.000 description 2
- 230000001613 neoplastic Effects 0.000 description 2
- 229920001542 oligosaccharide Polymers 0.000 description 2
- 150000002482 oligosaccharides Polymers 0.000 description 2
- 239000000546 pharmaceutic aid Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 150000003009 phosphonic acids Chemical class 0.000 description 2
- HZEBHPIOVYHPMT-LZFNBGRKSA-N polonium-215 Chemical compound [215Po] HZEBHPIOVYHPMT-LZFNBGRKSA-N 0.000 description 2
- SYUHGPGVQRZVTB-OIOBTWANSA-N radon-219 Chemical compound [219Rn] SYUHGPGVQRZVTB-OIOBTWANSA-N 0.000 description 2
- 230000002829 reduced Effects 0.000 description 2
- 230000000717 retained Effects 0.000 description 2
- 238000001542 size-exclusion chromatography Methods 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000002588 toxic Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 239000012581 transferrin Substances 0.000 description 2
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 2
- VWQVUPCCIRVNHF-OUBTZVSYSA-N yttrium-90 Chemical compound [90Y] VWQVUPCCIRVNHF-OUBTZVSYSA-N 0.000 description 2
- AEMOLEFTQBMNLQ-AZLKCVHYSA-M (2R,3S,4S,5S,6R)-3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound O[C@@H]1O[C@@H](C([O-])=O)[C@@H](O)[C@H](O)[C@@H]1O AEMOLEFTQBMNLQ-AZLKCVHYSA-M 0.000 description 1
- AEMOLEFTQBMNLQ-SYJWYVCOSA-M (2S,3S,4S,5S,6R)-3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound O[C@@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@@H]1O AEMOLEFTQBMNLQ-SYJWYVCOSA-M 0.000 description 1
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- 229920000160 (ribonucleotides)n+m Polymers 0.000 description 1
- WVDGHGISNBRCAO-UHFFFAOYSA-N 2-hydroxyisophthalic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=C1O WVDGHGISNBRCAO-UHFFFAOYSA-N 0.000 description 1
- PCDWFBFHIIKIPM-UHFFFAOYSA-N 3-ethyl-2H-1,3-benzothiazole-2-sulfonic acid Chemical compound C1=CC=C2N(CC)C(S(O)(=O)=O)SC2=C1 PCDWFBFHIIKIPM-UHFFFAOYSA-N 0.000 description 1
- MNUOZFHYBCRUOD-UHFFFAOYSA-N 3-hydroxyphthalic acid Chemical compound OC(=O)C1=CC=CC(O)=C1C(O)=O MNUOZFHYBCRUOD-UHFFFAOYSA-N 0.000 description 1
- XJKJWTWGDGIQRH-BFIDDRIFSA-N Alginic acid Chemical class O1[C@@H](C(O)=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](C)[C@@H](O)[C@H]1O XJKJWTWGDGIQRH-BFIDDRIFSA-N 0.000 description 1
- PQUCIEFHOVEZAU-UHFFFAOYSA-N Ammonium sulfite Chemical compound [NH4+].[NH4+].[O-]S([O-])=O PQUCIEFHOVEZAU-UHFFFAOYSA-N 0.000 description 1
- 229920002395 Aptamer Polymers 0.000 description 1
- 229940072107 Ascorbate Drugs 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- 108050001427 Avidin/streptavidin Proteins 0.000 description 1
- 230000036912 Bioavailability Effects 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 210000000170 Cell Membrane Anatomy 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 229960001231 Choline Drugs 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010019695 Hepatic neoplasm Diseases 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N L-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 206010024324 Leukaemias Diseases 0.000 description 1
- 102000013519 Lipocalin-2 Human genes 0.000 description 1
- 108010051335 Lipocalin-2 Proteins 0.000 description 1
- 206010025650 Malignant melanoma Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010061289 Metastatic neoplasm Diseases 0.000 description 1
- 208000003788 Neoplasm Micrometastasis Diseases 0.000 description 1
- 208000002154 Non-Small-Cell Lung Carcinoma Diseases 0.000 description 1
- 108009000071 Non-small cell lung cancer Proteins 0.000 description 1
- NMNFDTCOWIDEAV-UHFFFAOYSA-N OP(O)=O.OP(O)=O Chemical class OP(O)=O.OP(O)=O NMNFDTCOWIDEAV-UHFFFAOYSA-N 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 206010025310 Other lymphomas Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- ITRMROGJSNWFKO-FOCLMDBBSA-N P-Azobenzenearsonate Chemical compound C1=CC([As](O)(=O)O)=CC=C1\N=N\C1=CC=C([As](O)(O)=O)C=C1 ITRMROGJSNWFKO-FOCLMDBBSA-N 0.000 description 1
- 208000008443 Pancreatic Carcinoma Diseases 0.000 description 1
- 210000002381 Plasma Anatomy 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 210000002307 Prostate Anatomy 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 108010070144 Single-Chain Antibodies Proteins 0.000 description 1
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 1
- 208000000587 Small Cell Lung Carcinoma Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 102000011096 Somatostatin receptor family Human genes 0.000 description 1
- 108050001286 Somatostatin receptor family Proteins 0.000 description 1
- 150000001218 Thorium Chemical class 0.000 description 1
- 102000002070 Transferrins Human genes 0.000 description 1
- 108010015865 Transferrins Proteins 0.000 description 1
- 108010010691 Trastuzumab Proteins 0.000 description 1
- 230000036462 Unbound Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive Effects 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 229940050528 albumin Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000005262 alpha decay Effects 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000038129 antigens Human genes 0.000 description 1
- 108091007172 antigens Proteins 0.000 description 1
- 108010054176 apotransferrin Proteins 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 230000035514 bioavailability Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 230000001364 causal effect Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 229910010293 ceramic material Inorganic materials 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 150000004697 chelate complex Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- CRBHXDCYXIISFC-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CC[O-] CRBHXDCYXIISFC-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 201000011231 colorectal cancer Diseases 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000001472 cytotoxic Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000003247 decreasing Effects 0.000 description 1
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000005670 electromagnetic radiation Effects 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 description 1
- 229910052732 germanium Inorganic materials 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 102000034327 globular proteins Human genes 0.000 description 1
- 108091005889 globular proteins Proteins 0.000 description 1
- 150000004676 glycans Polymers 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 229910001410 inorganic ion Inorganic materials 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- WABPQHHGFIMREM-RNFDNDRNSA-N lead-211 Chemical compound [211Pb] WABPQHHGFIMREM-RNFDNDRNSA-N 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- 229920005684 linear copolymer Polymers 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000001394 metastastic Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 229940042880 natural phospholipids Drugs 0.000 description 1
- 201000011519 neuroendocrine tumor Diseases 0.000 description 1
- 230000000683 nonmetastatic Effects 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229920000620 organic polymer Polymers 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 239000003186 pharmaceutical solution Substances 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- NJRWNWYFPOFDFN-UHFFFAOYSA-L phosphonate(2-) Chemical compound [O-][P]([O-])=O NJRWNWYFPOFDFN-UHFFFAOYSA-L 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 108091008117 polyclonal antibodies Proteins 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 229910052704 radon Inorganic materials 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 238000002834 transmittance Methods 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 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
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
- A61K51/1045—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants
- A61K51/1051—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants the tumor cell being from breast, e.g. the antibody being herceptin
-
- 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
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
- A61K51/1075—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody the antibody being against an enzyme
-
- 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
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
- A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The present invention provides a method for generating a purified solution of at least one alpha-emitting radionuclide complex. The method comprises contacting a solution of the alpha-emitting radionuclide complex and at least one daughter nuclide with at least one selective binder for the daughter nuclide and subsequently separating the solution from the selective binder. The invention also provides a method for the removal of at least one daughter radionuclide from a solution comprising at least one alpha-emitting radionuclide complex. The method comprises contacting the solution with at least one selective binder for the daughter nuclide. nuclide and subsequently separating the solution from the selective binder. The invention also provides a method for the removal of at least one daughter radionuclide from a solution comprising at least one alpha-emitting radionuclide complex. The method comprises contacting the solution with at least one selective binder for the daughter nuclide.
Description
Pharmaceutical Preparation for use in radionuclide therapy
Background
The present invention relates to the field of endoradionuclide therapy, and in
particular to alpha-endoradionuclide therapy. More specifically the present
invention relates to the safety and efficacy of preparations for use in
endoradionuclide therapy, to such preparations and to methods for their preparation,
treatment and safe storage.
The basic principle of endo-radionuclide therapy is the selective destruction
of undesirable cell types, e.g. for cancer therapy. Radioactive decay releases
significant amounts of energy, carried by high energy particles and/or
electromagnetic radiation. The released energy causes cytotoxic damage to cells,
resulting in direct or indirect cell death. Obviously, to be effective in treating
disease, the radiation must be preferentially targeted to diseased tissue such that this
energy and cell damage primarily eliminates undesirable tumour cells, or cells that
support tumour growth.
