NZ743214A - Isotope preparation method - Google Patents
Isotope preparation methodInfo
- Publication number
- NZ743214A NZ743214A NZ743214A NZ74321416A NZ743214A NZ 743214 A NZ743214 A NZ 743214A NZ 743214 A NZ743214 A NZ 743214A NZ 74321416 A NZ74321416 A NZ 74321416A NZ 743214 A NZ743214 A NZ 743214A
- Authority
- NZ
- New Zealand
- Prior art keywords
- exchange resin
- solution
- eluting
- anion exchange
- base anion
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title description 5
- 239000002253 acid Substances 0.000 claims abstract description 93
- 239000000243 solution Substances 0.000 claims abstract description 76
- 229910052500 inorganic mineral Inorganic materials 0.000 claims abstract description 53
- 239000011707 mineral Substances 0.000 claims abstract description 53
- 239000003957 anion exchange resin Substances 0.000 claims abstract description 51
- 239000000203 mixture Substances 0.000 claims abstract description 46
- 239000007864 aqueous solution Substances 0.000 claims abstract description 33
- 238000011068 load Methods 0.000 claims abstract description 27
- 239000003729 cation exchange resin Substances 0.000 claims abstract description 26
- 239000000356 contaminant Substances 0.000 claims abstract description 13
- 239000012062 aqueous buffer Substances 0.000 claims abstract description 5
- QQINRWTZWGJFDB-IGMARMGPSA-N actinium-227 Chemical compound [227Ac] QQINRWTZWGJFDB-IGMARMGPSA-N 0.000 claims description 93
- 239000011347 resin Substances 0.000 claims description 24
- 229920005989 resin Polymers 0.000 claims description 24
- 150000001450 anions Chemical class 0.000 claims description 6
- ZSLUVFAKFWKJRC-FTXFMUIASA-N thorium-227 Chemical compound [227Th] ZSLUVFAKFWKJRC-FTXFMUIASA-N 0.000 abstract description 31
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 5
- 238000000926 separation method Methods 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 14
- 238000004519 manufacturing process Methods 0.000 description 13
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 150000003839 salts Chemical group 0.000 description 11
- 239000011780 sodium chloride Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 230000027455 binding Effects 0.000 description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 9
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 102000004965 antibodies Human genes 0.000 description 8
- 108090001123 antibodies Proteins 0.000 description 8
- 239000003446 ligand Substances 0.000 description 8
- 230000036499 Half live Effects 0.000 description 7
- MYRTYDVEIRVNKP-UHFFFAOYSA-N divinylbenzene Substances C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 7
- 238000003860 storage Methods 0.000 description 7
- 230000001476 alcoholic Effects 0.000 description 6
- 238000005349 anion exchange Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 150000002500 ions Chemical class 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- HCWPIIXVSYCSAN-OIOBTWANSA-N radium-223 Chemical compound [223Ra] HCWPIIXVSYCSAN-OIOBTWANSA-N 0.000 description 6
- 230000008929 regeneration Effects 0.000 description 6
- 238000011069 regeneration method Methods 0.000 description 6
- 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 5
- 201000010099 disease Diseases 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 5
- 230000005262 alpha decay Effects 0.000 description 4
- 210000004027 cells Anatomy 0.000 description 4
- 239000008139 complexing agent Substances 0.000 description 4
- 238000011109 contamination Methods 0.000 description 4
- 230000000875 corresponding Effects 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000002699 waste material Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000004166 bioassay Methods 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000002285 radioactive Effects 0.000 description 3
- 230000005258 radioactive decay Effects 0.000 description 3
- 230000000717 retained Effects 0.000 description 3
- 239000012607 strong cation exchange resin Substances 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 210000004940 Nucleus Anatomy 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229910052770 Uranium Inorganic materials 0.000 description 2
- 239000008351 acetate buffer Substances 0.000 description 2
- QQINRWTZWGJFDB-UHFFFAOYSA-N actinium Chemical compound [Ac] QQINRWTZWGJFDB-UHFFFAOYSA-N 0.000 description 2
- 229910052767 actinium Inorganic materials 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 239000012523 bacterial endotoxin Substances 0.000 description 2
- 230000005255 beta decay Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 230000022534 cell killing Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000003841 chloride salts Chemical class 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- JFALSRSLKYAFGM-UHFFFAOYSA-N uranium(0) Chemical compound [U] JFALSRSLKYAFGM-UHFFFAOYSA-N 0.000 description 2
- 238000010200 validation analysis Methods 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 1
- JHALWMSZGCVVEM-UHFFFAOYSA-N 2-[4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl]acetic acid Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CC1 JHALWMSZGCVVEM-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 210000000988 Bone and Bones Anatomy 0.000 description 1
- 230000035693 Fab Effects 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- GQZXNSPRSGFJLY-UHFFFAOYSA-N Hypophosphorous acid Chemical compound OP=O GQZXNSPRSGFJLY-UHFFFAOYSA-N 0.000 description 1
- 208000003788 Neoplasm Micrometastasis Diseases 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 102000005632 Single-Chain Antibodies Human genes 0.000 description 1
- 108010070144 Single-Chain Antibodies Proteins 0.000 description 1
- 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 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 230000003466 anti-cipated Effects 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 201000009030 carcinoma Diseases 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000001472 cytotoxic Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 230000005251 gamma ray Effects 0.000 description 1
- 230000002390 hyperplastic Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000003211 malignant Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000001613 neoplastic Effects 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000000737 periodic Effects 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000002901 radioactive waste Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- LBDSXVIYZYSRII-IGMARMGPSA-N α-particle Chemical compound [4He+2] LBDSXVIYZYSRII-IGMARMGPSA-N 0.000 description 1
Abstract
The present invention comprises a method for the generation of 227 Th of pharmaceutically tolerable purity comprising i) preparing a generator mixture comprising 227 Ac, 227 Th and 223 Ra; ii) loading said generator mixture onto a strong base anion exchange resin; iii) eluting a mixture of said 223 Ra and 227 Ac from said strong base anion exchange resin using a first mineral acid in an aqueous solution; iv) eluting 227 Th from said strong base anion exchange resin using a second mineral acid in an aqueous solution whereby to generate a first 227 Th solution containing contaminant 223 Ra and 227 Ac; v) loading the first 227 Th solution onto a strong acid cation exchange resin; vi) eluting at least a part of the contaminant 223 Ra and 227 Ac from said strong acid cation exchange resin using a third mineral acid in aqueous solution; and vii) eluting the 227 Th from said strong acid cation exchange resin using a first aqueous buffer solution to provide a second 227 Th solution. Purified thorium-227 of pharmaceutical purity and a pharmaceutical composition comprising the same are also provided. Ra and 227 Ac from said strong base anion exchange resin using a first mineral acid in an aqueous solution; iv) eluting 227 Th from said strong base anion exchange resin using a second mineral acid in an aqueous solution whereby to generate a first 227 Th solution containing contaminant 223 Ra and 227 Ac; v) loading the first 227 Th solution onto a strong acid cation exchange resin; vi) eluting at least a part of the contaminant 223 Ra and 227 Ac from said strong acid cation exchange resin using a third mineral acid in aqueous solution; and vii) eluting the 227 Th from said strong acid cation exchange resin using a first aqueous buffer solution to provide a second 227 Th solution. Purified thorium-227 of pharmaceutical purity and a pharmaceutical composition comprising the same are also provided.
