I 1111111111111111 1111111111 111111111111111 111111111111111 lll111111111111111
`US010596276B2
`
`c12> United States Patent
`de Palo et al.
`
`(IO) Patent No.: US 10,596,276 B2
`(45) Date of Patent:
`*Mar. 24, 2020
`
`(54) STABLE, CONC • NTRATED RADIONUCUDE
`COMPLEX SOLUTIO NS
`
`(7 I) Applicant: Advanced Accelerator Applications
`(Ita ly) Sri, Pozzilli (IT)
`
`(72)
`
`Inventors: Francesco de Palo, lvrea (IT)" Lorenza
`Fugazza, Ivrea (IT); Donato Barbato,
`Ivrea (IT); Ma urizio Ma riani, lvrea
`(IT)· Daniela Chicco, Albiano d'Jvrea
`(IT); Giovanni Tesoriere, Noicattaro
`(IT); Clementina Brambati , Turin (IT)
`
`EP
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`FOREIGN PATENT DO UMENTS
`
`0515313 Bl
`199701579
`2
`200210192 A2
`2008009444 A I
`2013.167130 Al
`2015063746 Al
`2015171792 . I
`2016207732 Al
`2018074918 Al
`2018081860 Al
`
`8/2000
`1/ 1997
`2/2002
`l/2008
`IJ/20.13
`5/2015
`11/2015
`12/2016
`4/2018
`512018
`
`OTIIER PUBLICATIONS
`
`(73) Assignee: ADVANCED ACCELE RATOR
`APPLICATIONS (ITALY) S. R.L.
`Pozzilli (Jsemia) (JT)
`
`( *) Notke:
`
`Subject to any djsclaimer. the term of this
`patent is extended or adjusted under 35
`. 154(b) by O days .
`U.S .
`
`This patent is subject to a tem1inal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 16/175,261
`
`(22) Filed:
`
`Oct. 30, 2018
`
`(65)
`
`Prior PubUcati on Data
`us 2020/0030464 1
`
`Jan. 30, 2020
`
`Related U.S. AppUeation Data
`
`(63) Continuation-in-part of application No. 16/140,962,
`filed on Sep. 25 2018, which is a continuation-in-part
`of application No. l 6/045,484, filed on Jul. 25, 2018.
`
`(5 1)
`
`(52)
`
`(58)
`
`(56)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2019.01)
`
`lnt. Cl.
`A61K 51/00
`A61M 36114
`A61K 51/04
`C22H 59/0fJ
`A61K 33124
`U.S. CI.
`CPC ....... ..... A61K 51/048 (2013.01); A61K 33/24
`(2013.01)- C22H 59/00 (2013.01); A6JK
`51/0482 (2013.01)
`
`Field of Classification Search
`None
`See application file for complete search hlstory.
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5/ 1998
`5,753,627 A
`5.776,894 A
`7/ 1998
`5,804,157 A
`9/ 1998
`11/1998
`5,830,431 A
`9/2000
`6,123,916 A
`6,183 ,721 Bl
`2/2001
`6.277,3 56 B1
`8/2001
`2007/0269375 Al• 11/2007
`
`Albert et al.
`Albert ct al .
`Srinivasan et al .
`Srinivasan et al.
`Krenning et al.
`Albert et al.
`Albert et al.
`hen .................. .. A61K 51 /088
`424/ 1.69
`
`De Blois et al. (Appl. Radiat. Tsolop. 2014, 85, 28-33).•
`Of Singh et al. (lnd. J. Nucl. Med. 2011 , 26, 135-138)."'
`RCM meeting (Developmenl and preclinical evaluation of thera(cid:173)
`peutic radiopharmaceulicals based on 177Lu- and 90Y-labelled
`monoclonal antibodies and peptides: Slip Republic of Macedonia
`Oct. L-5, 2012)!
`Breeman et al., Optimising onditions for RadiohLbelling ofDOTA(cid:173)
`peptides with 90Y, I l.l ln and 177Lu al High Specific Activities, Eur
`J Nucl Med Mo! Imaging. (2003), 30. 917-920.
`Breeman ct al., Overview of Development and Formulation of
`I 77Lu-DOTA-TATE for PRRT. urrenl futdioph;u·1naceuLicals.(2016),
`9, 8- 18.
`Maus ct al., Aspects on radiolabcling of I 77Lu-DOTA-TATE: After
`18 purification re-addition of ascorbic acid is required to maintain
`radiochemical purity, lnl'.J. Diagnostic Imaging, (20 14), I , 5-1 2.
