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(12) United States Patent (10) Patent N0.: US 7,887,782 B2 Schwarz Et A]

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(12) United States Patent (10) Patent N0.: US 7,887,782 B2 Schwarz Et A] 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 ion 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 chloride 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 radium 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 calcium chloride. 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.
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