Description
Isotope ation Method
Field of the Invention
The present invention relates to the preparation of thorium-227 (227Th), such as thorium-227
chloride, for ceutical use. In particular, the present ion relates to s for
potentially commercial-scale production ofthorium-227 having a purity acceptable for
pharmaceutical administration to human subjects.
Background to the Invention
Specific cell killing can be essential for the sful treatment of a variety of diseases in
mammalian subjects. Typical examples of this are in the treatment of malignant diseases such as
sarcomas and carcinomas. However the selective elimination of certain cell types can also play a
key role in the treatment of many other diseases, especially logical, hyperplastic and/or
other neoplastic diseases.
The most common methods of selective treatment are currently surgery, herapy and
external beam irradiation. Targeted endo-radionuclide therapy is, however, a promising and
developing area with the ial to deliver highly cytotoxic radiation to unwanted cell types.
The most common forms of harmaceutical currently authorised for use in humans employ
beta-emitting and/or gamma-emitting radionuclides. There has, however, been a recent surge in
interest in the use of alpha-emitting radionuclides in therapy because of their potential for more
specific cell killing. One alpha-emitting nuclide in particular, radium-223 (223Ra) has proven
remarkably effective, particularly for the treatment of diseases ated with the bone and
bone—surface. onal alpha-emitters are also being actively investigated and one isotope of
particular interest is the alpha-emitter thorium-227.
The radiation range of typical alpha emitters in physiological surroundings is generally less than
100 micrometers, the equivalent of only a few cell diameters. This makes these nuclei well
suited for the treatment oftumours, including micrometastases, because little of the radiated
energy will pass beyond the target cells and thus damage to surrounding healthy tissue might be
minimised (see Feinendegen et al., Radiat Res 148: 195-201 (1997)). In contrast, a beta particle
has a range of 1 mm or more in water (see Wilbur, Antibody Immunocon Radiopharm 4: 85-96
(1991)).
_ 2 _
The energy of alpha—particle radiation is high ed to beta particles, gamma rays and X-
rays, typically being 5-8 MeV, or 5 to 10 times that of a beta particle and 20 or more times the
energy of a gamma ray. Thus, this deposition of a large amount of energy over a very short
distance gives a-radiation an exceptionally high linear energy transfer (LET), high relative
ical efficacy (RBE) and low oxygen enhancement ratio (OER) compared to gamma and
beta radiation (see Hall, "Radiobiology for the ogist", Fifth edition, Lippincott Williams &
Wilkins, Philadelphia PA, USA, 2000). These properties explain the exceptional cytotoxicity of
alpha emitting radionuclides and also impose stringent demands on the level of purity required
where an isotope is to be administered internally. This is especially the case where any
contaminants may also be alpha-emitters, and most particularly where long ife alpha
emitters may be t, since these can potentially be retained in the body, causing significant
damage over an extended period of time.
The radioactive decay chain from 227Ac, generates 227Th and then leads to 223Ra and further
radioactive isotopes. The first three isotopes in this chain are shown below. The table shows the
element, molecular weight (Mw), decay mode (mode) and Half-life (in years (y) or days (d)) for
227Th and the es preceding and following it. Preparation of 227Th can begin from 227Ac,
which is itself found only in traces in uranium ores, being part of the natural decay chain
originating at 235U. One ton of uranium ore contains about a tenth of a gram of actinium and
thus although 227Ac is found naturally, it is more commonly made by the n irradiation of
226Ra in a nuclear reactor.
M"‘rElement
Mode
Half-life
It can be seen from this illustration that 227Ac, with a half-life of over 20 years, is a very
dangerous potential inant with regard to preparing 227Th from the above decay chain for
pharmaceutical use. In particular, although 227Ac itself is a beta-emitter, its long half-life means
that even very low activities represent a significant lifetime radiation exposure, and furthermore,
once it decays, the resulting daughter nuclei (i.e. 227Th) generate a further 5 alpha-decays and 2
beta-decays before ng stable 207Pb. These are illustrated in the table below:
227Th 223Ra 219Rn 215PO 21 le 21 lBi 207T1 207Pb
18-7d 11.4d 4.0s 1.8ms 36.1m 2.2m 4.8m stable
6.15
or-energy 5.64 6.75 7.39 6.55
/MeV
B-energy 1.37 1.42
It is evident from the above two decay tables that more than 35 MeV of energy is ted by
one 227Ac decay chain, representing a significant toxicity risk for essentially the entire lifetime of
any human subject administered with 227Ac. As a result, the content of 227Ac contaminant in
227Th for pharmaceutical use is recommended to be d to 0.002% A0227 (i.e. no more than
200 Bq 227Ac in 1 MBq 227Th). Thus for practical purposes, a method which is to provide 227Th
for pharmaceutical use should preferably provide a purity of better than 200 Bq 227Ac in 1 MBq
227“, preferably better than 100 or better than 50 Bq 227Ac in 1 MBq 227Th. Most le
methods will aim to provide a purity of 20 Bq 227Ac in 1 MBq 227Th or better (e.g. 1 to 20 Bq
227Ac in 1 MBq 227Th), preferably less than 20 Bq 227Ac in 1 MBq 227Th, more preferably less
than 10 Bq 227Ac in 1 MBq 227Th to ensure that the safety limit is always adhered to.
