US007887782B2

(12) United States Patent (10) Patent N0.: US 7,887,782 B2 Schwarz et a]. (45) Date of Patent: Feb. 15, 2011

(54) RADIOTHERAPEUTIC FORMULATIONS 4,859,431 A * 8/1989 Ehrhardt ...... 250/432 PD CONTAINING 224RA AND A METHOD FOR 5,457,323 A 10/1995 Geerlings THEIR PRODUCTION 5,854,968 A * 12/1998 Horwitz et a1...... 423/2

(75) Inventors: UWe SchWarz, Salzgitter (DE); Rolf Daniels, Salzgitter (DE) OTHER PUBLICATIONS Delikan, O. Health Phys. 1978, 35, 21-24.* (73) Assignee: Altmann Therapie GmbH & Co., Narbutt et al. (Appl. Radiat. lsot. 1998, 49, 89-91).* Salzgitter (DE) Orhan Delikan; Preparation of 224Ra for Therapy of Ankylosing Sp0ndylitis*; Health Physics Vol. 35 (July) pp. 21-24 Pergamon ( * ) Notice: Subject to any disclaimer, the term of this Press Ltd., 1978. patent is extended or adjusted under 35 Radioaktives Arzneimittel; Gebrauchsinformation und Fachinforma U.S.C. 154(b) by 671 days. tion; pp. 1-6, N0 English translation. Alberding, A. et al., “Wirksamkeit und Vertraglichkeit von (21) Appl. No.: 10/362,049 Radiumchlorid in der Behandlung der ankylo sierenden Spondylitis,” Z Rheumatol 2006, 65:245-251. (22) PCT Filed: Aug. 7, 2001 * cited by examiner (86) PCT No.: PCT/EP01/09121 Primary ExamineriMichael G Hartley Assistant ExamineriMelissa Perreira § 371 (0X1)’ (74) Attorney, Agent, or FirmiSam K. Tahmassebi; (2), (4) Date: Jul. 9, 2003 TechLaW LLP (87) PCT Pub. No.: WO02/15943 (57) ABSTRACT PCT Pub. Date: Feb. 28, 2002 The invention relates to novel radiotherapeutic formulations (65) Prior Publication Data containing 224Ra and methods for their production. The US 2004/0028606 A1 Feb. 12, 2004 invention discloses, in particular, radiotherapeutic formula tions comprising at least one salt of the isotope 224Ra, Which (30) Foreign Application Priority Data are characterized in that the content of other radionuclides, in particular, the respective content of certain longeval radionu Aug. 21, 2000 (DE) ...... 100 40 771 clides does not exceed a speci?c numerical value in mBq/g. The invention also relates to a method for producing radio (51) Int. Cl. therapeutic formulations of this type, Which is characterized A61K 51/00 (2006.01) by the following steps: after at least one centrifugation of an A61M 36/14 (2006.01) aqueous suspension of the compound 228Th(OH)4 and (52) U.S. Cl...... 424/1.11; 424/161 optionally after the resuspension of the raW sediment (58) Field of Classi?cation Search ...... 424/l.1l, obtained in said centrifugation, the precipitated 228Th(OH)4 424/ 1.61 sediment is separated. The supernatant solution of a 224Ra salt See application ?le for complete search history. that has been obtained is subsequently subjected to sterile ?ltration and is then made up to the required dose. Finally, (56) References Cited said solution is sterilized and bottled in ampoules in a manner U.S. PATENT DOCUMENTS knoWn per se.