Certain beta-particle emitters have long been regarded as effective in the
treatment of cancers. More recently, alpha-emitters have been targeted for use in
anti-tumour agents. Alpha-emitters differ in several ways from beta-emitters, for
example, they have higher energies and shorter ranges in tissues. The radiation
range of typical alpha-emitters in physiological surroundings is generally less than
100 m, the equivalent of only a few cell diameters. This relatively short range
makes alpha-emitters especially well-suited for treatment of tumours including
micrometastases, because when they are targeted and controlled effectively,
relatively little of the radiated energy will pass beyond the target cells, thus
minimising damage to the surrounding healthy tissue. In contrast, a beta-particle has
a range of 1 mm or more in water.
The energy of alpha-particle radiation is high compared to that from beta-
particles, gamma rays and X-rays, typically being 5-8 MeV, or 5 to 10 times higher
than from beta-particle radiation and at least 20 times higher than from gamma
radiation. The provision of a very large amount of energy over a very short distance
gives alpha-radiation an exceptionally high linear energy transfer (LET) when
compared to beta- or gamma-radiation. This explains the exceptional cytotoxicitiy
of alpha-emitting radionuclides and also imposes stringent demands on the level of
control and study of radionuclide distribution necessary in order to avoid
unacceptable side effects due to irradiation of healthy tissue.
Thus, while very potent, it is important to deliver the alpha-emitting
radionuclides to the tumour with little or no uptake in non-disease tissues. This may
be achieved analogously to what has been shown when delivering the beta-emitting
radionuclide yttrium-90 (Y-90) using a monoclonal antibody conjugated with the
chelating molecule DTPA as a carrier, i.e. the clinically used radiopharmaceutical
Zevalin® (Goldsmith, S.J, Semin. Nucl. Med. 40: 122-35. Radioimmunotherapy of
lymphoma: Bexxar and Zevalin.). Thus, a complex of the radionuclide and the
carrier-chelator conjugate is administered. Besides full length antibodies of different
origins, other types of proteinaceous carriers have been described, including
antibody fragments (Adams et al., A single treatment of yttriumlabeled CHX-
A"-C6.5 diabody inhibits the growth of established human tumor xenografts in
immunodeficient mice. Cancer Res. 64: 6200-8, 2004), domain antibodies (Tijink et
al., Improved tumor targeting of anti-epidermal growth factor receptor Nanobodies
through albumin binding: taking advantage of modular Nanobody technology. Mol.
Cancer Ther. 7: 2288-97, 2008), lipochalins (Kim et al., High-affinity recognition of
lanthanide(III) chelate complexes by a reprogrammed human lipocalin 2. J. Am.
Chem. Soc. 131: 3565-76, 2009), affibody molecules (Tolmachev et al.,
Radionuclide therapy of HER2-positive microxenografts using a Lu-labeled
HER2-specific Affibody molecule. Cancer Res. 15:2772-83, 2007) and peptides
(Miederer et al., Preclinical evaluation of the alpha-particle generator nuclide Ac
for somatostatin receptor radiotherapy of neuroendocrine tumors. Clin. Cancer Res.
14:3555-61, 2008).
Decomposition or “decay” of many pharmaceutically relevant alpha emitters
results in formation of "daughter" nuclides which may also decay with release of
alpha emission. Decay of daughter nuclides may result in formation of a third
species of nuclides, which may also be alpha emitter, leading to a continuing chain
of radioactive decay, a “decay chain”. Therefore, a pharmaceutical preparation of a
pharmaceutically relevant alpha emitter will often also contain decay products that
are themselves alpha emitters. In such a situation, the preparation will contain a mix
of radionuclides, the composition of which depends both on the time after
preparation and the half-lives of the different radionuclides in the decay chain.
The very high energy of an alpha-particle, combined with its significant
mass, results in significant momentum being imparted to the emitted particle upon
nuclear decay. As a result, when the alpha particle is released an equal but opposite
momentum is imparted to the remaining daughter nucleus, resulting in "nuclear
recoil". This recoil is sufficiently powerful to break most chemical bonds and force
the newly formed daughter nuclide out of a chelate complex where the parent
nuclide was situated when decomposing. This is highly significant where the
daughter nucleus is itself an alpha-radiation emitter or is part of a continuing chain
of radioactive decay.
Due to the recoil effects discussed above and due to the change in chemical
nature upon radioactive decay, the daughter nuclides thus formed from radioactive
decay of the initially incorporated radionuclide may not complex with the chelator.
Therefore, in contrast to the parent nuclide, daughter nuclides and subsequent
products in the decay chain may not be attached to the carrier. Thus, storage of an
alpha-emitting radioactive pharmaceutical preparation will typically lead to
accumulation “ingrowth” of free daughter nuclides and subsequent radionuclides in
the decay chain, which are no longer effectively bound or chelated. Unbound
radioisotopes are not controlled by the targeting mechanisms incorporated into the
desired preparation and thus it is desirable to remove the free daughter nuclides prior
to dose administration to patients.
Since the radioisotope thorium-227 will be generated and purified in a
dedicated production facility, a certain storage period between formation,
transportation, complexation and administration of the dose is inevitable, and it is
desirable that the pharmaceutical preparation be as free from daughter nuclides as
possible as is practicable. A significant problem with past methods has been to
administer a reproducible composition of a targeted alpha-radionuclide, which does
not contain variable amounts of non-targeted alpha-radionuclides (e.g. free daughter
nuclides) in relation to the targeted amount. It is further desirable to reduce the
exposure of organic components such as binding/targeting moieties and/or ligands to
ionising alpha-radiation. Removal of free radioisotopes from solution contributes to
reducing the radiolysis of such components and thus helps to preserve the quality of
the pharmaceutical preparation or precursor solution.
Although the decay of the desired nuclide during the storage and
transportation period can be calculated and corrected for, this does not avoid the
build-up of un-targeted daughter products which can render the composition more
toxic and/or reduce the safe storage period and/or alter the therapeutic window in
undesirable ways. In addition, it would thus be of benefit for the compositions to be
as free from daughter nuclides as possible and that a process for drug product dose
manufacture is established which ensures the injected dose has a composition which
can be assured as being acceptably safe.
The events following decomposition of thorium-227 may be considered as an
illustration of the challenge.
Decay chain of thorium-227
With a half-life of about 18.7 days thorium-227 decomposes into radium-223
upon release of an alpha-particle. Radium-223 in turn has a half-life of about 11.4
days, and decomposing into radon-219, giving rise to polonium-215, which gives
rise to lead-211. Each of these steps gives rise to alpha-emission and the half-lives
of radon-219 and polonium-215 are less than 4 seconds and less than 2 milliseconds,
respectively. The end result is that the radioactivity in a freshly prepared solution of
e.g. chelated thorium-227 will increase over the first 19 days, and then start to
decrease. Clearly the amount of thorium-227 available for being targeted to a tumor
is constantly decreasing, and thus the fraction of the total radioactivity deriving from
thorium-227 is dropping during these 19 days, when an equilibrium situation is
reached. If daughter nuclides could be specifically removed in a simple procedure,
only the amount of thorium-227 ( e.g. complexed to the biomolecule carrier) would
have to be considered, and the therapeutic window – the relation between
therapeutic effect and adverse effects would be unrelated to the time of storage prior
to removal of the daughter isotopes. This may be continuous during the storage of
the product or may be shortly before administration, such as at the fime of
formulation and complexation leading to drug product.
Thus, there is considerable ongoing need for improved radiotherapeutic
compositions (particularly for alpha-emitting radionuclides), and procedures for
making a solution ready for injection whose biological effects may be reproducibly
assessed, without having to consider ingrown radionuclides formed in the
radioactive decay chain; and/or there is a need for radiotherapeutic methods and kits
allowing facile preparation of a final radioactive formulation under sterile conditions
directly prior to administration to a patient; and/or it is desirable with a view to
producing high quality commercial products that meet the rigorous standards of the
cGMP principles that the manufacturing process is amenable to automation with
minimal manual intervention during dose preparation.
It is an object of this invention to provide methods, kits when used in such
methods, and devices, that go some way to addressing one or more of these needs;
and/or which at least provide the public with a useful choice.
Described are compositions, methods and procedures for removal of cationic
daughter nuclides from a radiopharmaceutical preparation containing a parent
radionuclide, which may be in solution or stably chelated to an entity comprising a
ligand and a targeting moiety, i.e. the parent radionuclide is complexed or
complexable to a ligand which is itself conjugated to a targeting moiety (such as an
antibody). In particular, the present inventors have surprisingly established that
daughter radionuclides may be safely and reliably captured onto various selective
binders, either continuously during storage of the radioisotope and/or shortly before
administration of the radioisotope in the form of a radiopharmaceutical. The
radionuclides captured by the selective binders are particularly alpha-emitting
radionuclides or generators for alpha-emitting radionuclides typically formed during
the decay of the parent alpha-emitting radionuclide and/or by further decay of the
resulting daughter nuclides. A typical decay chain for Th is described herein and
the isotopes indicated in that chain form preferred daughter isotopes which may be
removed and/or captured in the various embodiments as described herein. The final
therapeutic formulations obtained are suitable for use in the treatment of both cancer
and non-cancerous diseases.