`Liu el al., Ascorbic Acid: Useful as a Bufl'er Agent and Radiolylic
`Stabilizer for Metalloradiopharmaceuticals, Bioconjugate hem,
`(2003), 14, 1052-1056.
`Liu et al., Stabi lization of 90Y-Labeled DOT A-Biomolecule on(cid:173)
`jugates Using Gentisic Acid and Ascorbic Acid. Bioconjugate
`Chem, (2001), 12, 554-558.
`Banerjee et al., LutetilUn-177 Therapeutic Radiopharmaceuticals:
`Linking Chemistry, Radiochemist,y, and Practical Applications,
`Chem Rev (2015), l 15, 2934-2974.
`Declaration for Grace Period filed in PCT/1B201810574 L 5, Sep. 25,
`2018.
`Declaration for Grace Period filed in PCTflB2018/055575, Jul. 25,
`20L8.
`Aslani et al .. Lutetium-177 DOTATATE Production with and Auto(cid:173)
`mated Radio-phannaceutical Synthesis System, Asia Oceania Jour(cid:173)
`nal of Nuclear Medicine & Biology, (2015), 3. I 07- 115.
`(Continued)
`
`Primary Examiner - Michael G. Hartley
`Assistant Examiner - MeHssa J Perreira
`(74) Allorney, Agent, or Firm - Lian Ouyang
`
`(57)
`
`ABSTRACT
`
`Tbe present invention relates to radionuclide complex solu(cid:173)
`tions of high concentration and of high chemical stability,
`that allows their use as drng product for diagnostic and/or
`therapeutic purposes. The stability of the drug product is
`achieved by at least one stabilizer against radfolytic degra(cid:173)
`dation. The use or two stabilizers introduced during the
`manufacturing process at different stage was found to be of
`particular advantage.
`
`24 Claims,
`
`o Drawings
`
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`US 10,596,276 B2
`Page 2
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`(56)
`
`References Cited
`
`OTHER PUB I 110NS
`Lutathera, Advanced Accelerator Applications. Highligh1s of Pre(cid:173)
`scribing lnfonnalion, Jan. 20 18.
`Lutalhera. European Medicines gcncy, EPAR Public Assessment
`Repo1t. First Published Jan. 17, 2018.
`Luta.lhera, European Me-eticines Agency, EPA R Product IJJforma.(cid:173)
`lion, First Published Jan. l7, 201.8, last updated Apr. 11 , 2018.
`Lutathera. Eumpean Medicines Agency.
`llMP S1unmruy Positive
`Opinion, First Published Jul.21. 20 17 .
`Luna-Gutierrez et al., Freeze-Dried multi-dose kits for the fast
`preparation of 177Lu-Tyr3-octreotide and 177Lu-PSMA(inhibilor)
`under GMP condjtions, J Radioanal Nucl Chem. (2017). 314,
`218 1-2188.
`freeze(cid:173)
`Das el al., Preparation of DOTA-TATE and DOTA-NO
`dried kits for fonnulaLion of patient. doses of 177Lu-labeled agents
`and their comparison for peptide receptor radionucHde therapy
`appHcalion. J Rad.ioanaJ Nucl Chem, (2014) 299, 1389-1398.
`De Blois et al, Elfecti veness of Quenchers lo Reduce Radiolysis of
`I l I ln-or l 77-Lu-labelled Methionine-Containing Regulatory Peptides.
`Maintairung Radioche,rucaJ Purity as Measured by HPLC, Current
`Topics in Med Chem, (2012), 12, 2677-2685.
`
`Wild et al., DOTA-NO . a high-affinity ligand of somatostalin
`receptor subtypes 2, 3 and 5 for la.belling with various radiometals,
`Eur J Nucl Med Mo[ Imaging, (2003), 30. 1338-1347.
`Kwekkeboom ct al., [I 77-Lu-DOTAO, Tyr3]octreotate: comparison
`with [I l lln-DTPAO]octreotide in patients, Eur J Nucl Med Mol
`Imaging, (2001), 28, 1319-1325.
`Das et al, Preparation of Therapeutic Dose of 177Lu-DOT -TATE
`Usi ng a Novel Single Vial Freeze-dried Kil: A Comparison with
`'In-situ' Preparation al Hospital Ra.diopha.rma.cy. C urrent
`Radiopha.rmaceuticals, (2014) 7, 12-19.
