ISOTOPE PREPARATION METHOD

Abstract

The present invention comprises a method for the generation of .sup.227Th of pharmaceutically tolerable purity comprising i) preparing a generator mixture comprising .sup.227Ac, .sup.227Th and .sup.223Ra; ii) loading said generator mixture onto a strong base anion exchange resin; iii) eluting a mixture of said .sup.223Ra and .sup.227Ac from said strong base anion exchange resin using a first mineral acid in an aqueous solution; iv) eluting .sup.227Th from said strong base anion exchange resin using a second mineral acid in an aqueous solution whereby to generate a first .sup.227Th solution containing contaminant .sup.223Ra and .sup.227Ac; v) loading the first .sup.227Th solution onto a strong acid cation exchange resin; vi) eluting at least a part of the contaminant .sup.223Ra and .sup.227Ac from said strong acid cation exchange resin using a third mineral acid in aqueous solution; and vii) eluting the .sup.227Th from said strong acid cation exchange resin using a first aqueous buffer solution to provide a second .sup.227Th solution. Purified thorium-227 of pharmaceutical purity and a pharmaceutical composition comprising the same are also provided.

Claims

1) A method for the generation of .sup.227Th of pharmaceutically tolerable purity comprising the steps of: i) preparing a generator mixture comprising .sup.227Ac, .sup.227Th and .sup.223Ra; ii) loading said generator mixture onto a strong base anion exchange resin; iii) eluting a mixture of said .sup.223Ra and .sup.227Ac from said strong base anion exchange resin using a first mineral acid in an aqueous solution; iv) eluting .sup.227Th from said strong base anion exchange resin using a second mineral acid in an aqueous solution whereby to generate a first .sup.227Th solution containing contaminant .sup.223Ra and .sup.227Ac; v) loading the first .sup.227Th solution onto a strong acid cation exchange resin; vi) eluting at least a part of the contaminant .sup.223Ra and .sup.227Ac from said strong acid cation exchange resin using a third mineral acid in aqueous solution; and vii) eluting the .sup.227Th from said strong acid cation exchange resin using a first aqueous buffer solution to provide a second .sup.227Th solution.

2) The method of claim 1 additionally comprising the steps of: viii) loading the second .sup.227Th solution eluted in step vii) onto a second strong base anion exchange resin; ix) eluting .sup.223Ra and/or .sup.227Ac from said second strong base anion exchange resin using a fourth mineral acid in an aqueous solution; and x) eluting .sup.227Th from said second strong base anion exchange resin using a fifth mineral acid in an aqueous solution to provide a third .sup.227Th solution.

3) The method as claimed in claim 1 wherein at least 99.9% of the .sup.227Ac loaded onto the resin in step ii) is eluted in step iii).

4) The method as claimed in claim 1 wherein at least 70% of the .sup.227Th loaded onto the resin in step ii) is eluted in step vii).

5) The method of claim 1 additionally comprising the step of: y) storing the .sup.227Ac eluted in step iii) for a period sufficient to allow ingrowth of .sup.227Th by radioactive decay, whereby to regenerate a generator mixture comprising .sup.227Ac, .sup.227Th and .sup.223Ra.

6) The method of claim 1 wherein the method purifies sufficient .sup.227Th for more than 25 doses.

7) The method of claim 1 wherein a .sup.227Th radioactivity of at least 50 MBq is employed in step i).

8) The method of claim 2 wherein the strong base anion exchange resin and the second strong base anion exchange resin comprise the same base moieties.

9) The method of claim 1 wherein the strong base anion exchange resin is a polystyrene/divinyl benzene copolymer based resin, preferably containing 1-95% DVB.

10) The method of claim 1 wherein the strong base anion exchange resin and optionally the second strong base anion exchange resin is independently an RN.sup.+Me.sub.3 type (type I) resin or an RN.sup.+Me.sub.2CH.sub.2CH.sub.2OH (Type II) resin.

11) The method of claim 1 wherein the first mineral acid is an acid selected from H.sub.2SO.sub.4, HNO.sub.3 and mixtures thereof and preferably comprises HNO.sub.3.

12) The method of claim 1 wherein the first mineral acid is used at a concentration of 1 to 12 M.

13) The method of claim 1 wherein the second mineral acid is an acid selected from H.sub.2SO.sub.4 and HCl, preferably HCl.

14) The method of claim 1 wherein the second mineral acid is used at a concentration of 0.1 to 8 M.

15) The method of claim 1 wherein the strong acid cation exchange resin is a polystyrene/divinyl benzene copolymer based resin, preferably containing 1-95 DVB.

16) The method of claim 1 wherein the strong acid cation exchange resin is of SO.sub.3H type.

17) The method of claim 1 wherein the third mineral acid is an acid selected from H.sub.2SO.sub.4, HNO.sub.3 and HCl, preferably HNO.sub.3.

18) The method of claim 1 wherein the third mineral acid is used at a concentration of 0.1 to 8 M.

19) The method of claim 1 wherein the buffer solution has a pH of between 2.5 and 6.

20) The method of claim 1 wherein the buffer solution is an acetate buffer.