Alternative phrased; described is a composition allowing removal of
radioactive daughter nuclides during storage and/or immediately before
administration (e.g. injection) wherein ingrown radioactive decay products are
removed. This leads to minimal co-administration of daughter nuclides and hence
minimizing radiation dose and radiation damage to normal and non-target tissues.
Thereby, only the concentration and the half-life of the parent radionuclide
and of daughter nuclides formed in vivo have to be taken into consideration when
calculating the radioactive dose obtained by the patient. Most importantly this leads
to a reproducible situation with regard to the relation between efficacy and adverse
effects. Thus, the available therapeutic window will not change with storage time of
the pharmaceutical preparation.
Phrased differently; by applying the described technology the relation
between desired anti-tumour effects and adverse effects may be directly related to
the measured concentration of the primary nuclide and becomes independent of the
time of storage of the pharmaceutical preparation. In situations where the
concentration of the primary alpha-emitting radionuclide may be determined by
measuring one or more parallel emissions of gamma radiation, sufficiently separate
from and gamma emission from the daughter emissions, this may be performed
using standard equipment at the radiopharmacy. In fact, if the drug product is pure
with respect to the parent nuclide, the relevant dose of the pharmaceutical
preparation will depend only on the time after manufacturing and may be tabulated.
In principle there is no need for further measurements at the clinic and the
corresponding radiopharmaceutical could be handled in analogy to any other toxic
pharmaceutical (although such a procedure would counter current practice, which is
based on the fact that radioactivity can be easily measured). The enablement of this
new and simplified procedure for clinical handling of targeted alpha-emitting
radiotherapeutics is an important embodiment as described herein.
In a further embodiment, described is a kit for pharmaceutical preparation.
Kits are typically supplied to the hospital pharmacy or centralised radiopharmacy
and may be prepared for administration shortly (e.g. less than 6 hours) or
immediately (e.g. less than one hour) before administration. It would be a
considerable advantage if purification of the desired alpha-emitting radionuclide
could be accomplished at the time of readying of the pharmaceutical preparation for
administration. It would be a further advantage if that purification could be carried
out without undue burden and without complex handling, since all handling of
radioactive materials is desirably minimised.
A kit as described herein may be in the form of a device, e.g. a cassette
laboratory, where tubes or vials containing the various reagents are attached, as well
as a syringe to contain the final dosage form of the injectable pharmaceutical
preparation. The device performs the operations that would else be performed
manually.
It has been established by the present inventors that certain selective binding
materials, particularly in the form of or immobilised on a solid or gel, will, to a high
extent, retain cationic daughter nuclides after decay of the parent nuclide. The
selectivity of these materials allows retention of the daughters but allows the
complexed parent radioisotope (e.g a thorium isotope such as Th, complexed by a
ligand optionally attached to a biomolecule) to pass unhindered through the filter or
to be left in solution while the daughters are retained. This provides a considerable
advantage in the preparation and delivery of high quality radiopharmaceuticals
which can be prepared directly or shortly prior to administration but delivered with a
relatively low level of contamination from uncomplexed daughter radionuclides.
Summary of the Invention
In a first aspect, the invention provides a method for generating a purified
solution of at least one alpha-emitting thorium isotope, said method comprising
contacting a solution comprising said at least one alpha-emitting thorium isotope
complex and at least one radium isotope with at least one selective binder for said at
least one radium isotope and subsequently separating said solution of at least one
alpha-emitting thorium isotope complex from said at least one selective binder,
wherein the selective binder is selected from the group consisting of cation
exchange resins and ceramic hydroxyapatite, wherein said alpha-emitting thorium
isotope is in the form of a complex with a ligand, and wherein said ligand is
conjugated to a specific binding moiety.
In a second aspect, the invention provides a kit when used for the formation
of a pharmaceutical preparation of at least one alpha-emitting thorium isotope
complex, said kit comprising:
i) a solution of said at least one alpha-emitting thorium isotope and at
least one radium isotope;
ii) at least one ligand;
ii) a specific binding moiety;
iii) at least one selective binder for said at least one radium isotope,
wherein said alpha-emitting thorium isotope is complexed or complexable by said
ligand which is conjugated or conjugatable to said specific binding moiety and the
selective binder is selected from the group consisting of cation exchange resins and
ceramic hydroxyapatite.
In a third aspect, the invention provides an administration device comprising
a solution of at least one alpha-emitting thorium isotope complex and at least one
radium isotope, said device further comprising a filter containing at least one
selective binder for said radium isotope, wherein the selective binder is selected
from the group consisting of cation exchange resins and ceramic hydroxyapatite.
In a fourth aspect, the invention relates to a method for the formation of an
injectable solution of a thorium isotope complex comprising the steps of:
a) combining a first solution comprising a dissolved salt of an alpha-emitting
thorium isotope and at least one radium isotope with a second solution comprising at
least one ligand conjugated to at least one targeting moiety;
b) incubating the combined solutions at a suitable temperature for a period to
allow complex formation between said ligand and said alpha-emitting thorium
isotope whereby to form a solution of at least one alpha-emitting thorium isotope
complex;
c) contacting said solution of at least one alpha-emitting thorium isotope
complex with at least one selective binder for at least one of said radium isotope,
wherein the selective binder is selected from the group consisting of cation
exchange resins and ceramic hydroxyapatite.
d) separating said solution of at least one alpha-emitting thorium isotope
complex from said at least one selective binder.
Brief Description
Described herein is a pharmaceutical process capable of producing a
complexed alpha-emitting radionuclide-(optionally in the form of a biomolecule
conjugate). Preferably said process comprises as key component a selective binder
(such as a solid-phase resin filter) capable of selectively absorbing, binding,
complexing or otherwise removing from solution uncomplexed daughter nuclides
formed during decay of thorium-227. These may be the direct daughter nuclides or
those further down the radioactive decay chain. In particular, Ra and its well
219 215 215 211 211 211 207
known decay products (including Rn, At, Po, Po, Bi, Pb, Pb and
Tl) are typical daughter isotopes which will desirably be removed, as are any
shown in the thorium decay chain indicated herein.
A key embodiment as described herein is thus a method for generating a
purified solution of at least one complexed alpha-emitting radionuclide, said method
comprising contacting a solution comprising said least one alpha-emitting
radionuclide complex and at least one daughter nuclide with at least one selective
binder for said at least one daughter nuclide and subsequently separating said
solution of at least one alpha-emitting radionuclide complex from said at least one
selective binder.
In all embodiments as described herein , the daughter nuclides are generally
uncomplexed. This may be the result of the kinetic recoil generated upon alpha-
decay and/or as a result of differing complexation properties between the parent
nuclide and the daughter. All radionuclide used as described herein are typically
"heavy metal" radionuclides having, for example, an atomic mass greater than 150
amu (e.g. 210 to 230). Typical alpha-emitting heavy-metal radionuclides include
211 212 223 224 225 227
At, Bi, Ra, Ra, Ac and Th. Preferred alpha-emitting (parent)
radionuclides include alpha-emitting thorium radionuclides such as Th, which is
most preferred.
The inventors have surprisingly established that appropriate selective binding
materials (as described herein, e.g. solid-phase resin materials) are highly effective
in absorbing unwanted uncomplexed daughter ions in the preference to complexed
thorium optionally conjugated to targeting moieties (such as biomolecules).
Consequently, also described is a method for generating an injectable solution
comprising at least one complexed alpha-emitting radionuclide substantially free
from daughter nuclides, said method comprising contacting a sample with a suitabel
selective binder, Preferably this contat will be by means of a simple purification/
filtration step yielding highly radiochemically pure pharmaceutical preparations
comprising high levels of the desired alpha-emitting (e.g. thorium) complex
(optionally conjugated to a targeting moiety). Typically the separation of the
labelled thorium-complex (and optionally conjugate) will be followed immediately
by a sterile filtration. This is particularly appropriate as the final step prior to
administration.
Also described herein is a method for the removal of at least one daughter
radionuclide from a solution comprising at least one alpha-emitting radionuclide
complex, said method comprising contacting said solution with at least one selective
binder for said at least one daughter nuclide.
As described herein, the alpha-emitting radionuclide which is desired for
administration (the "parent" radionuclide) will be as described herein and will be
"complexed" or "in the form of a complex". These terms take their common
meaning in that the alpha-emitting radionuclide will be in the form of a coordination
complex comprising a cation of the heavy metal radionuclide and at least one ligand
bound thereto. Suitable ligands, including those described herein, are well known in
the art.
Since pharmaceutical preparations may be generated from the solutions as
described herein, the specification describes such pharmaceutical preparations.
These will comprise a solution of the alpha-emitting radionuclide and will be
substantially free of daughter nuclides as indicated herein. In a pharmaceutical
preparation as described herein, the alpha-emitting radionuclide will be complexed
by at least one ligand and the ligand will be conjugated to a targeting (specific
binding) moiety as described herein. The solutions as described herein may be
provided directly in an administration device (such as a syringe, cartridge or syringe
barrel) ready for administration, with the described technology allowing for
purification of the solution into a pharmaceutical preparation at the time of
administration and even by the act of administration (e.g. by administration through
a suitable specific binder in the form of a syringe filter). Thus the devices as
described herein may be administration devices such as syringes. Also described
herein is an administration device comprising a solution as described herein. Such a
device may additionally comprise, for example, a filter, such as a sterile filter.