`Mathur et al., Bulk Scale Formulation of Therapeutic Dosed of
`linica.l Grade Ready-to-Use 177Lu-DOT -TATE: The Intricate
`Radiochemistry Aspects Cancer Biothcrapy and Radiopha.nnaceuticals,
`(2017), 32, 7, 266-273 .
`Advanced Accelerator Applications Announces European Approval
`of Lutetium ( l 77Lu) Oxodotreotide (Lutathera )
`for
`Gastroenteropancreatic Neuroendocrine (GEP-NET) Tumors, Press
`Release Sep. 29, 20 I 7.
`Advanced Accelerator Applications Receives US FDA Approval for
`Lutathera
`forTreat.ment ofGastroenteropancreatic Neuroendocrine
`Tumors, Press Release. Jan . 26 2018.
`i.n
`frilling et al ., "Treatment with 90Y- and l 77Lu-DOTATO
`palients with mel'astalic neuroendocrine tumors". Surgery, vol. 140,
`pp. 968-977, 2006.
`
`* cited by examjner
`
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`US l 0,596,276 B2
`
`1
`STABLE, CONCENTRATED RADIONUCLIDE
`COMPLEX SOLUTIONS
`
`RELATED APPLICATIONS
`
`TI1is application is a continuation-in-part application of
`U.S. application Ser. No. 16/ 140,962 filed Sep. 25, 2018.
`which is a continuation-in-part of U.S. application Ser. No.
`16/045,484 filed Jul.25.2018 and claims priority to, and the
`benefit of International Application No. PCT/182018/
`055575 filed Jul. 25, 2018, the contents of each of which are
`hereby incorporated by reference in their entireties.
`
`FIELD OF THE [NVENTION
`
`The present invention relates to radionuclide complex
`solutions of high concentration and of high chemical and
`radiochemical stability, that aliows their use as coJ11J11ercial
`drng product for diagnostic and/or therapeutic purposes.
`
`BACKGROUND OF THE INVENTION
`
`5
`
`2
`Radioanal Nuc/ Chem 2014, 299, 1389-1398; Das et al.
`Current Radiopharmaceu/icals 2014, 7, 12-19; Luna-Guti(cid:173)
`errez et al. J Radioanal Nuc/ Chem 2017, 314, 2181-2188).
`However, those kits are not "ready-to-use" as they require
`l11e reconstitution step and in addition further processing
`steps (e.g. applying heat for the complexation react'ion) as
`well as purification and sterilization steps before the drug
`can be finally administered.
`To reduce radiolysis of radiopharmaceutical drng prod-
`to ucts and thus improve stability, various strategies have been
`explored wil11 more or less success: 11:ie drug product may
`be stored at low temperatures, or produced in high dilution,
`or stabilizers may be added.
`Adding stabilizers however may be problematic as those
`t5 chemicals may have a negative impact on the complexation
`of the radionuclide into the chelating agent or may have a
`limited solubility and precipitate from the solution. Ethanol
`has been reported as stabilizer against radiolysis (WO 2008/
`009444). While et11anol might not have a negative impact on
`20 the complexation or a solubility issue, higl1er amounts of
`ethanol in an iu:fosion solution may be physiologically
`problematic and may have a negative impact on the toler(cid:173)
`ability of the drug product.
`Producing the drug product in high dilution bas the
`25 disadvantage tliat large volumes of infusion solutiODS need
`to be administered to patients. For the convenience of
`patients and for drng tolerability reasons it would be highly
`desirable to provide the radiopharmaceutical drug product ill
`a higl1 concentration. Those highly concentrated solutions
`30 however are in particular prone to radiolysis. Therefore,
`there are contradictory positions between, on the one baud,
`avoiding radiolysis by dilution of the drug product but, ou
`the other hand, avoiding patieut discomfort during treatment
`by providing a concentrated drug solution. In Mathur et al.
`35 Cancer Biotherapy and Radiopharmaceulicals, 2017, 32(7),
`266-273 a product of high concentration has been reported
`and claimed being ready-to-use. However, that composition
`may be problematic with respect to tolerability as it contains
`high amounts of ethanol.
`It remains therefore a challenge TO design a ready-to-use
`radiopbarmaceutical drng product which can be produced at
`commercial scale and delivered as a sufficiently stable and
`sterile solution in a lligl1 concentration which leads to a
`convenient small infi.ision volume for patients and which has
`45 a composition of high physiological tolerability (e.g. a
`composition which does not contain ethanol).