_ 4 _
Previously known preparations for 227Th have generally been for small quantities and/or not
tested for purity to pharmaceutical standards. In WO2004/09l668, for example, 227Th was
ed by anion exchange from a single column and used for experimental purposes without
validation of the purity.
No previously known method for the generation of 227Th addresses issues such as yield of 227Th,
speed of the purification process, automation, minimising ofwasted isotopes and corresponding
production ofradioactive waste or any similar issues ated with al and/or commercial-
scale production. Furthermore, few methods attempt to measure and te the purity with
respect to 227Ac contamination.
In view of the above, there is a erable need for an improved method by which 227Th may
be generated and purified for pharmaceutical use at a purity appropriate for direct ion into
human subjects. It would be a considerable advantage if the method were to provide a high yield
of 227Th, a low loss of 227Ac parent isotopes and/or utilise widely available separation media. It
would be flirther advantageous if the method was rapid, was viable for relatively large
(clinical/commercial scale) radioactive samples, included only a minimum number of manual
handling steps, and/or was suitable for tion.
Brief ption of the Invention
The present inventors have now established that by tion of a 227Ac/227Th generator
(containing also 223Ra and its daughter isotopes) using a strong base anion exchange resin,
followed by separation utilising a strong acid cation exchange resin, a 227Th solution of very high
radiochemical purity may be produced while providing a number of desirable advantages in the
method. It is preferable that the 227Th is generated as, or converted to, at least one
pharmaceutically acceptable salt form. Thorium-227 chloride is preferred in this t.
In a first aspect, the present invention therefore provides a method for the generation of 227Th of
pharmaceutically tolerable purity comprising
i) preparing a generator e comprising 227Ac, 227Th and 223Ra;
ii) loading said generator mixture onto a strong base anion exchange resin;
_ 5 _
iii) eluting a mixture of said 223Ra and 227Ac from said strong base anion exchange
resin using a first mineral acid in an aqueous solution;
iv) eluting 227Th from said strong base anion exchange resin using a second mineral
acid in an aqueous solution whereby to generate a first 227Th solution containing
contaminant 223Ra and 227Ac;
V) loading the first 227Th solution onto a strong acid cation exchange resin;
vi) optionally eluting the contaminant 223Ra and 227Ac from said strong acid cation
exchange resin using a third mineral acid in aqueous solution; and
vii) eluting the 227Th from said strong acid cation exchange resin using a first aqueous
buffer solution to provide a second 227Th solution.
The process will optionally and preferably also include a second anion exchange tion
comprising the steps of:
viii) loading the second 227Th solution eluted in step vii) (or the 227Th rom) onto
a second strong base anion exchange resin;
ix) optionally eluting any ing 223Ra and 227Ac from said second strong base
anion exchange resin using a fourth mineral acid in an aqueous solution; and
x) eluting 227Th from said second strong base anion exchange resin using a fifth
mineral acid in an aqueous solution.
Steps vi) and ix) of the above methods relate to al steps. In these methods, contaminant
223Ra and/or 227Ac will preferably be eluted and may be recycled or disposed of as waste. In an
ative embodiment, however, steps Vi) and/or ix) may be omitted and contaminant 223Ra
and/or 227Ac retained on the resin when the 227Th is .
The process will lly include recovery of the 227Ac eluted in step iii) and may additionally
comprise the step of:
y) storing the 227Ac eluted in step iii) for a period sufficient to allow ingrowth of
227Th by radioactive decay, whereby to regenerate a generator mixture comprising
227Ac 227Th and 223Ra.
After ingrowth step y), the generator mixture may be re—used to generate a further batch of 227Th,
and a single 227Ac sample will ably be used repeatedly (e. g. more than 10 times, such as 50
to 500 times). Evidently, where a useful amount of 227Ac is eluted in step vi), this may also be
red and returned to the generator.
W0 2017/118591
_ 6 _
In a further aspect, the present invention provides a solution of 227Th comprising less than 20 Bq
227Ac per 1MBq 227Th, preferably a solution of 227Th comprising less than 20 Bq 227Ac in l MBq
227Th (e.g. l to 20 Bq 227Ac in l MBq 227Th), preferably less than 200 Bq 227Ac in l MBq 227Th,
more preferably less than 10 Bq 227Ac in l MBq 227Th. Such a on is optionally formed or
formable by any ofthe methods herein described, and is preferably formed or le by the
preferred s herein described. Correspondingly, the methods of the ion are
preferably for the formation of a solution of 227Th comprising less than 10 Bq 227Ac in 1 MBq
227Th (e.g. l to 20 Bq 227Ac in l MBq 22ml), preferably less than 20 Bq 227Ac in l MBq 227Th,
more preferably less than 15 Bq 227Ac in l MBq 227Th.
Detailed Description of the Invention
A very significant aspect ofthe present invention is the ability for the 227Ac of the generator
e to be stripped from the separation resin and regenerated with high efficiency. In
particular, the present method relates to a process for long-term clinical/commercial use, and as
such should be capable of allowing the ed use of the generator mixture for many years.
The useful life of the generator mixture will certainly be of the order of the half-life of the
ating 227Ac isotope, and thus potentially several tens of years (e.g. 10 to 50 years). There
are several issues which result from this which have not been addressed in any of the 227Th
production or purification systems previously bed.
A first issue arising from the potentially long clinical/commercial lifetime of the generator
mixture is the stability of its storage environment. Specifically, any material exposed to the
generator mixture is ially receiving more than a million beta decays per second from the
227Ac, plus around the same number of alpha decays per second from the ed 227Th and up
to the same number of alpha decays again from the in—growing 223Ra and from each of its alpha-
emitting daughter nuclides. This is very much more concentrated than any 227Th
generator/separation system previously ed in any detail.
Alpha irradiation in particular is highly ionising and so over the course of a number of years, the
1013 or more alpha-decays per year to which the surroundings of the generator will be exposed is
very likely to cause significant damage to any organic components in long term proximity. As a
result, it will be desirable that the originating 227Ac is not retained on the column but is re—
_ 7 _
generated so that a new column may be utilised as often as necessary or ient (e. g. at each
separation).
Periodic replacement of the separation materials not only avoids loss of the generator mixture
but also guarantees that the purity of the product will be as high after several decades as it was
when the system was first employed since the retention properties of the separation medium will
not be degraded. The tor system will thus be recovered from the separation material after
every use and may be stored as a solution or evaporated to dryness (or to a concentrated solution)
for storage.