Syringe-filters are appropriate for syringes and similar devices.
Described herein is an administration device comprising a solution of at least
one complexed alpha-emitting radionuclide and at least one daughter nuclide, said
device further comprising a filter containing at least one selective binder for said
daughter nuclide. Other devices as described herein which will also comprise a
solution of alpha-emitting radionuclide, a ligand, a targeting moiety and a selective
binder, will be in the form of (preferably disposable) cartridges, cassettes, rotors,
vials, ampoules etc which may be used in the methods as described herein, by
manual steps and/or by automated procedures in an automated apparatus.
A further key embodiment as described herein is a kit by which a
pharmacuetical preparation may be generated. In a further embodiment, described
herein is a kit for the formation of a pharmaceutical preparation of at least one
alpha-emitting radioisotope, said kit comprising:
i) a solution of said at least one alpha-emitting radioisotope and at least
one daughter isotope;
ii) at least one ligand;
ii) a specific binding moiety;
iii) at least one selective binder for said at least one daughter isotope.
Wherein said alpha-emitting radioisotope is complexed or complexable by
said ligand which is conjugated or conjugatable to said specific binding moiety.
In one embodiment, the alpha-emitting radionuclide will be complexed by
the ligand but may not be conjugated to the specific binding (targeting) moiety.
Alternatively, the ligand may be stably conjugated to the targeting moiety and
present in a separate vessel from the radio-isotope. Having the organic molecules of
the complex (the ligand and/or the targeting moiety) separate from the alpha-emitter
reduces the radiation damage (e.g. oxidation) of the organic material due to exposure
to alpha-irradiation during storage.
In one embodiment, the kit may be provided as two vials. Such a kit
comprises a radioisotope (e.g. thorium-227) vial and a second vial containing a
buffered solution of biomolecule-conjugate suitably conjugated with a ligand
(chelate) which complexes thorium-227. Immediately prior to drug product
preparation the thorium-227 vial is mixed with the biomolecule-conjugate solution.
The capture of free (uncomplexed) radionuclides, particularly free daughter
radionuclides, from a solution containing at least one complexed alpha-emitting
radioisotope (such as a parent radioisotope) and at least one organic component
(such as a complexing agent and/or targeting agent) serves to reduce the exposure of
the organic component to ionising radiation from the further decay of the free
radionuclides (e.g. daughters). Correspondingly, in a further embodiment described
is a method for reducing the radiolysis of at least one organic component in a
solution comprising at least one alpha-emitting radionuclide complex, at least one
daughter radionuclide and at least one organic component (such as a complexing
agent and/or targeting agent), said method comprising contacting said solution with
at least one selective binder for said at least one daughter nuclide. This method may
be illustrated by a reduction in H O concentration in the solution.
In all appropriate embodiments as described herein, the “daughter”
radionuclide (equivalently radioisotope) will typically be “free” in solution. This
indicates that the radionuclide is in the form of a dissolved ion and is not (or not to
any significant degree) complexed or bound by ligands in the solution. The
daughter radionuclide may obviously be bound to the specific binder but generally
this will not be in solution (as described herein). As used herein, the term
“daughter” radionuclide takes its common meaning in the art, in that such nuclides
are generated directly or indirectly from the decay of another radioisotope. In the
present case, at least one “daughter” radionuclide present in the solutions referred to
herein in any and all embodiments as described herein will be a direct (first
generation) or indirect (second, third or subsequent generation) decay product of the
radionuclide present in the alpha-emitting radionuclide complex. It is preferably
that at least the first generation decay product of the radionuclide comprised in the
alpha-emitting radionuclide complex will be present in such solutions and will be
bound by the selective binder.
The term “comprising” as used in this specification and claims means
“consisting at least in part of”. When interpreting statements in this specification and
claims which includes the “comprising”, other features besides the features prefaced
by this term in each statement can also be present. Related terms such as “comprise”
and “comprised” are to be interpreted in similar manner.
Detailed Description
As described previously it is dependent on time of storage and transportation
how much ingrowth of daughter radionuclides are present in thorium vial at the time
of complexation. The daughter nuclides however do not effect the complexation of
alpha-emitting radionuclide (thorium-227) to the biomolecule conjugate as the
chelate is chosen such that the desired radionuclide (e.g. thorium) has a significantly
higher affinity for the chelate compared to the daughters. In a second, batch-wise
process, the daughter nuclides are separated from the now thorium-labelled
biomolecule by filtration through a specific binder. This may be in the form of a
solid-phase filter cartridge.
This process of separation of the alpha-emitting material from the organic
ligand and/or targeting moiety has the added advantage of reducing the rate of
radiolysis (e.g. of the biomolecule carrier and/or chelating moiety) of the
radiopharmaceutical and may be applied to all embodiments as described herein.
Because the radioactive product is manufactured ‘closer to bedside’ than other
strategies currently being employed, the material should have higher radiochemical
purity and/or higher purity of the organic material (ligand and/or targeting moiety
components). This is beneficial in terms of maintaining shelf-life requirements.
The injectable solutions formed or formable by the methods and uses as
described herein are highly suitable for use in therapy, particularly for use in the
treatment of hyperplastic or neoplastic disease. Pharmaceutical preparations formed
or formable by the various methods as described herein form further embodiments
as described herein.
As used herein, the term "pharmaceutical preparation" indicates a
preparation of radionuclide with pharmaceutically acceptable carriers, excipients
and/or diluents. However, a pharmaceutical preparation may not be in the form
which will ultimately be administered. For example, a pharmaceutical preparation
may require the addition of at least one further component prior to administration
and/or may require final preparation steps such as sterile filtration. A further
component can for example be a buffer solution used to render the final solution
suitable for injection in vivo. In the context as described herein, a pharmaceutical
preparation may contain significant levels of uncomplexed radionuclides resulting
from the radioactive decay chain of the desired radionuclide complex which will
preferably be removed to a significant degree by a method as described herein
before administration. Such a method may involve the batch-wise removal (eg.
selective binding, chelation, complexation or absorption) of such uncomplexed
daughter radionuclides over a significant part of the storage period of the
preparation, or may take place at the final stage, immediately before administration.
In contrast to a pharmaceutical preparation, an "injectable solution" or "final
formulation" as used herein indicates a medicament which is ready for
administration. Such a formulation will also comprise a preparation of complexed
radionuclide with pharmaceutically acceptable carriers, excipients and/or diluents
but will additionally be sterile, of suitable tonicity and will not contain an
unacceptable level of uncomplexed radioactive decay products. Such levels are
discussed in greater detail herein. Evidently, an injectable solution will not
comprise any biopolymer component, although such a biopolymer will preferably
have been used in the preparation for that solution as discussed herein.
Injectable solutions formed or formable by any of the methods as described
herein form a further embodiment as described herein.
Described is a simple method or process for purification and preparation of a
sterile final formulation of a radioactive preparation ready for administration, using
specific binders in the form of absorbent materials and/or filters to capture unwanted
radioactive decay products yielding rapid separation unwanted nuclides during
storage and/or immediately prior to administration to a patient. The separation may
be followed by the sterile filtration performed as the final formulation is drawn into
the syringe, subsequently to be used for administration to the patient or may even
take place as part of the act of administration.
Implemented as described, described is a simple kit (as described herein) for
purification and final formulation of a radioactive medicament for use in therapy.
The kits as described herein may for example include a thorium vessel (such as a
vial, syringe or syringe barrel) containing a solution of a radioactive thorium salt
(e.g. a Th salt), a vessel (e.g. vial) with a pharmaceutical solution (e.g. a ligand
conjugated to a targeting moiety such as an antibody or recepor), a filter containing
at least one specific binder for the daughter nuclide(s), optionally a sterile filter and
a syringe. The components of the kit may be separate or coupled together into one
unit or flow cell forming a closed system therefore reducing the likelihood of
introducing unwanted byproducts during the manufacture. Avoiding steps during
which radiochemical contamination can be caused is an obvious advantage of kits
having components fully or partially sealed together such that material remains
within the kit for as many process steps as possible.
Described is the use of the procedure for preparation of a final formulation
for injection, for example using components provided as a kit. The procedure of any
of the methods and/or uses as described herein may include an incubation step
where the solution or pharmaceutical preparation is mixed for example by gentle
shaking, to enable optimal complexation of thorium with the biomolecule-chelate
conjugate, followed by filtration to remove unwanted daughter nuclides.
One example procedure for the formation of an injectable solution of an
alpha-radionuclide comprises the steps of:
a) Combining a first solution comprising a dissolved salt of an alpha-emitting
radionuclide and at least one daughter nuclide with a second solution comprising at
least one ligand conjugated to at least one targeting moiety;
b) Incubating the combined solutions at a suitable temperature (e.g. 0°C to
50°C, preferably 20°C to 40°C) for a period to allow complex formation between
said ligand and said radioisotope whereby to form a solution of at least one
complexed alpha-emitting radioisotope;
c) Contacting said solution of at least one complexed alpha-emitting
radioisotope with at least one selective binder for at least one of said dauther
nuclides.
d) separating said solution of at least one complexed alpha-emitting
radionuclide from said at least one selective binder.