`
`TI1e concept of targeted drug delivery is based on cell
`receptors which are overexpressed in the target cell in
`contrast to the Dot-to-be-targeted cells. If a dmg has a
`binding site to those overexpressed cell receptors it allows
`the delivery of the drug after its systemic administration in
`high concentration to those target cells while leaving ot11er
`cells, which are not of interested, unaffected. For example,
`if tumor cells are characterized by an overexpression of a
`specific cell receptor, a drng with binding affinity to said
`receptor will after intravenous infusion accumulate in high
`concentration in the trnuor tissue while leaving the nonnal
`tissue tu1alfected.
`This targeted drng delivery concept has also been used in
`radiomedicine to deliver radionuclides selectively to the
`target cells for diagnostic or therapeutic purposes.
`For this radiomedicinal application the target cell receptor
`binding moiety is typically lin.ked to a chelating agent which
`is able to fonn a strong complex with the metal ions of a 40
`radionuclide. This radiophannaceutical drug is then deliv(cid:173)
`ered to the target cell and the decay of the radionuclide is
`then releasing high energy electrons, positrons or alpha
`particles as well as gamma rays at the target site.
`One technical problem with those radiophannaceutical
`drug products is that the decay of the radionuclide occurs
`constantly, e.g. also during the manufacturing and during
`storage of the drug product, and the released high energy
`emissions induce the cleavage of the chemical bonds of the
`molecules which fonn part of the drug product. This is often 50
`referred to as radiolysis or radiolytic degradation. The
`radiolytfo degradation of the receptor binding moiety of the
`drug may lead to a decrease in its efficacy to act as a
`diagnostic and/or therapeutic.
`The poor stability of those radiopbarmaceutical drng 55
`products and their lack of any siguificant shelf-life required
`that those drugs have so far to be manufactured as an
`individual patient's dose unit in l11e laboratories at the
`hospital and administered immediately to the patient who
`had to be present at that hospital already awaiting the 60
`radiological treatment. To faci litate such drug preparation in
`the hospital
`laboratories, "cold" (i.e. non-radioactive)
`freeze-dried kits have been developed which comprise the
`cell receptor binding moiety linked to a chelating agent
`without the radionuclide. The freeze-dried content of those 65
`kit vials is then to be reconstituted with a solution of the
`radionuclide short before administration (Das et al. J
`
`SUMMARY OF THE INVENTION
`
`The present inventors have now found a way to design
`and produce a highly concentrated radionuclide complex
`solution which is chemically and radiochemically very
`stable even if stored at ambient or short tenu elevated
`temperatures so that it can be produced on commercial scale
`and supplied as ready-to-use radiopharmaceutical product.
`The present invention is provided in various aspects as
`outlined in the following:
`A phannaceutical aqueous solution comprising
`(a) a complex formed by
`(ai) a radionuclide, and
`(aii) a cell receptor binding organic moiety liJ1ked to a
`chela1i11g agen1: and
`(b) at least one stabilizer against radiolytic degradation;
`wherein
`said radionuclide is present in a concentration that it
`provides a volwnetric radioactivity of at least 100 MBq/mL,
`preferably of at least 250 MBq/mL.
`
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`15
`
`4
`one stabilizer dnring complex fomrntion and another stabi(cid:173)
`lizer added after the complex formation is of advantage as it
`ensures that already during the complexation reaction, the
`cell receptor-binding molecule is protected against radioly-
`5 sis and tbe other stabilizer enl1ances the protecting eflect for
`the shelf-life period. Further, by this sequential application
`of the two stabilizers it is ensured, that during complexation
`only a relatively small amount of stabilizer is present (which
`minimizes the potential interference of that stabilizer with
`10 the complexation reaction) and after complexation a large
`amornll of a stabilizer combination is present (which
`strengthens the protective power of the stabilizers for the
`following drng product storage time period).
`This sequential application of two stabilizers also reduces
`the overall themiaJ stress of those stabilizers as one of them
`is not present when the complexation reaction, which
`involves high 1emperat11res, takes place.
`Further, particularly the use of two different stabilizers is
`advantageous as this combination is more efficacious in
`reacting to the various different radicals possibly formed by
`the radiolysis of the cell receptor binding molecule than only
`one single stabilizer can do.
`The composition of the radiopharmaceutical solution does
`25 1101 require the presence of ethanol. The solution is suffi(cid:173)
`ciently stable without ethanol. The absence of ethanol is of
`advantage with respect to the physiological tolerability of
`the solutiou.