Where a generator mixture is recovered from a separation medium it is important that this
happen to a very high degree. The loss of only 0.1% ofthe generator isotope would be entirely
insignificant in any laboratory or testing environment, but for a al/commercial system is an
important factor. Assuming that the generator is used every 3rd week, then regeneration of the
227Ac occurs 17 times a year. At a 0.1% loss each time, this would result in a total loss of 12%
ofthe original 227Ac over a 10 year . This, ed with the natural decay loss due to the
21 year ife of the isotope increases the total reduction in activity from 73% (of the original
activity) due to natural decay down to 61% including the regeneration loss. At 21.8 years, this
effect is still more dramatic, taking the 50% activity expected after one half-life down to
approximately 35% and evidently reducing the useful commercial life of the system by this
stage.
In the present method, the regeneration of the generator mixture has been shown to lose only not
more than 0.05 % of the al 227Ac at each regeneration cycle. Preferably this will be
achievable by recovering 227Ac at only one point in the process (step iii)). If necessary, 227Ac
recovered at other steps may be included, however.
The regeneration step iii) will typically have the following features:
a) The first mineral acid may be any mineral acid or e thereof, but will preferably
comprise nitric acid. The first l acid may se, consist essentially of or
consist of an acid selected from H2804, HN03 and es thereof and will preferably
comprise, consist essentially of or consist ofHN03 in aqueous so lution.
_ 8 _
b) The first mineral acid may be used at a concentration of 0.1 to 12M, preferably 1 to 12M,
more ably 6 to 10M (e. g. around 8M).
With regard to optional but highly preferable step y), the regeneration of the 227Th will begin by
natural radioactive decay as soon as the existing 227Ac is eluted in step iii). It is preferable to
allow sufficient time for significant ingrowth of 227Th before the generator mixture is again
separated, and the period which is suitable will depend upon the quantity of 227Ac t and the
quantity of 227Th which it is desired to separate in each batch. Eventually, the level of activity of
each isotope in the decay chain will equilibrate and fiirther storage will achieve little or no
enhancement in 227Th t. Thus to minimise the separation effort required, longer storage
will be used while to maximise the recovery of useful 227Th, frequent tion will be
undertaken. Typically the e time will be commensurate with the half-life of the 227Th (~19
days) and so storage step y) may be undertaken for around 5 to 100 days, preferably around 10 to
50 days. Frequent separation (e.g. daily) may be undertaken if it is desired to maximise the yield
of separated 227Th from the tor. The skilled worker will have no difficulty ing a
suitable ingrowth period based upon the characteristics of each particular system.
The present invention provides a method for the production of 227Th at a purity le for use in
endo-radionuclide therapy. A number of preferred features of the system are indicated below,
each of which may be used in ation with any other feature where technically viable,
unless indicated otherwise.
The methods and all corresponding embodiments of the invention will preferably be carried out
on a clinical/commercial scale and thus will be capable and suitable for use at this scale while
maintaining all of the other characteristics described herein as appropriate (such as radionuclear
purity, optionally methanol content etc). A commercial scale will typically be a scale r
than that required for the treatment of a single subject, and may be, for example, the purification
ofmore than 10, preferably more than 25 and most preferably more than 45 typical doses of
227Th. Evidently, a typical dose will depend upon the ation, but anticipated typical dose
may be from 0.5 to 200 MBq or 0.5 to 100 MBq, preferably 1 to 75 MBq, most preferably
around 2 to 50 MBq.
Step i) of the method of the invention relates to preparing a generator mixture sing 227Ac,
227Th and 223Ra. Such a mixture will inherently form by the gradual decay of a sample of 227Ac,
2016/082835
_ 9 _
but for use in the invention will preferably also have one or more of the following features, either
individually or in any viable combination:
a) a 227Ac radioactivity of at least 500 MBq (e.g. 500 MBq to 50 GBq), preferably at least
lGBq, more preferably at least 2.5 GBq;
b) a 223Ra radioactivity of at least 25 MBq or at least 100 MBq (e.g. 100 MBq to 50 GBq),
ably at least 800 MBq, more preferably at least 1.5 GBq;
c) a volume ofno more than 100 ml (e.g. 0.1 to 10 ml), preferably no more than 50 ml,
more preferably no more than 10 ml.
d) a 227Th radioactivity of at least 25 MBq, at least 50MBq or at least 100 MBq (e. g. 100
MBq to 50 GBq), preferably at least 800 MBq, more preferably at least 1.5 GBq;
The generator may be stored as a solution or in dry form. Where the generator is stored in
on, this will typically be evaporated and re-dissolved during loading step ii).
Step ii) of the method of the invention relates to the loading of the generator e onto a
strong base anion ge resin. This step and the entities referred to therein may have the
following preferable features, either individually or in any viable combination, and optionally in
any viable combination with any of the features of the other steps as described herein:
a) The strong base anion exchange resin may be a polystyrene/divinyl benzene copolymer
based resin, preferably containing 1—95 %; divinyl benzene
b) The strong base anion exchange resin may be an R-N+M€3 type (type I) resin or an R-
N+Me2CH2CH20H (Type II) resin, preferably a type I resin;
c) The strong base anion exchange resin may have an exchange ty of 0.2 to 5 meq/ml,
preferably 0.6 to 3 meq/ml, most preferably 1 to 1.5 meq/ml (e.g. around 1.2 meq/ml);
d) The strong base anion exchange resin may have a particle size grading of 10 to 800 mesh,
preferably 50 to 600 mesh, more preferably 100 to 500 mesh (e.g. around 200 to 400
mesh).
e) The strong base anion exchange resin may be used in the form of a column.
f) The volume of resin used (e.g. when packed in a column) may be 10 ml or less, (e.g. 0.1
to 10 ml), preferably 5 ml or less, more ably 0.1 to l (e.g. around 0.25 ml).
g) The strong base anion exchange resin may be DOWEX 1X8 (e.g. DOWEX AG 1X8) or
equivalent resin and may optionally and ably have a 200-400 mesh size.
h) The generator may be evaporated to dryness and re—dissolved in a loading solution.
i) The loading on may comprise a mineral acid, preferably HNOg.