In the method of formation of an injectable solution, steps c) and d)
constitute a purification method which may be in accordance with any of the
appropriate embodiments as described herein. In this embodiment, the nuclides,
binders, ligands and all appropriate aspects will be as indicated herein.
The pharmaceutical preparations as described herein, along with the purified
solutions generated by the methods of the invention and the injectable solutions
formed by the methods as described herein will desirably have a low concentration
of uncomplexed daughter metal ions. Typically, for example, the solution
concentration of daughter nuclides should preferably contribute no more than 10%
of the total count of radioactive decays per unit time (from the solution), with the
remainder being generated by decay of the complexed (e.g. thorium) alpha
radionuclide. This will preferably be no more than 5% of the total count and more
preferably no more than 3%.
Preferably the alpha radionuclide conjugates as described herein contain
thorium-227 wherein the process is most effective in removing preferably
Ra..Other daughter isotopes as indicated herein may also be removed. In the
pharmaceutical preparations as described herein and correspondingly in the resulting
solutions for injection, as well as in all embodiments as described herein, the
radionuclide is complexed or complexable by means of a suitable
complexing/chelating entity (generally referred to herein as a ligand). Many suitable
ligands are known for the various suitable alpha-emitting radionuclides, such as
those based on on DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)
and other macrocyclic chelators, for example containing the chelating group
hydroxy phthalic acid or hydroxy isophthalic acid, as well as different variants of
DTPA (diethylene triamine pentaacetic acid), or octadentate hydroxypyridinone-
containing chelators. Preferred examples are chelators comprising a
hydroxypyridinone moiety, such as a 1,2 hydroxypyridinone moiety and/or a 3,2-
hydroxypyridinone moiety. These are very well suited for use in combination with
Th. In one embodiment as described herein, the alpha-emitting radionuclide
complex is an octadentate 3,2-HOPO complex of a Th ion.
In the pharmaceutical preparations as described herein and correspondingly
in the resulting solutions for injection and all other embodiments as described
herein, the at least one complexed alpha-emitting radionuclide is preferably
conjugated or conjugateable to at least one targeting moiety (also described herein as
a specific binding moiety). Many such moieties are well known in the art and any
suitable targeting moiety may be used, individually or in combination. Suitable
targeting moieties include poly- and oligo-peptides, proteins, DNA and RNA
fragments, aptamers etc. Preferable moieties include peptide and protein binders,
e.g. avidin, strepatavidin, a polyclonal or monoclonal antibody (including IgG and
IgM type antibodies), or a mixture of proteins or fragments or constructs of protein.
Antibodies, antibody constructs, fragments of antibodies (e.g. Fab fragments, single
domain antibodies, single-chain variable domain fragment (scFv) etc), constructs
containing antibody fragments or a mixture thereof are particularly preferred.
Antibodies, antibody constructs, fragments of antibodies (e.g. Fab fragments
or any fragment comprising at least one antigen binding region(s)), constructs of
fragments (e.g. single chain antibodies) or a mixture thereof are particularly
preferred. Suitable fragments particularly include Fab, F(ab')2, Fab' and/or scFv.
Antibody constructs may be of any antibody or fragment indicated herein.
In addition to the various components indicated herein, the pharmaceutical
preparations may contain any suitable pharmaceutically compatible components. In
the case of radiopharmaceuticals, these will typically include at least one stabiliser.
Radical scavengers such as ascorbate, p-ABA and/or citrate are highly suitable.
Serum albumin, such as BSA, is also a suitable additive, particularly for protection
of protein and/or peptide components such as antibodies and/or their fragments.
In the methods and uses as described herein, the contacting between the
solution part of the pharmaceutical preparation and the selective binding agent (e.g.
solid-phase resin filter) may take place over an extended period of time (e.g. at least
minutes, such as at least one 1 hour or at least 1 day). In this embodiment, the
selective binder may be present with the solution of alpha-emitting radionuclide
during storage. In an alternative embodiment, however, said contacting will occur
rapidly (such as over less than 30 minutes, less than 10 minutes, or less than 5
minutes (e.g. less than 1 minute or no more than 30 seconds). In such an
embodiment, the selective binder will typically be in the form of or bound to a solid
material (as described herein) and may be formed into a separation column, pad or
filter through which the solution may be passed. Such passage may be under gravity
or by centrifugal force, may be driven by suction or most preferably will be driven
by positive pressure, such as by application of pressure to a syringe barrel. In such a
case, the contacting takes place.as the solution is pushed through the
filter/pad/column. Although rapid separation is the most preferred method,
alternatively, the contacting and filtration step may be carried out over longer time
periods (e.g. 3 to 20 minutes) to ensure maximum radiochemical purity.
In an alternative embodiment, said contacting/ filtering takes place for no
more than 30 seconds preferably no more than 1 minute followed by a sterile
filtration and will thus also generate a sterile solution suitable for injection.
Correspondingly, the kits as described herein may optionally and preferably
additionally comprise a filter (e.g. of pore size 0.45 m or of pore size of about 0.22
m). In all cases filtration through a filter of pore size no larger than 0.45 m,
preferably no larger than 0.22 m is preferred. Such a filter may serve to retain the
selective binder employed in the various embodiments as described herein.
In the various embodiments as described herein, the ligand moiety is
generally conjugated or conjugatable to at least on specific binding (targeting)
moiety. Such conjugation may be by means of a covalent bond (such as a carbon-
carbon, amide, ester, ether or amine bond) or may be by means of strong non-
covalent interactions, such as the binding of a pair of specific-binding moieties, such
as biotin to avidin / streptavidin. Most preferably the ligand is conjugated to the
targeting moiety by means of a covalent bond, optionally by means of a linker (such
as a C1 to C10 alkyl group independently substituted at each end by an alcohol,
acid, amine, amide, ester or ether group)
In all embodiments as described herein, the selective binder is typically a
solid or gel, or is immobilised on a solid or gel matrix (such as a porous matrix or
membrane). This allows for ease of handling and separation and also for ease of
contacting the selective binder with the alpha-emitting radioisotope complex and
subsequent separation. A "solid" material may be taken as one which will hold its
shape under gentle mechanical pressure including that provided by manual use of a
syringe or by the pressure provided in an automated apparatus. Typically the
selective binder will be in the form of or immobilised to a porous material such that
the solution can pass though the pores of the material. Suitable matrices for
supporting selective binders are discussed herein and will be well known to those of
skill in the art. These include metal oxides (e.g. silica, alumina, titania) glass, metal,
plastics etc. selective binders may be immobilised on the surface of such matrices
or may form porous matrices in themselves. Any of the materials indicated may
form a support in the form of membranes, resin beads, gel beads, self-assembled
lipid structures (e.g. liposomes), microparticles, nanoparticles, powders, crystals and
polymer structures as appropriate. Evidently more than one such structure may be
used.
As the selective binding material will be chosen at least one substance
having greater affinity for the daughter radionuclide(s) in solution over the alpha-
emitting radionuclide complex. Such materials suitable for selective binders include
at least one of cation exchange resins, size exclusion resins, zeolites, molecular
sieves, alginates, liposomes, phosphonates, polyphosphonates, phospholipids,
glycolipids, lipo-proteins, oligosaccharides, ferritin, transferrin, phytic acid and co-
precipitation agents. Highly preferred selective binders include cation exchange
resins, hydroxyapatite, and zeolites.
In one embodiment, the selective binders as described herein do not
comprise any polysaccharide. In one embodiment the selective binders do not
comprise any alginate. In a further embodiment, the binder comprises, consists
essentially of or consists of at least one inorganic material, such as at least one
ceramic material. Inorganic resins (e.g. inorganic ion exchange resins), metal oxides
(such as silica, alumina, titania, especially when porous such as mesoporous),
hydroxyapatite (including substituted hydroxyapatites), molecular sieves and
zeolites form highly preferred inorganic binding materials.
Details of certain materials suitable for use as selective binding agents are
indicated below in Table 1. Examples given in the description column form
preferred choices of material for use as selective binders as described herein.
Table 1:
Material Description
Cation exchange resins An insoluble matrix normally in the form of small
beads, usually white or yellowish, fabricated from an
organic polymer substrate. The material has highly
developed structure of pores on the surface of which
are sites with easily trapped and released ions. The
trapping of ions takes place only with simultaneous
releasing of other ions; thus the process is called
ion-exchange.
Size exclusion/gel filtration Size-exclusion chromatography (SEC) is a
resins chromatographic method in which molecules in
solution are separated by their size, and in some
cases molecular weight.
Molecular sieves material containing tiny pores of a precise
and uniform size that is used as an adsorbent
Alginate (= salts of alginic acid) linear copolymer with
homopolymeric blocks of (1-4)-linked β-D-
mannuronate (M) and its C-5 epimer α-L-guluronate
(G) residues, respectively, covalently linked together
in different sequences or blocks
Liposomes (sterically artificially-prepared vesicle primarily
stabilized) composed of a lipid bilayer. Liposomes are
composed of natural phospholipids, and
may also contain mixed lipid chains with surfactant
properties. A
liposome design may employ surface ligands.