3,993,538 A * 11/1976 Lebowitz et a1...... 376/195 4,663,129 A 5/1987 Atcher et al. 20 Claims, No Drawings US 7,887,782 B2 1 2 RADIOTHERAPEUTIC FORMULATIONS above described defects of the formulations of the prior art by CONTAINING 224RA AND A METHOD FOR a degree of purity Which is higher than in knoWn formula THEIR PRODUCTION tions, especially by a much loWer content of the above described long-lived nuclides 228Th, 226Ra, 228Ra or 227Ac. SPECIFICATION It has unexpectedly been found that this object is achieved by a novel therapeutic formulation Which contains the 224Ra This invention relates to novel, 224Ra-containing, radio isotope. therapeutic formulations and processes for their production. This formulation as claimed in the invention comprises at Ankylosing spondylitis (BechtereW’s disease) is a clinical least one salt of the isotope 224Ra and is characterized in that picture Which has been knoWn for a long time and Which is the content of other radionuclides, especially the content of accompanied by degenerative ossi?cation processes of the the radionuclides cited beloW, does not exceed the indicated spinal column and residual spinal curvature. The use of for numerical value for each: mulations based on salts of the radioisotope 224Ra for treat ment of this disease is prior art Which likeWise has been knoWn for decades. Thus Orhan Delikan in the literature citation Health Physics, Vol. 35 (July), pp. 21-24, Pergamon Maximum Radionuclide: concentration (mBq/ g) Press Ltd., 1978 describes that the limitation of the content of contaminating radioisotopes, such as for example the espe 228Ra 60 cially long-lived, alpha particle-emitting nuclides 228Th, 228Th 30 210% 30 226Ra, 228Ra or 227Ac, acquires decisive importance for the 20 226Ra 30 success or failure of one such therapy. These contaminants are 238U 20 easily incorporated by the patient into the bone substance and 231m 60 accumulated there as a result of their pronounced structure 227AC 10 chemical isomorphism With the isotope 224Ra; this Works 232U 50. against the actual radiotherapy or is at least associated With 25 considerable side effects Which burden the patient. Since According to one preferred embodiment the formulation as production of the therapeutic isotope 224Ra proceeding from claimed in the invention is characterized in that the content of the isotope 228Th takes place With emission of an alpha par other radionuclides, especially the content of the radionu ticle (4He), both prior puri?cation of the parent material 228Th clides Which are listed beloW, does not exceed the indicated Which has been used and also subsequent separation of the 30 numerical value for each: resulting product isotope 224Ra as thoroughly as possible from the reaction mixture With respect to the desired produc tion of a therapeutic agent Which is as effective as possible Without undesirable peripheral effects and side effects Maximum Radionuclide: concentration (mBq/ g) acquire great importance. 35 According to the prior art the parent material 228Th is 228Ra 2 6 puri?ed by exchange chromatographic separation of the 228Th 3.6 210% 23 aforementioned disruptive isotopes. Then precipitation of the 226Ra 29 228Th as a poorly soluble hydroxide and Washing of the sedi 238U 19 ment take place. After the daughter isotope 224Ra is neWly 40 231m 55 formed over the course of roughly 5 to 10 days, then extrac 227A0 9.3 tion of the 228Th Which is present as the hydroxide in an 232U 20. aqueous solution takes place using a calcium solu tion; after being repeated several times this leads to a more or According to one especially preferred embodiment the less pure aqueous (22“Ra)RaCl2 solution. 45 formulation as claimed in the invention is characteriZed in The tWo above described puri?cation steps are hoWever that the content of other radionuclides, especially the content described as extremely unsatisfactorily by specialists. Thus of the radionuclides Which are listed beloW, does not exceed the aforementioned literature citation from Delikan in the the indicated numerical value for each: paragraph betWeen pages 22 and 23 remarks that 228Th extraction is “very critical” since here different boundary 50 conditions and process parameters Which are dif?cult to adjust must be Watched at the same time; adherence to them Maximum subsequently makes it dif?cult or impossible to effectively Radionuclide: concentration (mBq/ g) carry out the puri?cation step even for the best trained and 228Ra 22 equipped individual skilled in the art. On page 23, left col 55 228Th 3.3 210% 17 umn, at the start of the ?rst complete paragraph it is moreover 226Ra 26 noted that 224Ra-containing formulations Which have been 238U 15 produced using one such process of the prior art generally 231m 55 contain a still measurable residual content of the aforemen 227A0 8.4 tioned, long-lived radionuclides in spite of all puri?cation 60 steps; this can be attributed to the fact that the salts of these nuclides are not completely insoluble and thus in part even According to another preferred embodiment the formula after extraction of the 228Th remain in the therapeutically tion as claimed in the invention is characteriZed in that the salt used 224Ra formulation. of the radionuclide 224Ra is chloride (224RaCl2). Thus, according to the prior art there is a demand for a 65 Moreover, the formulation