_ 10 _
j) The mineral acid in the loading solution may be at a tration of 0.1 to 5M,
preferably 0.5 to 3M, more ably 1 to 2 M.
k) The loading solution may comprise at least one alcoholic solvent.
1) The alcoholic solvent may comprise or consist of an alcohol selected from methanol,
ethanol, n-propanol, i-propanol and mixtures thereof, preferably methanol.
m) The alcoholic solvent may be an aqueous alcohol or mixture thereof at a concentration of
to 95%, preferably 50 to 90%, more preferably 75 to 88% (e.g. around 82%).
Step iii) of the method of the invention relates to eluting a mixture of said 223Ra and 227Ac from
the strong base anion exchange resin using a first mineral acid in aqueous solution. This step
and the entities referred to therein may have the following preferable features, either individually
or in any viable combination, and optionally in any viable combination with any of the features
ofthe other steps as described :
a) The first mineral acid may be an acid selected from H2SO4 or HN03 ably HNO3.
b) The first mineral acid may be used at a concentration of 1 to 12M, such as 3 to 10 M or 5
to 9 M, preferably 7 to 8.5 M (e.g. around 8M), particularly where the first mineral acid
is HNO3.
c) The s solution may be free or substantially free of any l. In particular, the
aqueous solution may contain less than 1% (e. g. 0 to 1%) of any alcohol selected from
methanol, l and isopropanol, particularly methanol;
d) The mixture of said 223Ra and 227Ac may be eluted from said strong base anion exchange
resin using 1 to 200 column volumes of the first mineral acid in aqueous solution.
Preferably the amount will be 5 to 100 column volumes (e.g. around 50 column
Step iv) of the method of the invention relates to eluting 227Th from said strong base anion
exchange resin using a second mineral acid in an aqueous solution whereby to generate a first
227Th solution (typically containing low levels of contaminant 223Ra and . This step and
the es referred to therein may have the following preferable features, either individually or
in any viable combination, and ally in any viable combination with any of the features of
the other steps as described herein:
a) The second mineral acid may be an acid selected from H2SO4 and HCl, preferably HCl.
_ 11 _
b) The second mineral acid may be used at a concentration of 0.1 to 8M, preferably 0.5 to
5M, more ably 2 to 4M, most preferably around 3M. This applies particularly
Where the second mineral acid is HCl.
c) The first 227Th solution may be eluted from said strong base anion exchange resin using 1
to 200 column volumes of the second mineral acid in aqueous solution. Preferably the
amount will be 5 to 100 column volumes (e.g. around 50 column volumes).
d) The aqueous solution may be free or substantially free of other solvents such as alcoholic
solvents.
e) The first 227Th solution will preferably have a contamination level ofno more than 100
(e.g. l to 100) Bq 227Ac per lMBq 227Th, more preferably no more than 45 Bq 227Ac per
lMBq 227Th (e.g. no more than 30) and most ably no more than 10 Bq 227Ac per
1MBq 227Th.
f) The steps ii) to iv) of loading the generator mixture onto the base anion exchange resin,
eluting a e of said 223Ra and 227Ac and a first 227Th solution may provide a
separation ratio of 227Th to 227Ac of at least 10,000:l (e.g. 10,0002] to 500,000:1),
ably at least 20,000:1, more preferably at least 30,000: 1.
g) The 227Th may be eluted from said strong base anion exchange resin in uncomplexed
form, such as in the form of a simple salt in solution (e. g. as the salt of the second
mineral acid, such as the chloride salt).
h) Optionally, the use of complexing agents such as DTPA may be avoided, and in one
ment all solutions used in steps ii to iv) are substantially free of xing
agents, such as DTPA.
Step v) of the method of the invention relates to loading the first 227Th solution eluted from the
anion exchange resin in step iv) onto a strong acid cation exchange resin. This step and the
entities referred to n may have the following preferable features, either individually or in
any viable combination, and optionally in any viable combination with any of the features of the
other steps as described herein:
a) The strong acid cation exchange resin may be a yrene/divinyl benzene copolymer
based resin, preferably containing 1-95 % DVB;
b) The strong acid cation exchange resin may be an SOgH type.
c) The strong acid cation exchange resin may have an ge capacity of 0.2 to 5 meq/ml,
preferably 0.6 to 3 meq/ml, most preferably 1 to 2 meq/ml (e. g. around 1.7 meq/ml);
_ 12 _
d) The strong acid cation exchange resin may have a particle size grading of 10 to 800
mesh, preferably 50 to 600 mesh, more preferably 100 to 500 mesh (e.g. around 200 to
400 mesh).
The strong acid cation exchange resin may be used in the form of a .
The volume of resin used (e.g. when packed in a column) may be 5 ml or less, (e.g. 0.1 to
ml), preferably 2 ml or less, more preferably 0.1 to 1 ml (e. g. around 0.15 ml).
g) The strong acid cation exchange resin may be DOWEX 50WX8 or equivalent resin and
may optionally and preferably have a 200-400 mesh size.
h) The strong acid cation exchange resin may be pre-treated with a mineral acid such as
HNO3.
The first 227Th solution eluted from the anion exchange resin in step iv) may be loaded
ly onto the strong cation exchange resin.
j) The first 227Th solution eluted from the anion exchange resin in step iV) may be mixed
with one or more mineral acids, such as HN03 prior to loading onto the strong cation
exchange resin.
k) The first 227Th solution eluted from the anion exchange resin in step iV) may be fully or
lly evaporated and optionally redissolved in a mineral acid such as HN03 prior to
loading onto the strong cation exchange resin.
Step Vi) of the method of the invention is optional but preferable and relates to eluting at least a
part of the contaminant 223Ra and 227Ac from said strong acid cation exchange resin using a third
mineral acid in aqueous solution. This step and the entities ed to therein may have the
ing preferable features, either individually or in any viable combination, and optionally in
any viable combination with any of the features of the other steps as described herein:
a) The third mineral acid may be an acid selected from H2804, HN03 and HCl, preferably
HNO3;
b) The third mineral acid may be used at a concentration of 0.1 to 8 M, preferably 0.5 to
6M, more preferably 1.0 to 5M, most preferably 2 to M (e.g. around 2.5 M). This applies
particularly where the second mineral acid is HNO3;
The aqueous solution preferably does not comprise any cant amount (e.g. less than
0.1% v/v) of any alcohol ed from ol, ethanol and isopropanol. Preferably
the aqueous solution is free or substantially free ofmethanol;
d) The 223Ra and 227Ac may be eluted from said strong acid cation exchange resin using 1 to
200 column volumes of the third mineral acid in aqueous on. Preferably the amount
_ 13 _
will be 1 to 100 column volumes, more preferably 10 to 25, especially around 20 column
V0lumes.