(Poly-) phosphonate Phosphonates or phosphonic acids are organic
compounds containing C-PO(OH)2 or C-PO(OR)2
groups (where R=alkyl, aryl). Phosphonic acids are
known as effective chelating agents. The
introduction of an amine group into the molecule to
obtain -NH2-C-PO(OH)2 increases the metal binding
abilities of the phosphonate.
Nano-particles nanoparticles are sized between 100 and 1 nano-
meters. Large surface to volume ratio. Liposomes
are an example of nanoparticles.
Phospho-lipids A class of lipids that are a major component of all
cell membranes as they can form lipid bilayers. Most
phospholipids contain a diglyceride, a phosphate
group, and a simple organic molecule as choline.
Glycolipids lipids with a
carbohydrate attached
Material Description
Co-precipitation The carrying down by a precipitate of substances
normally soluble under the conditions employed.
Since the trace element is too dilute
(sometimes less than a part per trillion) to precipitate
by conventional means, it is typically
coprecipitated with a carrier, a substance that has a
similar crystalline structure that can incorporate
the desired element. Occurs by inclusion, adsorption
or occlusion.
Ferritin/ Apoferritin, Ferritin is a globular protein complex keeping iron in
transferrin / apotransferrin a soluble and non-toxic form. Ferritin that is not
combined with iron is called apoferritin. Transferrins
are iron-binding blood plasma glycoproteins that
control the level of free iron in biological fluids.
Lipo-proteins a biochemical assembly that contains both proteins
and lipids
Cyclo-dextrines cyclic oligosaccharides
Phytic acid (phytate when in Phosphorus compound with chelating actions. It
salt form) occurs naturally in plants
as the insoluble calcium magnesium salt and is a
major source of phosphate in the diet,
although there is debate about its bioavailability.
Excess intake of phytate has been
associated with deficiencies of elements such as
calcium, iron, and zinc.
Surface modifications Agents with possible affinity for 223-Ra:
Phytic acid
Phospholipids
Phosphonates
Carriers:
Liposomes
Mikroparticles/ nanoparticles/ resins/ alginate/
polymer beads/
cyclodextrines
In one embodiment, the selective binder(s) are in the form of a column or
filter. In this and other appropriate embodiments, the means of contacting will be
the flow of solution through or past the selective binder. Alternatively, where the
selective binder is immobilised on a support then the flow may be through or past
such a support. Subsequent flow through a sterile-filtration membrane (as described
herein) is preferred.
The injectable solution obtained from compositions or pharmaceutical
formulations as described herein are suitable for treatment of a range of diseases and
are particularly suitable for treatment of diseases relating to undesirable cell
proliferation, such as hyperplastic and neoplastic diseases. For example, metastatic
and non-metastatic cancerous diseases such as small cell and non-small cell lung
cancer, malignant melanoma, ovarian cancer, breast cancer, bone cancer, colorectal
cancer, pancreatic cancer, bladder cancer, cervical cancer, sarcomas, lymphomas,
leukemias, tumours of the prostate, and liver tumours are all suitable targets. The
"subject" of the treatment may be human or animal, particularly mammals, more
particularly primate, canine, feline or rodent mammals.
Other embodiments as described herein are the provision of a composition as
described herein, or alternatively the use of a composition as described herein in the
manufacture of a medicament for use in therapy. Such therapy is particularly for the
treatment of diseases including those specified herein above. By "treatment" as used
herein, is included reactive and prophylactic treatment, causal and symptomatic
treatment and palliation.
Use of the medicament resulting as described herein in therapy may be as
part of combination therapy, which comprises administration to a subject in need of
such treatment an injectable solution as described herein and one or more additional
treatments. Suitable additional treatments include surgery, chemotherapy and
radiotherapy (especially external beam radiotherapy).
In a further embodiment as described herein encompasses apparatus, kit as
described herein. Such kits will comprise an alpha-emitting radioisotope, a ligand, a
targeting moiety and a selective binding material for binding daughter nuclides.
Typically, in use, the alpha-emitting radionuclide will either be present as an alpha-
emitting radionuclide complex, or will be formed into such complex by contact
between a first solution of said kit (comprising the alpha-emitting radionuclide and
any daughter nuclides) and a second solution of said kit (comprising the ligand
conjugated to the targeting moiety). Following conjugation the alpha-emitting
radionuclide complex will be contacted with the selective binder. That contact may
be in any way described herein, but will preferably be by passing the alpha-emitting
radionuclide complex solution through a column, pad, filter, membrane or plug of
selective binding material.
The kits as described herein will generally include the selective binding
material in the form of a filter or column. The alpha-emitting radionuclide solution
will be present in a first vessel but this and all vessels referred to herein may be a
vial, syringe, syringe barrel, cartridge, cassette, well, ampoule or any other
appropriate vessel as well as a part of such a vessel, such as one well in a plate or
one void within a multi-reagent cartridge or cassette. The first and second vessels,
where present, may form part of the same device (e.g. may be separate wells or
voids in a multi-component plate or cassette) and may be in fluid communication
with each other, optionally by means of removing a seal, plug or opening a tap or
removing a restriction, clamp etc to allow mixing of solutions. Such mixing may be
initiated manually or may be the result of a manipulation within an automated
apparatus.
One embodiment of the kits as described herein is in the form of cartridges
for an automated apparatus, for example, an automated synthesiser. Such automated
apparatus allow for performing the methods as described herein with minimal
manual intervention to ensure compliance with cGMP principles. Thus, a typical
apparatus includes an automated synthesiser such as the GEHC FastLab or
TracerLab which will contain or be loaded with the kit or device as described herein
. An automated apparatus comprising a kit or device as described herein thus forms
a further embodiment as described herein . The kit as described herein may be in
the form of a device, cartridge, rotor, reagent pack etc for any of these or any similar
apparatus. An automated apparatus may be used for fully automated process
comprising radionuclide (e.g. thorium-227) complexation to a ligand/biomolecule
conjugate, removal of daughter nuclides by filtration on a selective binder (e.g.
solid-phase resin) sterile filtration and dispensing into a drug product vial. Thus, the
various methods as described herein may be carried out by means of an automated
apparatus such as one containing a kit or device as described herein.
In a related embodiment, described is an administration device. Such a
device may contain a solution of alpha-emitting radionuclide complex and daughter
nuclides and will comprise a selective binder for said daughter nuclide(s). In use,
such an administration device may concomitantly remove daughter nuclides by
passage of the solution through or past the selective binder and also deliver the
resulting purified solution to a subject.
The injectable solutions formed and formable from the pharmaceutical
compositions as described herein and those formed by use of the kits of the
invention will evidently form a further embodiment as described herein. Such
solutions may be, for example an injectable solution comprising a solution of at least
one complexed alpha-emitting radionuclide and at least one pharmaceutically
acceptable carrier or diluent wherein the solution concentration of any uncomplexed
ions resulting from the radioactive decay chain of said least one complexed alpha-
emitting radionuclide is no greater than 10% of the solution concentration of said
least one complexed alpha-emitting radionuclide.
One embodiment as described herein relates to a method for reducing the
radiolysis of at least one organic component in a solution. Generally this will be a
solution as described herein in respect of any embodiment and may comprise at least
one alpha-emitting radionuclide complex, at least one daughter radionuclide and at
least one organic component. Typically in this and all embodiments, the daughter
will be a daughter isotope formed by radioactive decay of at least one alpha-emitting
radionuclide in or from a corresponding complex. The organic material may be any
organic component including any pharmaceutically acceptable carrier, diluent,
buffer etc (any of which, organic or not, may be incorporated into the solutions as
described herein). Most commonly the organic component will comprises a
complexing agent and/or targeting agent, which will typically be the complexing
agent of the said complex as described herein. The targeting agent may be any
suitable targeting moiety (such as an antibody, antibody fragment (Fab, F(ab’) scFv
etc), antibody or fragment conjugates etc). The targeting agent will typically be
conjugated to the complex by covalent or non-covalent conjugation. By contacting
such a solution at least one selective binder for the at least one daughter nuclide
(especially at least one selective binder as described in any embodiment herein but
most particularly inorganic binders such as hydroxyapatite) then the daughter
radionuclides may be sequestered out of solution and separated from both the
organic material and other materials, including water, that can readily be ionised or
converted into a radical form. As well as direct benefit from reduced direct
radiolysis, this reduction in radiolysis will evidently also be an indirect benefit in
that the lower concentration of radical and oxidising species will reduce undesirable
reactions with the organic material of the complex or targeting moiety. As an
embodiment of this method, described is a method for reducing the H O
concentration in a solution comprising at least one alpha-emitting radionuclide
complex, at least one daughter radionuclide and optionally at least one organic
component (such as a complexing agent and/or targeting agent), said method
comprising contacting said solution with at least one selective binder for said at least
one daughter nuclide.
In all embodiments, “reducing” radiolysis or the concentration of a
component relates to a reduction in comparison with a control solution containing all
corresponding component of the solution except for the specific binder(s).
Similarly, “removing” relates to removing a radionuclide from free solution, such as
by entrapping that radionuclide within a separable material such as a gel or solid
(such as a ceramic, porous solid etc).