`A shelf-life of at least 3 days is required to allow a
`radiophannaceutical drug product 10 be mauufactured from
`a centralized phannaceutical production site and to com(cid:173)
`mercialize it as a ready-to-use d.rng product.
`Therefore, due to the high stability (72 b at 25° C.) the
`present invention allows centralized pbanuaeeutical produc(cid:173)
`tion at highest quality standards (e.g. cGMP) and at indus(cid:173)
`trial scale, e.g. at 74 GBq or 148 GBq batch size which
`provides the d.rng product in numerous dose units, e.g.
`enough dose units for the treatment of JO to 20 patients at the
`same tin1e.
`Further, due to the high stability, there is sufficient time
`for the present invention to be shipped from a centralized
`pharmaceutical production site to remote clinical centers.
`Even forther, due 10 the high stability, the present inven(cid:173)
`tion can be provided as a ready-to-use infusion solution
`45 which can be immediately administered to the patient with(cid:173)
`out a need for the clinical staff to perform any preparatory
`work before administration.
`The present invention of particular suitability for the
`somatotatin receptor binding peptides, here in particular for
`50 the very sensitive somatostatin analogues octreotide and
`octreotate which are in particular prone to degradation
`reactions. Further, the present invention of particular suit(cid:173)
`ability for the radionuclide Lutetium-.177 with its specific
`radioactivity characteristics.
`DE1AJLED DESCRIPTJON OF nm
`INVENTION
`
`3
`Said stabilizcr(s), component (b), is (are) present in a total
`concentration of at least 0.2 mg/mL, preferably at least 0.5
`mg/mL, more preferably at least J .0 mg/mL. even more
`preferably at least 2.7 mg/mL.
`A pham1aceutical aqueous solution, comprising
`(a) a complex fonued by
`(ai) the radionuclide 177Luterium (Lu-177), present in a
`concentration that it provides a volumetric radioac(cid:173)
`tivity of from 250 to 500 MBq/mL, and
`(aii) the chelating agent linked somatostatin receptor
`binding organic moiety DOTA-TATE (oxodot(cid:173)
`reotide) or DOTA-TOC (edotreotide);
`(bi) gentisic acid or a salt thereof as the first stabilizer
`against radiolytic degradation present in a concentra(cid:173)
`tion of from 0.5 to I mg/mL;
`(bii) ascorbic acid or a salt thereof as the second stabilizer
`against radiolytic degradation present in a concentra(cid:173)
`tion of from 2.0 to 5.0 mg/mL.
`A process for manufactnring said phanuaceutical aqueous
`solution as defined above, comprising the process steps: 20
`(1) Forming a complex of the radionuclide and the
`chelating agent linked cell receptor binding organic
`moiety by
`(I .I ) preparing an aqueous solution comprising the
`radionuclide;
`(1 .2) preparing an aqueous solution compnsrng the
`chelating agent linked cell receptor binding organic
`moiety, a first stabilizer, optionally a second stabi(cid:173)
`Jizer; and
`(1.3) mixing the solutions obtained in steps (1.1) and 30
`(1.2) and heating the resulting mixture;
`(2) Diluting the complex solution obtained by step (I) by
`(2.1) preparing an aqueous dilution solution optionally
`comprising a second stabilizer; and
`(2.2.) mixing the complex solution obtained by step (1) 35
`with the dilmion solution obtained by the step (2.1).
`The present invention provide the following advantages:
`The bigb concentration allows administering a high dose
`within a short time frame. E.g. in the case of 177Lu-DOTA.(cid:173)
`TATE. the high dose of7.4 GBq can be provided in a small 40
`volume of 20.5 10 25.0 mL which allows the N
`infusion
`administration to be completed within about 20 to 30
`minutes.
`·n1e use of suitable stabilizer(s), according 10 the present
`invention as described. herein ensures high stability, at least
`95%, 96%, 97%, 98%, 99% or 100% chemical stability with
`respect to the chemical purity for the cell receptor-binding
`molecule after 72 hours at 25° C., even if this molecule is a
`sensitive peptide molecule. E.g. for DOTA-TATE JOO%
`chemical purity were found after 72 hours at 25° C. and even
`after 48 hours at 32° C. were found. Even under short term
`elevated temperature conditions (32° C. for 12 hand 25° for
`60 h) such high stability was found with respect to chemical
`purity.