Step vii) of the method of the invention relates to eluting 227Th fiom said strong acid cation
exchange resin using a first aqueous buffer on whereby to generate a second 227Th solution.
This step and the entities referred to therein may have the following preferable features, either
individually or in any viable combination, and ally in any viable ation with any of
the features of the other steps as described herein:
a) The first buffer on may have a pH of between 2.5 and 6, preferably between 3.5 and
b) The first buffer solution may comprise at last one acid and a salt of that acid, each in
concentrations of n 0.1 and 5M, preferably between 0.5 and 3M.
c) The first buffer solution may comprise at least one organic acid and a salt of that organic
acid, such as a metal or ammonium salt (e. g. a pharmaceutically tolerable salt such as
sodium, potassium, calcium, and/or ammonium salt).
d) The first buffer on may comprise or consist ially of or consist of an acetate
buffer. Preferably the acetate buffer will comprise acetic acid and ammonium acetate,
most preferably each at concentrations as ted herein (e.g. between 0.5 and 3M).
e) The second 227Th solution will preferably have a contamination level ofno more than 100
(e.g. 0.0001 to 100 or 0.0001 to 40) Bq 227Ac per 1MBq 227Th, more preferably no more
than 50 Bq 227Ac per 1MBq 227Th and most preferably no more than 40 Bq 227Ac per
1MBq 227Th;
f) The second 227Th on will preferably have a methanol content of not more than 100
ppm per dose of 227Th, preferably no more than 50mg, and more preferably no more than
ppm per dose (where a dose of 227Th is as described herein, such as l to 75 MBq).
g) The steps of loading the first 227Th solution onto the acid cation exchange resin and
eluting the second 227Th solution may provide a separation ratio of227Th to 227Ac of at
least 10:1 (e.g. 10:1 to 10,00021), preferably at least 100:1, more preferably at least
500: 1.
h) The 227Th may be eluted from said strong acid cation exchange resin in uncomplexed
form, such as in the form of a simple salt in solution.
i) The use of complexing agents such as DTPA may be avoided, and in one embodiment all
solutions used in step iv) to vi) are substantially free of complexing agents.
_ 14 _
In addition to the two-column separation method indicated above, further purification of the
second 227Th solution is achieved by an additional, optional but highly preferably purification
step. This ation step will typically take place ly after step vii) and typically
comprises:
Viii) loading the second 227Th solution eluted in step Vii) onto a second strong base
anion exchange resin;
ix) eluting 223Ra and/or 227Ac from said second strong base anion exchange resin
using a fourth mineral acid in an aqueous solution; and
x) g 227Th from said second strong base anion exchange resin using a fifth
mineral acid in an aqueous solution to provide a third 227Th solution.
Step Viii) of the method of the invention s to the loading of the second 227Th solution eluted
in step Vii) onto a second strong base anion exchange resin. This step and the entities referred to
n may have the following preferable features, either individually or in any Viable
combination, and optionally in any Viable combination with any of the features of the other steps
as described herein:
a) The second strong base anion exchange resin may be a yrene/divinyl benzene
copolymer based resin, preferably containing 1-95 %; divinyl benzene
b) The second strong base anion exchange resin may be an R-NlMeg type (type I) resin or
an R—N+M€2CH2CH20H (Type II) resin, preferably a type I resin;
c) The strong base anion exchange resin may have an exchange capacity of 0.2 to 5 meq/ml,
preferably 0.6 to 3 meq/ml, most preferably 1 to 1.5 meq/ml (e.g. around 1.2 meq/ml);
d) The second strong base anion exchange resin may have a particle size grading of 10 to
800 mesh, preferably 50 to 600 mesh, more ably 100 to 500 mesh (e.g. around 200
to 400 mesh).
e) The second strong base anion exchange resin may be the same as the first strong base
anion exchange resin.
f) The second strong base anion exchange resin may be used in the form of a column.
f) The volume of resin used (e.g. when packed in a column) may be 10 ml or less, (e.g. 0.5
to 10 ml), preferably 5 ml or less, more preferably 0.5 to 2 ml (e.g. around 0.25 ml).
W0 20171118591
_ 15 _
g) The second strong base anion exchange resin may be DOWEX 1X8 (e. g. DOWEX AG
1X8) or equivalent resin and may optionally and preferably have a 0 mesh size.
h) The second 227Th solution may be acidified prior to g on the second strong base
anion exchange resin.
i) The second 227Th solution may be acidified with a l acid, preferably HNOs.
j) The second 227Th solution may be acidified with a l acid at a concentration of 5 to
24M, preferably 10 to 22M, more preferably 14 to 18 M.
k) The second 227Th solution may be acidified with a mineral acid free or substantially free
of any alcoholic solvent (e.g. less than 1%).
Step ix) of the method of the invention is optional but preferable and relates to eluting 223Ra
and/or 227Ac from the second strong base anion ge resin using a fourth mineral acid in
aqueous on. This step and the entities referred to n may have the following preferable
features, either individually or in any viable combination, and optionally in any viable
combination with any ofthe features of the other steps as described herein:
a) The fourth mineral acid may be an acid selected from H2804 or HN03 preferably HNOs.
b) The first mineral acid may be used at a concentration of l to 12M, such as 3 to 10 M or 5
to 9 M, preferably 7 to 8.5 M (e.g. around 8M), particularly where the fourth mineral acid
is HNO3.
c) The aqueous solution may be free or substantially free of any alcohol. In particular, the
aqueous solution may contain less than 1% (e. g. 0 to 1%) of any alcohol selected from
ol, ethanol and isopropanol, particularly methanol;
d) The 223Ra and/or 227Ac may be eluted from said second strong base anion exchange resin
using 1 to 200 column volumes of the first mineral acid in aqueous solution. Preferably
the amount will be 5 to 100 column volumes (e.g. around 50 column volumes).