as claimed in the invention pref radiotherapeutic formulation for treatment of ankylosing erably comprises an isotonic solution, especially preferably spondylitis (:BechtereW’s disease) Which a priori avoids the of a calcium salt, especially . US 7,887,782 B2 3 4 The formulation as claimed in the invention is produced tion of the 232U(t 10:72 years) took place; its Was captured as using a process Which is characterized in that the process the chloride, dried and stored in order to obtain 2281b. steps (a) to (d) Which are described below are carried out: This material Was dissolved in HNO3 and passed via an (a) At least one-time centrifuging of an aqueous suspension of anion exchange column. Under these conditions thorium is the compound 228Th(OH)4, optionally after resuspension bound as [Th(NO3)6]2_ on the column and the daughters of of the resulting raW sediment; 2281b and 232U Were Washed from the column using HNO3. (b) Separation of the 228Th(OH)4 sediment Which has been Then 228Th Was Washed from the column With 0.5 m HCl. precipitated after step (a); After determining the concentration, this solution Was trans (c) Sterile ?ltration and subsequent bottling of the desired ferred to glass vessels and dried. dose of the supernatant solution of the 224Ra salt Which Was Production of [228Th] Thorium Hydroxide obtained after step (b); 1 . The [22 8Th] thorium chloride is taken up using the carrier (d) Sterilization of the bottling obtained after step (c) in the solution [23 2Th] thorium nitrate pentahydrate in hydrochloric conventional manner. acid 10%, Ph. Eur.*) in component steps in the primary con One preferred embodiment of the process as claimed in the tainer and transferred into a 50 ml centrifuge tube. invention is characterized in that the centrifuging in step (a) is 2. The insoluble thorium hydroxide is precipitated from carried out tWice and the resulting precipitate is resuspended this solution With ammonia solution (26%). Calcium chloride afterwards using an isotonic aqueous solution, especially solution is added to 30 ml and centrifuging is done at 2000 g preferably of a calcium salt, especially a 1.14% by Weight for 10 minutes. The addition of [232Th] thorium nitrate pen CaCl2 solution. tahydrate as the carrier in step 1 guarantees the formation of 20 Another especially preferred embodiment of the process as relatively large amounts of precipitate Which can be quanti claimed in the invention is characterized in that centrifuging tatively separated by centrifuging, and minimizes adsorption is carried out in step (a) With a rotational speed corresponding effects of 228Th. to a centrifugal acceleration of 2000 g for 10 minutes. 3. The supernatant is carefully suctioned through a glass suction ?lter. The residue is mixed With calcium chloride Another preferred embodiment of the process as claimed in 25 the invention is characterized in that the separation in step (b) solution 1.14% and after stirring With a magnetic stirrer, is carried out by suction and ?ltration. centrifuged again. This Washing step is repeated once more in Another preferred embodiment of the process as claimed in order to completely remove traces of unsedimentable thorium the invention is characterized in that sterile ?ltration in step hydroxide Which may be present. During the last suction the entire supernatant is removed as much as possible. (c) is carried out using a knoWn sterile material, especially 30 preferably using a material based on a ?uorine-containing 4. The raW sediment Which has been obtained in this man organic service polymer or an optionally modi?ed and/or ner is dried. derivatized polysaccharide. 5. The dried raW sediment is resuspended in calcium chlo One especially preferred embodiment of the process as ride solution 1.14% and stored in a closed centrifuge tube. claimed in the invention is characterized in that the sterile 35 2. Production of [224Ra] Radium Chloride ?lter material is cellulose, cellulose acetate or polytetra?uo rethylene, especially preferably cellulose acetate. Production of [224Ra] radium chloride takes place in 4 One preferred embodiment of the process as claimed in the stages. Stages 1-3 are carried out in a gastight box With lead invention is characterized in that the sterile ?lter material has shielding and remote control. The inlet air is ?ltered sterile by a pore size in the range from roughly 0.01 micron to 10 40 a ?lter of suspended matter of class S. The required articles microns, especially preferably in the range from roughly 0.2 can be placed in the box via airlocks. micron to 5 microns and especially roughly 0.2 microns. Another preferred embodiment of the process as claimed in Stage 1 Extraction and Centrifuging the invention is characterized in that the sterilization step (d) The soluble [224Ra] radium chloride is desorbed With cal is carried out using a conventional autoclave, especially pref 45 cium chloride solution from the insoluble [228Th] thorium erably at a temperature of roughly 1210 C. for roughly 20 hydroxide and separated by centrifuging. minutes. This step is repeated several times. The supematants are Another preferred embodiment of the process as claimed in WithdraWn after each centrifuging and then combined into the the invention is characterized in that the therapeutic salt of the batch stock solution. The production suspension is resus radionuclide 224Ra is radium chloride (224RaCl2). 