`Further, the use of suitable stabiJizer(s), according to the 55
`present invention as described, herein ensures high stability,
`at least 95% radiochemical stability with respect to the
`radiochemical purity radionuclide complex. E.g. for 177Lu(cid:173)
`DOTA-TATE at least 95% radiochemical purity were found
`after 72 hours at 25° C. Even under short term elevated 60
`temperature conditions (32° C. for 12 band 25° for 60 b)
`such high stability was found with respect to radiochemical
`purity.
`While sufficient stability may be achieved already with
`one single stabilizer, the use of two stabilizers bas been 6 5
`found to be of particular suitability in stabilizing sensitive
`radiophannaceutical solutions. ln part'icular, the presence of
`
`Herein after, the present invention is described in further
`detail and is exemplified.
`In general, the present i1wentiou is concerned about a
`phannaceutical aqueous solution, in particular a radiophar(cid:173)
`maceutical aqueous solution. The solution is for intravenous
`(IV) use/application/administration. The solution is stable,
`concentrated, and ready-to-use.
`The stability of 1be solution ascertained by the use of
`stabilizers against radiolytic degradation.
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`20
`
`25
`
`30
`
`5
`In general, t:he stabilizers used in accordance with t:he
`present inventions may be selected from gentisic acid (2,5-
`dihydroxybenzoic acid) or salts thereof. ascorbic acid
`(L-ascorbic acid, vitamin C) or salts thereof (e.g. sodium
`ascorbate), methionine, histidine, melatonin, ethanol, aud 5
`Se-methionine. Preferred stabilizers are selected from gen(cid:173)
`tisic acid or saJts thereof and ascorbic acid or salts thereof.
`Ethanol is considered as less preferred stabilizer due to
`tolerability issues associated with it if present in higher
`concentrations. Ethanol should be ideally avoided in the 10
`solutions of the present invention (in other words: free of
`ethanol), at least the amount of ethanol in the solutions of the
`present invention should be limited, e.g. less than 5%.
`preferably less than 2%, more preferably Jess than 1 % in the
`final solution which is forest--en to be injected/infused. Even 15
`more preferably, the solution is free of ethanol.
`In accordance with the present invention the following
`embodiments are provided:
`1. A phamiaceutical aqueous solution comprising
`(a) a complex fonued by
`(ai) a radionuclide, and
`(aii) a cell receptor binding organic moiety linked to a
`chelating agent; and
`(b) at least one stabilizer against radiolytic degradation;
`wherein
`said radionuclide is present in a concentration that it
`provides a volumetric radioactivity of at least I 00
`MBq/mL, preferably of at least 250 MBq/mL.
`2. The pharmaceutical aqueous solution according to
`embodiment 1.
`wherein said stabilizer(s), component (b), is (are) present
`in a total concentration of at least 0.2 mg/mL, prefer(cid:173)
`ably at least 0.5 mg/mL, 1uore preferably at least 1.0
`mg/mL, even more preferably at least 2.7 mg/mL.
`3. The pharmaceutical aqueous solution according to any 35
`one of the preceding embodiments, wherein said radio(cid:173)
`nuclide is present in a concentration that it provides a
`volumetric radioactivity of from JOO to 1000 MBq/(cid:143) lL.
`preferably from 250 to 500 MBq/mL.
`4. The pharmaceutical aqueous solution according to any 40
`one of the preceding embodiments, wherein said stabilizer
`(s) is (are) present in a total concentral'ion of from 0.2 to
`20.0 mg/mL, preferably from 0.5 to 10.0 mg/mL, more
`preferably from 1.0 lo 5.0 mg/mL, even more preferably
`from 2.7 to 4.1 mg/mL.
`5. The pharmaceutical aqueous solution according to any
`one of the preceding embodiments,
`wherein the component (b) is only one stabilizers against
`radiolytic degradation, i.e. only a first stabilizer.
`6. The pharmaceutical aqueous solution according to any 50
`one of the preceding embodiments,
`wherein the component (b) are at least two stabilizers
`against radiolytic degradation, i.e. at least a first aud a
`second stabilizer, preferably only two stabilizers, i.e.
`only a first and a second stabilizer.
`7. 111e pharmaceutical aqueous solution according to any
`one of the embodiments 5 to 6, wherein the first stabilizer
`is present in a concentration of from 0.2 to 5 mg/nlL,
`preferably from 0.5 to 5 mg/mL, more preferably from 0.5
`to 2 mg/mL. even more preferably from 0.5 to J mg/mL. 60
`even more preferably from 0.5 to 0.7 mg/mL.