The invention will now be illustrated by reference to the following non-limiting
Examples, and the Figures below, in which:
Figure 1 shows the generation of hydrogen peroxide by radiolysis of water in
the presence or absence of a selective binder
EXAMPLE 1
Radium-223 uptake on gravity columns using ceramic hydroxyapatite
100 mg ceramic hydroxyapatite was weighed out and transferred to the columns.
HEPES buffer (5 mM, pH 8) was used to equilibrate the column (3 x 1 ml). 1 ml
HEPES buffer was then added to the column which was left standing over night
before 140 kBq radium-223 in 1 mL was loaded. Uptake was immediate. The
column was then washed with HEPES buffer (3 x 1 ml), before uptake of radium-
223 on the column material was determined using a HPGe-detector instrument
(Ortec, Oak Ridge, TN).
The material removed 98.9 % of radium-223 and daughter nuclides (Table 2).
Table 2 Average percentage retention of radium-223 for ceramic hydroxyapatite (n=3).
Samples Average retention of radium-223
Ceramic hydroxyapatite 98.9
EXAMPLE 2
Purification of a Targeted Thorium Conjugate in phosphate buffer on spin columns
with propylsulfonic acid silicabased cation exchange resin
A trastuzumab chelator conjugate prepared as described previously
(WO2011/098611A) was labeled with thorium-227 (forming a Targeted Thorium
Conjugate, TTC), using thorium-227 stored for 5 days in HCl following purification
and hence containing ingrown radium-223 and progenies of radium-223 decay. Each
sample contained 0.21 mg TTC, 520 kBq thorium-227 and 160 kBq radium-223 in
300 µl saline phosphate buffer pH 7.4 (Biochrome PBS Dulbecco, Cat no L1825).
The sample was added to a column with 15 mg propylsulfonic acid silica based
cation exchange resin. The columns were centrifuged (10 000 rcf, 1 min) and the
eluate collected. The distribution of thorium-227 (TTC) and radium-223 between the
column and eluate was determined using a HPGe-detector instrument (Ortec, Oak
Ridge, TN).
The retention of TTC (represented by thorium-227) and radium-223 on the column
was 5.5 and 99.1 %, respectively (Table 3).
Table 3 Retention of Targeted Thorium Conjugate (TTC) and radium-223 after purification
on spin columns with cation exchange resin
Amount of cation TTC on column (%) radium-223 on
exchange resin (mg) column (%)
.5 99.1
EXAMPLE 3
Removal of radium-223 in citrate and phosphate buffer on spin columns with
propylsulfonic acid silicabased cation exchange resin
160 kBq radium-223 in 300 µl 50 mM citrate buffer pH 5.5 with 0.9 % sodium
chloride or saline phosphate buffer pH 7.4 (Biochrome PBS Dulbecco, Cat no
L1825) was added to a column with 60 mg propylsulfonic acid silica based cation
exchange resin. The columns were then centrifuged (10 000 rcf, 1 min) and the
eluate collected. The distribution of radium-223 between the column and eluate was
determined using a HPGe-detector instrument (Ortec, Oak Ridge, TN).
The retention of radium-223 on the column was 96.5 % for the citrate buffer and
99.6 % for the phosphate buffer, respectively (Table 3).
Table 3 Retention of radium-223 after purification on spin columns with cation exchange
resin
Buffer type Average radium-223 on
column (%)
Citrate 96.5
phosphate 99.6
Example 4 - Further comparison of selective binder materials
Strontium and calcium alginate gel beads, DSPG liposomes, ceramic
hydroxyapatite, Zeolite UOP type 4A, and two cation exchange resins (AG50WX8
and SOURCE 30 S) were selected as materials to be studied for radium-223 uptake .
Passive diffusional uptake of nuclides was tested by having materials present as
suspensions in the formulation. Measurements were taken with the aid of a
Germanium detector after 1 hour equilibration at 25 ºC with shaking. Removal of
free nuclides on gravity columns was also studied.
Uptake of radium-223
All materials, to some degree, removed radium-223 and daughters by passive
diffusional uptake ranging from 30.8 ± 5.8 to 95.4 ± 2.5 % uptake at the selected
experimental conditions. All the materials tested removed radium-223 and daughters
on the gravity column set-up with near complete uptake. The results were
significantly higher (~ 100 %) and with minimal variation (< 1 %) compared to
passive diffusional uptake of radium-223, for all tested materials except for alginate
gel beads (see Table 4).
Average
Average
Relative Standard
Relative standard
uptake of
uptake of
deviation uptake
deviation uptake of
Samples radium-223
radium-223 on
radium-223 by
of radium-223 on
by passive
gravity
passive diffusion(%)
gravity column (%)
diffusion (%)
column (%)
Liposomes 95.4 2.5 - -
SOURCE 30S
cation exchange 78.7 15.8 99.5 0.1
resins
Ceramic
77.8 20.1
hydroxyapatite 98.9 0.7
Calcium alginate
71.9 9.7 8.2 20.7
gel beads
Strontium
alginate gel 68.2 16.7 - -
beads
Zeolite UOP type
49.7 7.4 - -
Calcium alginate
33.1 1.7 - -
gel beads
AG50WX8 cation
.8 5.8 99.8 0.2
exchange resins
Various materials suitable for capturing radium-223 daughter isotopes have been
identified. Strontium and calcium alginate gel beads, DSPG liposomes, ceramic
hydroxyapatite, Zeolite UOP type 4A, and two cation exchange resins (AG50WX8
and SOURCE 30 S) were tested and all materials were found to remove radium-223
and daughters.
DSPG liposomes were superior when testing passive diffusional uptake while the
other materials were suboptimal when used as suspensions and for uptake by passive
diffusion. The cation exchange resins and ceramic hydroxyapatite were however
excellent when used on gravity columns.
Example 5 – Reduction in radiolysis
Abstract
Formation of hydrogen peroxide (H O ) in the water phase of the formulation was
studied as a measure of radiolysis in the presence and absence of ceramic
hydroxyapatite, which was one of the materials shown to efficiently bind the
radionuclides from solution. Radiolysis and formation of free radicals in the water
phase may degrade the radionuclide complex thus minimization of the generation
and amount of H O present is desirable. After 3 days the concentration of H O in
2 2 2 2
samples with ceramic hydroxyapatite was significantly lower than the controls, and
223 227
the uptake of Ra and Th from solution was near complete.
Method
The UVmini-1240 single beam spectrophotometer (190 – 1100 nm) from Shimadzo
(Kyoto, Japan) was used and light transmittance recorded at 730 nm for analyzes of
the H O concentration. Photometric mode was used where the absorbance of a
sample is measured at a fixed wavelength (n=3). The cuvettes used were Plastibrand
disposable 1.5 ml semi-micro (12.5 x 12.5 x 45 mm) cuvettes made of polystyrene.
A 0.5 mg/ml horseradish peroxidase solution and 2 mg/ml peroxidase substrate
(2.2′-Azino-bis(3-ethylbenzothiazolinesulfonic acid) diammonium salt) solution
were made by dissolution in metal free water. The peroxidase enzyme converts the
peroxidase substrate from colorless to a green color with H O as substrate. H O
2 2 2 2
standards at 1.765, 0.882, 0.441, 0.221, and 0.110 mmol/L H O were made by
diluting 30 % (w/w) H O in metal free water (n=3). The linearity of the standard
curve was R =0.9995.
Samples consisted of 100 mg/ml ceramic hydroxyapatite in 250 μl 9 mg/ml sodium
chloride which was loaded with a freshly prepared Th solution to a concentration
of 0.5 kBq/µl (n=3).
Two types of control samples were analyzed; one negative control with only Th
and no binding material, and one positive control with binding material but no
radioactive source (n=3). The negative controls were analyzed to check the
homogeneity of the radionuclides in the sodium chloride solution and the amount of
H O generated in the absence of binding material, while the positive controls were
analyzed to see if a significant level of H O was developed without the presence of
radioactivity.
For calculation of the percentage uptake of radionuclides in ceramic hydroxyapatite
samples and homogeneity of radionuclides in the negative controls, each sample or
control was measured on the HPGe-detector before 60 µl supernatant was removed.
Samples, controls and standards were further prepared for H O analysis by mixing
900 µl 9 mg/ml sodium chloride with 50 µl peroxidase substrate solution, 25 µl
horseradish peroxidase solution and 25 µl of the respective supernatant from sample,
control or standard. The samples, control or standard were carefully mixed and
measured immediately by UV-vis spectrophotometry. For radioactive samples and
controls, the remaining sample volume was finally measured on the HPGe-detector.
Uptake of radionuclides in ceramic hydroxyapatite or homogeneity of radioactivity
in the sodium chloride solution was calculated by the aid of HPGe-spectra.
H O concentration in the samples, standards and controls were analyzed by UV-vis
spectrophotometry at 730 nm, at time points 0, 3, 7, 10 and 14 days.