50 pended and stored. This invention is described in greater detail in the folloWing Stage 2 Filling of Injection Vials With Doses text sections using the corresponding representative embodi To determine the [224Ra] radium chloride concentration a ments. radioactivity check measurement of an aliquot of the batch stock solution is taken. EMBODIMENTS 55 Based on the determined activity concentration the inj ec tion vials are ?lled With the batch stock solution and accord 1. Production of [228Th] Thorium Hydroxide ingly calcium chloride solution (1 . 14%) using a dual syringe dilutor With sterile syringe end ?lters. If ?lling is done for Production of 228Th several calibration times on the same day, the amount of the 60 batch stock solution to be added is changed according to the Production of 2281b takes place proceeding from 231 Pa by decay of the radium-224 (T 1 /2 p hys:3.66 days) and the amount the 231P(n y) 232Pa reaction. The 232 Pa Which has been of calcium chloride solution is increased to make 1.1 ml. The formed in this reaction decays ?rst into 232U and then into vials are then closed and sealed. 228Th. For production, the daughters of protactinium pentox ide Were removed from it, the protactinium pentoxide Was 65 Stage 3 Sterilization sealed in quartz vials and irradiated in a reactor. After a decay The preparation is sterilized at 121 ° C. for 20 minutes in a time of a feW Weeks ion exchange chromatographic separa laboratory autoclave. US 7,887,782 B2 5 6 Stage 4 Labelling of the Outer Containers and Packaging (e) Resuspending the 228Th(OH)4 using an aqueous solu After sterilization, the vials Which Were already labelled tion comprising 1.14% by Weight CaCl2 and at least before ?lling are removed from the production box and pack one-time centrifuging the resulting aqueous suspension; aged. and The invention claimed is: (f) Sterile ?ltration and subsequent bottling of the desired 1. A radiotherapeutic formulation comprising at least one dose of the supernatant solution of the centrifugation salt of the isotope 224Ra, Wherein the content of radionuclides step in step (e); listed beloW does not exceed the indicated numerical value for Wherein the content of 228Th in the formulation does not each: exceed 3.6 mBq/ g, and Wherein the content of 227Ac in the formulation does not exceed 9.3 mBq/g. 6. The process of claim 5, Wherein centrifuging is carried out in step (e) With a rotational speed corresponding to a Maximum Radionuclide: concentration (mBq/g) centrifugal acceleration of 2000 g for 10 minutes. 7. The process of claim 5, Wherein sterile ?ltration in step 228Ra 2 6 (f) is carried out using a knoWn sterile ?lter material. 228Th 3.6 210% 23 8. The process of claim 7, Wherein the sterile ?lter material 226Ra 29 is cellulose, cellulose acetate or polytetra?uorethylene. 238U 19 9. The process of claim 7, Wherein the sterile ?lter material 231m 55 has a pore size in the range from roughly 0.01 micron to 10 227m 9.3 20 232U 20. microns. 10. The process of claim 5, further comprising the step of sterilization of the bottled dose obtained after step (f) using a 2. The radiotherapeutic formulation of claim 1, Wherein the conventional autoclave. content of radionuclides listed beloW does not exceed the 11. The process of claim 5, Wherein the therapeutic salt of indicated numerical value for each: 25 radionuclide 224Ra is radium chloride (224RaCl2). 12. A method of treating ankylosing spondylitis (Bech tereW’ s disease) comprising administering the radiotherapeu Maximum tic formulation of claim 1 to a patient in need of such a Radionuclide: concentration (mBq/g) treatment. 30 13. The radiotherapeutic formulation of claim 2, Wherein 228Ra 22 228Th 3.3 the salt of the radionuclide 224Ra is radium chloride 210% 17 (224RaCl2). 226Ra 2 6 14. The radiotherapeutic formulation of claim 2, Wherein 238U 15 the formulation comprises an isotonic. 231m 55 35 227m 8.4 15. The radiotherapeutic formulation of claim 3, Wherein the formulation comprises an isotonic. 16. The process of claim 7, Wherein the sterile ?lter mate 3. The radiotherapeutic formulation of claim 1, Wherein the rial is based on a ?uorine-containing organic service polymer or an optionally modi?ed and/or derivatized polysaccharide. salt of the radionuclide 224Ra is radium chloride (224RaCl2). 40 4. The radiotherapeutic formulation of claim 1, Wherein the 17. The process of claim 8, Wherein the sterile ?lter mate formulation comprises an isotonic. rial is cellulose acetate. 5. Process for producing a radiotherapeutic formulation 18. The process of claim 9, Wherein the sterile ?lter mate comprising at least one salt of the isotope 224Ra, Wherein the rial has a pore size in the range from roughly 0.2 micron to 5 process comprises the steps of: 45 microns. (a) Obtaining 228Th from 232U; 19. The process of claim 18, Wherein the sterile ?lter mate (b) Binding the 228Th of step (a) as the anion [228Th(NO3) rial has a pore size of roughly 0.2 microns. 6]2 on an anion exchange column; 20. The process of claim 10, Wherein the sterilization step (c) Washing the bound 228Th of step (b) from the anion (d) is carried out at a temperature of roughly 1210 C. for exchange column using a solution of HCl: 50 roughly 20 minutes. (d) Precipitating the resulting 228Th of step (c) as 228Th