Step x) of the method of the invention relates to eluting 227Th from said second strong base anion
exchange resin using a fifth mineral acid in an aqueous solution whereby to generate a third
227Th solution. This step and the entities referred to therein may have the following preferable
features, either individually or in any viable combination, and ally in any viable
combination with any ofthe features of the other steps as described herein:
a) The fifth mineral acid may be an acid selected from H2804 and HCl, preferably HCl.
_ l6 _
b) The fifth mineral acid may be used at a concentration of 0.1 to 8M, preferably 0.5 to 5M,
more preferably 2 to 4M, most preferably around 3M. This applies particularly where the
second mineral acid is HCl.
c) The third 227Th solution may be eluted from said second strong base anion exchange resin
using 1 to 200 column s of the second mineral acid in aqueous solution.
Preferably the amount will be 1 to 100 column volumes (e.g. around 50 column
volumes).
d) The aqueous solution may be free or substantially free of other solvents such as alcoholic
solvents (e.g. less than 1%).
e) The third 227Th solution will preferably have a contamination level ofno more than 100
(e.g. l to 50) Bq 227Ac per lOOMBq 227Th, more preferably no more than 45 Bq 227Ac per
lOOMBq 227Th (e.g. no more than 30) and most preferably no more than 5 Bq 227Ac per
lOOMBq 227Th. A purity of 1 Bq 227Ac per lOOMBq 227Th or around 0.5 Bq 227AC per
lOOMBq 227Th may most desirably be achieved in the third solution;
f) The steps Viii) to X) of loading the second 227Th solution onto the second base anion
exchange resin, eluting 223Ra and/or 227Ac and eluting a third 227Th solution may provide
a separation ratio of 227Ac to 227Th of at least 5:1 000 000 (e.g. 5:1 000 000 to 5:10 000
000 ), preferably at least 5:50 000 000, more preferably at least 5: 100 000 000.
g) The 227Th may be eluted from said strong base anion exchange resin in uncomplexed
form, such as in the form of a simple salt in solution (e. g. as the salt of the fifth l
acid such as the chloride salt).
h) Optionally, the use of complexing agents such as DTPA may be avoided, and in one
embodiment all solutions used in steps viii) to x) are substantially free of xing
agents, such as DTPA.
In addition to the above steps, the methods of the invention and all corresponding aspects may
comprise additional steps, for example to te the purity of the 227Th for pharmaceutical
purposes, to exchange counter-ions, concentrate or dilute the solution or to control factors such
as pH and ionic strengths. Each of these steps thus forms an optional but preferable additional
step in the various aspects of the present invention.
It is able that the methods of the present invention e for a high yield of the 227Th
product. This is not only because of the desire to avoid wastage or a le product but also
because all lost radioactive al forms radioactive waste which must then be disposed of
_ 17 _
safely. Thus, in one embodiment, at least 70% of the 227Th loaded in step ii) is eluted in step
vii). Similarly, where steps viii) to x) are carried out, at least 70% of the 227Th loaded in step ii)
is eluted in step x). These will preferably be at least 75%, more preferably at least 78% and most
preferably at least 80% yields.
In the final eluted solutions (second or third) and in the 227Th product (optionally formed or
formable by the methods ofthe invention), the 227Th may comprise less than 10 Bq 227Ac per
100MBq 227Th. This will preferably be less than 5 Bq 227Ac per 100MBq 227Th.
Following production by the methods bed herein, the second or third 227Th on may
undergo any or all of the following optional steps for validation and preparation for distribution:
xi) Visual check of product, appearance.
xii) Dispensing of a dose into a suitable vessel such as a glass Vial.
xiii) Evaporation of solvent from the solution.
ixx) Sealing, labelling and/or ing for ort.
xx) Quality control assay/sampling, e.g. to validate for assay of 227Th t, radionuclidic
identity (227Th), radionuclidic purity, especially to confirm an acceptable level of 227Ac
content and 223Ra and/or to test for bacterial endotoxins.
In a corresponding aspect of the present invention, there is additionally ed pharmaceutical
composition comprising the 227Th and optionally at least one pharmaceutically acceptable
diluent. Such a pharmaceutical composition may comprise 227Th of a purity indicated herein,
optionally formed or formable by the methods of the present invention. Suitable carriers and
diluents including water for injection, pH adjusters and buffers, salts (e. g. NaCl) and other
suitable als will be well known to those of skill in the art.
The pharmaceutical ition will comprise the 227Th as bed here, typically as an ion,
such as the Th4+ ion. Such compositions may comprise a simple salt of the 227Th of the invention
but will more preferably se a complex of the 227Th of the invention with at least one
ligand, such as an octadentate 3,2- hydroxypyridinone (3,2-HOPO) ligand, a DOTA
(tetraazacyclododecane-tetraacetic acid, such as l,4,7,10-tetraazacyclododecane-l,4,7,10-
tetraacetic acid) ligand and/or a NOTA (triazacyclononane—triacetic acid, such as 1,4,7-
triazacyclononane-N,N',N"-triacetic acid) ligand. Suitable ligands are disclosed in
W0201 1/09861 1, which is hereby incorporated by reference, particularly with reference to
_ 18 _
formulae I to IX disclosed therein, which represent typical suitable HOPO s. Such ligands
may be used in lves or conjugated to at least one targeting moiety, such as an antibody.
Antibodies, antibody constructs, fragments of antibodies (e.g. FAB or F(AB)’2 nts or any
fragment comprising at least one n binding region(s)), constructs of fragments (e.g. single
chain antibodies) or a mixture thereof are particularly preferred. The pharmaceutical
compositions ofthe invention may thus comprise Th4+ ion of 227Th of pharmaceutical purity as
disclosed herein, complexed to a conjugate of a ligand, such as a 3,2- hydroxypyridinone (3,2-
HOPO) ligand, and at least one antibody, antibody fragment or antibody construct, plus
optionally pharmaceutically acceptable carriers and/or diluents.
As used herein, the term “comprising” is given an open meaning such that additional
components may optionally be present (thus disclosing both “open” and “closed” forms). In
contrast the term “consisting of” is given a closed g only, such that (to an effective,
measurable and/or absolute ), only those substances indicated ding any optional
substances as appropriate) will be present. Correspondingly, a e or substance described as
sting essentially of” will in essence consist of the stated components such that any
additional components do not affect the essential behaviour to any significant . Such
mixtures may, for example, contain less than 5% (e.g. 0 to 5%) of other components, preferably
less than 1% and more preferably less than 0.25% of other components. Similarly, where a term
is given as “substantially”, d”, “about” or “approximately” a given value, this allows for
the exact value given, and independently allows for a small variability, particularly where this
does not affect the substance of the property described. Such ility may be, for example
::5% (e.g. ::0.001% to 5%), preferably ::l%, more preferably ::0.25%. All % herein are given by
weight unless otherwise indicated.