`8. The pharmaceutical aqueous solution according to
`embodiment 6 or 7, wherein the second stabilizer is
`present in a concentration of from 0.5 to 10 mg/mL, more
`preferably from 1.0 to 8.0 mg/mL, even more preferably 65
`from 2.0 to 5.0 mg/mL, even more preferably from 2.2 to
`3.4 mg/mL.
`
`45
`
`55
`
`6
`9. The phannaceutical aqueous solution according to any
`one of the preceding embodiments, wherein the stabilizer
`(s) is (are) selected from gentisic acid (2,5-dihydroxyben(cid:173)
`zoic acid) or salts thereof; ascorbic acid (L-ascorbic acid,
`vitamin C) or salts thereof (e.g. sodium ascorbate),
`methionine, histidine, melatonin, ethanol, and Se-methio(cid:173)
`nine, preferably selected from gentisic acid or salts
`thereof and ascorbic acid or salts thereof.
`I 0. The pharmaceutical aqueous solution according to any
`one of the embodiments 5 to 9, wherein the first stabilizer
`is selected from gentisic acid and ascorbic acid, preferably
`the first stabilizer is gentisic acid.
`11. The pharmaceutical aqueous solution according to any
`one of the embodiments 6 to 10, wherein the second
`stabilizer is selected from gentisic acid and ascorbic acid,
`preferably the second stabilizer is ascorbic acid.
`12. The pharmaceutical aqueous solution according to any
`one of the embodiments 6 to 8, wherein the first stabilizer
`is gentisic acid or a salt thereof and the second stabilizer
`is ascorbic acid or a salt thereof, and the ratio of the
`concentration (in mg/mL) of the first stabilizer to the
`concentration (in mg/mL) of the second stabilizer is from
`1:3 to I :7, preferably from I :4 to J:5.
`I 3. The pharmaceutical aqueous solution according to any
`one of the preceding embodiments, wherein the radionu(cid:173)
`clide is selected from 1 77Lu 68Ga 18F 99"'Tc 21 1 At 82Rb
`l66Ho, 225 Ac, Ill In, 1231: 1311: 89zr, 9oY, pref era bl;
`selected from 177Lu and 68Ga, more preferably is 177Lu.
`14. The phannaceutical aqueous solution according to any
`one of the preceding embodiments, wherein the cell
`receptor binding moiety is a somatostatin receptor binding
`peptide, preferably said somatostatin receptor binding
`peptide is selected from octreotide, octreotate, lanreotide,
`vapreotide and pasireotide, preferably selected from oct(cid:173)
`reotide and octreotate.
`15. The pharmaceutical aqueous solution according to any
`one of the preceding embodiments, wherein the chelating
`agent is selected from DOTA, DTPA, NTA, EDTA,
`OO3A, NOC and NOTA, preferably is DOTA.
`16. The pharmaceutical aqueous solution according to any
`one of the preceding embodiments, wherein the cell
`receptor binding moiety and the chelating agent fonn
`together molecules selected from DOTA-OC, DOTA(cid:173)
`TOC (~'<lotreotide), DOTA.-NOC, DCYfA-TATE (oxodot(cid:173)
`reotide), DOTA-LAN. and DOTA-VAP. preferably
`selected from DOTA-TOC and DOTA-TATE, more pref(cid:173)
`erably is DOTA-TATE.
`J 7. The pharmaceutical aqueous solution according to any
`one of the preceding embodiments, wherein the radionu(cid:173)
`clide, the cell receptor binding moiety and the chelating
`agent form together the complex 177Lu-DO1A.-TOC
`177Lu-edotreotide) or 177Lu-DOTA.-TATE (177Lu-oxodo(cid:173)
`treotide), preferably 177Lu-DOTA-TATE.
`18. The pharmaceutical aqueous solution according to any
`one of the preceding embodiments. further comprising a
`buffor. preferably said b11ffer is an acetate buffer, prefer(cid:173)
`ably in an amount to result in a concenlnition of from 0.3
`to 0.7 mg/mL (preferably about 0.48 mg/mL) acetic acid
`and from 0.4 to 0.9 mg/mL (preferably about 0.66
`mg/mL) sodium acetate.
`19. The pham1aceutical aqueous solution according to any
`one of the preceding embodiments, fi.rrther comprising a
`sequestering agent, preferably said sequestering agent is
`diethylentriaminepentaacetic acid (DTPA) or a salt
`thereof, preferably in an amount to result in a concentra(cid:173)
`tion of from O.OJ to 0.10 mg/mL (preferably about 0.05
`mg/mL).