Results
The measured level of H O formed during 14 days storage in samples of suspended
ceramic hydroxyapatite and freshly prepared Th was significantly lowered
compared to negative controls without ceramic hydroxyapatite (Fig. 1). The positive
controls containing ceramic hydroxyapatite without radioactivity did not show any
H O formation outside the statistical error of the method (Fig. 1). The passive
diffusional uptake of freshly prepared Th in a suspension of ceramic
hydroxyapatite was 81 ± 3 % at 90 minutes reaction time. The consecutive uptake of
227 223
Th and generated Ra by ceramic hydroxyapatite was 99 ± 5 % and 102±12 %,
respectively, when measured after 14 days incubation.
The measured reduction in H O demonstrates a reduced production of radicals and
oxidising agents due to radiolysis of the containing solution.
In this specification where reference has been made to patent specifications, other
external documents, or other sources of information, this is generally for the purpose
of providing a context for discussing the features of the invention. Unless
specifically stated otherwise, reference to such external documents is not to be
construed as an admission that such documents, or such sources of information, in
any jurisdiction, are prior art, or form part of the common general knowledge in the
art.
The invention is defined in the claims. However, the disclosure preceding the claims
may refer to additional methods and other subject matter outside the scope of the
present claims. This disclosure is retained for technical purposes.
Claims (39)
1) A method for generating a purified solution of at least one alpha-emitting thorium isotope, said method comprising contacting a solution comprising said at least one alpha-emitting thorium isotope complex and at least one radium isotope 5 with at least one selective binder for said at least one radium isotope and subsequently separating said solution of at least one alpha-emitting thorium isotope complex from said at least one selective binder, wherein the selective binder is selected from the group consisting of cation exchange resins and ceramic hydroxyapatite, wherein said alpha-emitting thorium isotope is in the form of a 10 complex with a ligand, and wherein said ligand is conjugated to a specific binding moiety.
2) A method as claimed in claim 1 wherein the specific binding moiety is an antibody.
3) A method as claimed in claim 1 or claim 2 wherein said selective binder is in the form of, or is attached to, a solid support or gel support.
4) A method as claimed in 3 wherein said solid or gel support is in the form of, 20 or attached to, least one selected from membranes, resin beads, gel beads, self- assembled lipid structures, microparticles, nanoparticles, powders, crystals, ceramics and polymer structures.
5) A method as claimed in claim 4 wherein self-assembled lipid structures are 25 liposomes.
6) A method as claimed in any one of the preceding claims wherein said solution is contacted with said selective binder by means of flow of said solution through or past said selective binder or through or past a support upon which said 30 selective binder is immobilised.
7) A method as claimed in claim 6 wherein said contacting is by means of a filtration in which said solution flows through or past said selective binder or through or past a support upon which said selective binder is immobilised. 5
8) A method as claimed in claim 6 wherein said filtration further comprises flowing said solution through a sterile filtration membrane.
9) A method as claimed in any one of the preceding claims wherein said contacting takes place for a period of less than 30 minutes.
10) A method as claimed in any one of the preceding claims wherein said contacting takes place for a period of less than 10 minutes.
11) A method as claimed in any one of the preceding claims wherein said 15 contacting takes place for a period of less than 5 minutes or less than 1 minute.
12) A method as claimed in any one of the preceding claims wherein said contacting takes place for a period of no more than 30 seconds. 20
13) A method as claimed in any one of claims 1 to 4 wherein said solution is contacted with said selective binder by means of addition of said selective binder and said solution to a vessel.
14) A method as claimed in claim 13 wherein said vessel is a sealed or partially 25 sealed vessel.
15) A method as claimed in claim 13 or 14 wherein said contacting takes place for 30 minutes or longer. 30
16) A method as claimed in any one of claims 13 to 15 wherein said contacting takes place for 1 hour or longer.
17) A method as claimed in any one of claims 13 to 16 wherein said contacting takes place for 1 day or longer.
18) A kit when used for the formation of a pharmaceutical preparation of at least 5 one alpha-emitting thorium isotope complex, said kit comprising: i) a solution of said at least one alpha-emitting thorium isotope and at least one radium isotope; ii) at least one ligand; 10 ii) a specific binding moiety; iii) at least one selective binder for said at least one radium isotope, wherein said alpha-emitting thorium isotope is complexed or complexable by said ligand which is conjugated or conjugatable to said specific binding moiety and the 15 selective binder is selected from the group consisting of cation exchange resins and ceramic hydroxyapatite.
19) A kit as claimed in claim 18 wherein said solution of said at least one alpha- emitting thorium isotope and at least one radium isotope is present in a first vessel 20 and said ligand conjugated to said specific binding moiety is present in a second vessel.
20) A kit as claimed in claim 19 wherein said first vessel is a vial or syringe. 25
21) A kit as claimed in claim 18 or claim 19 wherein said selective binder is present in the form of at least one filter through which said solution of alpha- emitting thorium isotope can be passed after complexation by said ligand and optionally after conjugation to said specific binding moiety. 30
22) A kit as claimed in claim 21 wherein said at least one filter is a syringe filter.
23) A kit as claimed in any one of claims 18 to 20 wherein said selective binder is present in the form of or attached to at least one solid or gel support.
24) A kit as claimed in claim 23 wherein said selective binder is present in said 5 first vessel.
25) A kit as claimed in any one of claims 18 to 24 wherein said selective binder is arranged to be separated from said solution by the process of administration of said solution.
26) A kit as claimed in claim 25 wherein said solid or gel support is least one selected from membranes, resin beads, gel beads, self-assembled lipid structures, microparticles, nanoparticles, powders, crystals and polymer structures. 15
27) A kit as claimed in claim 26 wherein said self-assembled lipid structures are liposomes.
28) A kit as claimed in any one of claims 18 to 27 additionally comprising a filter and/or an administration device.
29) A kit as claimed in any one of claims 18 to 28 comprising a filter of pore size of no larger than 0.22 m
30) An administration device comprising a solution of at least one alpha-emitting 25 thorium isotope complex and at least one radium isotope, said device further comprising a filter containing at least one selective binder for said radium isotope, wherein the selective binder is selected from the group consisting of cation exchange resins and ceramic hydroxyapatite. 30
31) A device as claimed in claim 30 in the form of a disposable syringe and syringe filter.
32) A kit as claimed in any one of claims 18 to 29 comprising an administration device comprising a solution of at least one complexed alpha-emitting radionuclide and at least one daughter nuclide, said kit further comprising a selective binder for said daughter nuclide in the form of a filter.
33) A method for the formation of an injectable solution of a thorium isotope complex comprising the steps of: a) combining a first solution comprising a dissolved salt of an alpha-emitting thorium isotope and at least one radium isotope with a second solution comprising at 10 least one ligand conjugated to at least one targeting moiety; b) incubating the combined solutions at a suitable temperature for a period to allow complex formation between said ligand and said alpha-emitting thorium isotope whereby to form a solution of at least one alpha-emitting thorium isotope complex; 15 c) contacting said solution of at least one alpha-emitting thorium isotope complex with at least one selective binder for at least one of said radium isotope, wherein the selective binder is selected from the group consisting of cation exchange resins and ceramic hydroxyapatite. d) separating said solution of at least one alpha-emitting thorium isotope 20 complex from said at least one selective binder.
34) A method for the formation of an injectable solution as claimed in claim 33 wherein the suitable temperature in step b) is 0°C to 50°C. 25
35) A method for the formation of an injectable solution as claimed in claim 33 or claim 34 wherein the suitable temperature in step b) is 20°C to 40°C)
36) A method for the formation of an injectable solution as claimed in claim 33 wherein steps c) and d) comprise a method for generating a purified solution as 30 claimed in any one of claims 1 to 17.
37) A method as claimed in any one of claims 1 to 17 and 33 to 36, substantially as herein described with reference to any example thereof and with or without reference to the accompanying drawing. 5
38) A kit as claimed in any one of claims 18 to 29 and 32, substantially as herein described with reference to any example thereof and with or without reference to the accompanying drawing.
39) A device as claimed in claim 30 or 31, substantially as herein described with 10 reference to any example thereof and with or without reference to the accompanying drawing.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1310028.4 | 2013-06-05 | ||
GBGB1310028.4A GB201310028D0 (en) | 2013-06-05 | 2013-06-05 | Pharmaceutical preparation |
PCT/EP2014/061743 WO2014195423A1 (en) | 2013-06-05 | 2014-06-05 | Pharmaceutical preparation |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ714737A NZ714737A (en) | 2021-02-26 |
NZ714737B2 true NZ714737B2 (en) | 2021-05-27 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20220023449A1 (en) | Pharmaceutical preparation | |
AU2012235881B2 (en) | Pharmaceutical preparation | |
US20240091391A1 (en) | Mof for radiotherapy | |
US10729794B2 (en) | Isotope purification method | |
EA008195B1 (en) | Thorium-227 for use in radiotherapy of soft tissue disease | |
CN108601991A (en) | Method of purification | |
NZ714737B2 (en) | Pharmaceutical preparation | |
JP6901498B2 (en) | Isotope preparation method | |
EA040260B1 (en) | PHARMACEUTICAL PREPARATION FOR USE IN ENDORADIONUCLIDE THERAPY | |
WO2024147743A1 (en) | Mofs with beta-emitters for radiotherapy |