The invention will now be illustrated further by reference to the following miting examples
and the attached s, in which:
Figure 1 Shows a typical manufacturing process and control, comprising an embodiment of
the method of the present invention including several optional steps. In Figure l
the following steps are included:
(1) Storage of the generator for in—growth of 227“.
(2) Evaporation of the generator to dryness prior to loading
_ 19 _
(3) Dissolution of the dry generator in methanolic nitric acid and loading onto a first anion
ge .
(4) Elution of 223Ra and 227Ac using nitric acid eration of 227Ac for the generator) and
n of a first 227Th solution with HCl.
(5) Loading of the first 227Th solution onto a cation exchange column, n of 227Ac and
223Ra with nitric acid (to waste) and elution of a second 227Th solution with acetate
(6) Acidification of the second 227Th solution with trated nitric acid and loading onto
a second anion exchange column.
(7) Elution of 227Ac and 223Ra with nitric acid (to waste) and elution of a third 227Th solution
With HCl.
(8) Dispensing of 227Th does into glass vials
(9) Evaporation of the third 227Th solution to leave 227Th chloride
(10) Quality control of the 227Th chloride drug substance.
Example 1 — Outline of Typical Process
The thorium-227 is generated by natural decay of actinium—227. The separation and purification
to form the radionuclide component thorium-227 chloride, is performed in a dedicated
manufacturing line for thorium-227 chloride.
The starting material in the manufacturing process of the thorium-227 chloride is actinium—227
in nitric acid solution (A-generator).
A-generators are stored for in—growth of thorium-227 in—between manufacturing of thorium-227
chloride batches, and are used repeatedly for the manufacturing of thorium—227 chloride. The
amount of actinium—227 in the A-generator and the in—growth time for the A-generator used, will
determine the ctivity level in the resulting thorium-227 chloride batch. Solid phase
extraction (SPE) on anion and cation ge resins are applied to separate thorium-227 from
its predecessor nuclide actinium—227 and to further remove radium-223 and radium-223
daughters.
The manufacture ofthorium-227 consists of the following steps:
1) Storage for wth of thorium-227
2) Evaporation to Dryness
3) Dissolution
4) Thorium-227 Separation
) Thorium-227 Purification #1
6) Acidification of Thorium-227 eluate from Purification #1
7) Thorium-227 Purification #2
8) Dispensing of thorium-227 eluate
9) Evaporation by heat
) Testing and Release
The separation step on the first anion exchange SPE cartridge (step 4) is based on the formation
ofnegatively charged complexes of thorium-227 with the eluent solution and the trapping of
these negatively charged complexes on the first anion ge SPE cartridge, whereas
actinium-227 and radium-223 pass through the resin under the conditions applied and are
regenerated back into the A—generator. The thorium—227 eluate from the anion exchange SPE
cartridge is loaded on to a cation ge SPE cartridge (second cartridge — step 5). This is
followed by further ation on an additional anion exchange SPE cartridge (third cartridge —
step 7).
The second and third SPE cartridges are used mainly to remove residual s of actinium
from the first thorium-227 eluate which passed the first purification cartridge. For these
separation and purification steps, raw material solutions and premixed raw material solutions
with ed s are used to minimize the number of handling steps and in—process
controls. During the s these solutions are applied, trapped and , as in solid phase
extraction, with no selection of fractions at any of the three separation/purification steps. The
final purified thorium—227 eluate is dispensed into Vials and evaporated by heat to form a film of
thorium-227 chloride.
Example 2 — Batch Purification
Data from one 227Th batch of 110 MBq Vials is provided in the below table.
Test Batch no.
A503001
Appearance No e liquid
Radionuclidic ty (RNI) Complies
(thorium-227)
uclidic purity (RNP) Not detected,
Actiniurn—227 LT 0.001%
Radionuclidic purity (RNP) LT 0.2%
Radium-223
Assay thorium-227 110 MBq/Vial
Bacterial endotoxins LT 5 EU/Vial
Date of manufacture 201509
Actiniurn—227 used 3800 MBq
Ingrowth 75%
Thorium-227 produced 2280 MBq
Throiiurn—227 yield 80%
Batch size 18 Vials
EU = Endotoxin Unit; LT= Less Than
WO 18591
Claims (5)
1) A method for the generation of 227Th ofpharmaceutically tolerable purity comprising preparing a tor mixture comprising 227Ac, 227Th and 223Ra; ii) loading said generator mixture onto a strong base anion exchange resin; iii) eluting a mixture of said 223Ra and 227Ac from said strong base anion exchange resin using a first mineral acid in an aqueous solution; iV) eluting 227Th from said strong base anion exchange resin using a second mineral acid in an aqueous solution whereby to generate a first 227Th solution containing inant 223Ra and 227Ac; loading the first 227Th solution onto a strong acid cation exchange resin; Vi) eluting at least a part of the contaminant 223Ra and 227Ac from said strong acid cation exchange resin using a third mineral acid in aqueous solution; and vii) eluting the 227Th from said strong acid cation exchange resin using a first aqueous buffer solution to provide a second 227Th solution.
2) The method of claim 1 additionally comprising the steps of: viii) loading the second 227Th solution eluted in step Vii) onto a second strong base anion exchange resin; ix) eluting 223Ra and/or 227Ac from said second strong base anion ge resin using a fourth mineral acid in an aqueous solution; and eluting 227Th from said second strong base anion exchange resin using a fifth mineral acid in an aqueous solution to provide a third 227Th solution.
3) The method as claimed in claim 1 or claim 2 wherein at least 99.9% of the 227Ac loaded onto the resin in step ii) is eluted in step iii).
4) The method as claimed in any of claims 1 to 3 wherein at least 70% of the 227Th loaded onto the resin in step ii) is eluted in step Vii) and/or in step x).
5) The method of any of claims 1 to 4 onally comprising the step of: W0 20171118591
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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GB1600154.7 | 2016-01-05 |
Publications (1)
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NZ743214A true NZ743214A (en) |
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