`
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`US l 0,596,276 B2
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`25
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`7
`20. 111e pbanuaceutical aqueous solution according to any
`one of the preceding embodiments, whlch has a shelf life
`of at least 24 hours (h) at s25° C., at least 48 hat s25° C..
`at least 72 hat s25° C., of from 24 h to 120 hat s25° C.,
`from 24 b to 96 b at s25° C., from 24 b to 84 b at s25° 5
`C., from 24 h to 72 hat s25° C., in particular has a shelf
`life of 72 hat s25° C.
`21. The phannaceutical aqueous solution according to any
`one of the preceding embodiments, wherein said solution
`is produced at commercial scale manufacturing, in par- 10
`ticular is produced at a batch size of at least 20 GBq, at
`least 50 GBq, or at least 70 GBq.
`22a. The pharmaceutical aqueous solution according to any
`one of the preceding embodiments, which is ready-to-use.
`22b. The phamiaceutical aqueous solution according to auy
`one of the preceding embodiments, whlch is for coilliller(cid:173)
`cial use.
`23. A phannaceutical aqueous solution. comprising
`(a) a complex fonued by
`(ai) the radionuclide 177Lutetium (Lu-177), presenl in a 20
`concentration that it provides a volumetric radioac(cid:173)
`tivity of from 250 to 500 MBq/mL, and
`(aii) l11e chelating agent linked somatostatin receptor
`binging organic moiety DC>TA-TA.TE (oxodot(cid:173)
`reotide) or DOTA-TOC (edotreotide);
`(bi) gentisic acid or a salt thereof as the first stabilizer
`against radiolytic degradation present in a concentra(cid:173)
`tion of from 0.5 to I mg/mL;
`(bii) ascorbic acid or a salt thereof as the second stabilizer
`against radiolytic degradation present in a concentra- 30
`tion of from 2.0 to 5.0 mglmL.
`24. The pharmaceutical aqueous solution according to
`embodiment 23, further comprising:
`(c) Diethylentriaminepentaacetic acid (DTPA) or a salt
`thereof in a concentration of from 0.01 to 0.10 mglmL. 35
`25. The phannaceutical aqueous solution according to
`embodiments 23 or 24, further comprising:
`(d) acetic acid in a concentration of from 0.3 to 0.7
`mglmL and sodium acetate in a concentration from 0.4
`to 0.9 mg/mL.
`26. The phannaceutical aqueous solution according to any
`one of the preceding embodiments wherein the stabilizer
`(s) is (are) present in the solution during the complex
`fonnation of components (ai) and (aii).
`27. The phannaceutical aqueous solution according to any
`one of embodiments 5 to 26 wherein only the first
`stabilizer is present during the complex fonnation of
`components (ai) and (aii), preferably in an amount to
`result in a concentration of from 0.5 to 5 mglmL. more
`preferably from 0.5 to 2 mglmL. even more preferably 50
`from 0.5 to 1 mglmL, even more preferably from 0.5 to
`0.7 mglmL, in the final solution.
`28. 111e pham1aceutical aqueous solution according to any
`one of embodiments 6 to 27 wherein a part of the amount
`of the second stabilizer is already present in the solution
`during the complex fom1ation of components (ai) and (aii)
`and another part of the amount of the second stabilizer is
`added after the complex fon11ation of components (ai) and
`(aii).
`29. The pharmaceutical aqueous solution according to any 60
`one of embodiments 6 to 28 wherein the second stabilizer
`is added after the complex fonnation of components (ai)
`and (aii).
`30. The pharmaceutical aqueous solution according to
`embodiment 6 or 29 wherein the second stabilizer is 65
`added after the complex fom1ation of components (ai) and
`(aii), preferably in an amount to result in a concentration
`
`8
`of from 0.5 to 10 mg/mL, more preferably from l .0 to 8.0
`mg/mL, even more preferably from 2.0 to 5.0 mg/mL,
`even more preferably from 2.2 to 3.4 mglmL, in the final
`solution.
`31. The pharmaceutical aqueous solution according to any
`one of the preceding embodiments, further comprising a
`sequestering agent, added after the complex formation of
`components (ai) and (aii), for removing any uncomplexed
`Lu, preferably said sequestering agent is diethylentri(cid:173)
`aminepentaacetic acid (DTPA) or a salt thereof, prefer(cid:173)
`ably in an amount to result in a concentration of from O.OJ
`to 0.J O mglmL (preferably about 0.05 mg/m