21) The method of claim 1 wherein the buffer solution does not comprise any significant amount of any alcohol selected from methanol, ethanol and isopropanol.

22) The method of claim 1 wherein the second .sup.227Th solution has a contamination level of no more than 200 Bq .sup.227Ac per 1 MBq .sup.227Th.

23) The method of claim 1 wherein said generator mixture is dissolved in an alcoholic aqueous solution comprising a loading mineral acid prior to loading said generator mixture onto a strong base anion exchange resin in step ii).

24) The method of claim 2 wherein step viii) comprises acidifying the second .sup.227Th solution prior to loading onto said second strong base resin.

25) The method of claim 2 wherein said fourth mineral acid is an acid selected from H.sub.2SO.sub.4, HNO.sub.3 and HCl, preferably HNO.sub.3.

26) The method of claim 2 wherein said fourth mineral acid is used at a concentration of 1 to 12 M.

27) The method of claim 1 wherein the fifth mineral acid is an acid selected from H.sub.2SO.sub.4 and HCl, preferably HCl.

28) The method of claim 1 wherein the fifth mineral acid is used at a concentration of 0.1 to 8 M.

29) .sup.227Th comprising less than 5 Bq .sup.227Ac per 100 MBq .sup.227Th.

30) .sup.227Th produced by a method of claim 1 and which comprises less than 5 Bq .sup.227Ac per 100 MBq .sup.227Th.

31) A pharmaceutical composition comprising the .sup.227Th as claimed in claim 29 and optionally at least one pharmaceutically acceptable diluent.

Description

[0146] The invention will now be illustrated further by reference to the following non-limiting examples and the attached figures, in which:

[0147] FIG. 1 Shows a typical manufacturing process and control, comprising an embodiment of the method of the present invention including several optional steps. In FIG. 1 the following steps are included: [0148] (1) Storage of the generator for in-growth of .sup.227Th. [0149] (2) Evaporation of the generator to dryness prior to loading [0150] (3) Dissolution of the dry generator in methanolic nitric acid and loading onto a first anion exchange column. [0151] (4) Elution of .sup.223Ra and .sup.227Ac using nitric acid (regeneration of .sup.227Ac for the generator) and elution of a first .sup.227Th solution with HCl. [0152] (5) Loading of the first .sup.227Th solution onto a cation exchange column, elution of .sup.227Ac and .sup.223Ra with nitric acid (to waste) and elution of a second .sup.227Th solution with acetate buffer.

[0153] (6) Acidification of the second .sup.227Th solution with concentrated nitric acid and loading onto a second anion exchange column.

[0154] (7) Elution of .sup.227Ac and .sup.223Ra with nitric acid (to waste) and elution of a third .sup.227Th solution with HCl.

[0155] (8) Dispensing of .sup.227Th does into glass vials

[0156] (9) Evaporation of the third .sup.227Th solution to leave .sup.227Th chloride

[0157] (10) Quality control of the .sup.227Th chloride drug substance.

EXAMPLES

Example 1Outline of Typical Process

[0158] 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.

[0159] The starting material in the manufacturing process of the thorium-227 chloride is actinium-227 in nitric acid solution (A-generator).

[0160] 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 radioactivity level in the resulting thorium-227 chloride batch. Solid phase extraction (SPE) on anion and cation exchange resins are applied to separate thorium-227 from its predecessor nuclide actinium-227 and to further remove radium-223 and radium-223 daughters.

[0161] The manufacture of thorium-227 consists of the following steps:

[0162] 1) Storage for in-growth of thorium-227

[0163] 2) Evaporation to Dryness

[0164] 3) Dissolution

[0165] 4) Thorium-227 Separation

[0166] 5) Thorium-227 Purification #1

[0167] 6) Acidification of Thorium-227 eluate from Purification #1

[0168] 7) Thorium-227 Purification #2

[0169] 8) Dispensing of thorium-227 eluate

[0170] 9) Evaporation by heat

[0171] 10) Testing and Release

[0172] The separation step on the first anion exchange SPE cartridge (step 4) is based on the formation of negatively charged complexes of thorium-227 with the eluent solution and the trapping of these negatively charged complexes on the first anion exchange 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 exchange SPE cartridge (second cartridgestep 5). This is followed by further purification on an additional anion exchange SPE cartridge (third cartridgestep 7).

[0173] The second and third SPE cartridges are used mainly to remove residual amounts 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 specified volumes are used to minimize the number of handling steps and in-process controls. During the process these solutions are applied, trapped and eluted, 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 2Batch Purification

[0174] Data from one .sup.227Th batch of 110 MBq vials is provided in the below table.

TABLE-US-00002 Batch no. Test A503001 Appearance No visible liquid Radionuclidic identity (RNI) Complies (thorium-227) Radionuclidic purity (RNP) Not detected, Actinium-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 2015 Mar. 9 Actinium-227 used 3800 MBq Ingrowth 75% Thorium-227 produced 2280 MBq Throiium-227 yield 80% Batch size 18 vials EU = Endotoxin Unit; LT = Less Than