I 1111111111111111 1111111111 111111111111111 IIIII IIIII IIIII 111111111111111111
`USO l 0596278B2
`
`c12) United States Patent
`de Palo et al.
`
`(10) Patent No.: US 10,596,278 B2
`(45) Date of Patent:
`*Mar. 24, 2020
`
`(54) STABLE, CO1 CE TRATED RADIONUCLIDE
`COMPLEX SOLUTIO S
`
`(7 1) Applicant: Advanced Accelerator Applications
`(ftaly) Sri, Pozzilli (IT)
`
`(72)
`
`Inventor : Francesco de Palo, lvrea (IT): Lorenza
`Fugazza, lvrea (IT)· Donato Barbato.
`lvrea (IT): Maurizio Mariani, lvrea
`(JT); Daniela hicco, Albiano d' lvrea
`(lT)· Giovanni Tesoriere, Noicanaro
`(IT): Clementina Brambati, Turin (IT)
`
`(73) A signee: ADVANCED ACCELERATOR
`APPUCATIONS (ITALY)
`.R.L.,
`Pozzi Iii (lsernia) (IT)
`
`( * ) Notice:
`
`ubject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`Thi patent i subject to a terminal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 16/175,239
`
`(22) Filed:
`
`Oct. 30, 2018
`
`Prior Publication Data
`
`US 2020/0030467 Al
`Related U.S. Application Data
`
`Jan. 30 2020
`
`Continuation of application No. 16/140,962. fi led on
`ep. 25, 2018. which is a continuation-in-part of
`application No. 16/045,484, filed on Jul. 25 , 2018.
`
`(65)
`
`(63)
`
`(51)
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`(52)
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`(58)
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`(56)
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`0515313 Bl
`199701579 A2
`200210 192 A2
`2008009444 A I
`2013167 130 A l
`2015063746 A l
`20 1517 1792 A l
`20 16207732 A I
`20 180749 18 A l
`20 18081860
`1
`
`8/2000
`1/1997
`2/2002
`1/2008
`11/2013
`5/20 15
`11 /2015
`12/20 16
`4/2018
`5/2018
`
`OTl-l ER PUB ICATJONS
`
`Maus ct al. (lnl. J. Diagnost. Imaging 20 14, I, 5-12).*
`de Blois et al. (Appl. Radial. Isolop. 2014, 85, 28-33).*
`Singh el al . (Ind. J. ucl. Med. 2011. 26, 135-138). •
`RCM meeting (Development and preclinical evaluation of thera(cid:173)
`peutic radiophannaceuli cals based on J 77Lu- and 90Y-labelled
`monoclonal antibodies and peptides: Stip, Republic of Macedonia
`Oct. 1-5. 2012).•
`Frilling el al. (Surgery 2006. l40. 968-977).•
`Breeman et al .. Optimising Conditions for Radiolabelling ofDOTA(cid:173)
`pcptides with 90Y, I .I 11.n an d l 77 Lu al High Specific Activities, Eur
`J Nucl Med Mol Imaging. (2003), 30, 9 17-920.
`Breeman et al., Ove1view of Development and Formulation of
`177 u-DOTA-TATEforPRRT, UJTenl Radiophannaceuticals, (2016),
`9, 8-18 .
`Maus et al.. Aspects on radiolabeling of 177Lu-DOTA-TATE: After
`18 purification re-addi tion of ascorbic ac id is required to maintain
`radiochemical purity. Int J. Diagnostic lmaging, (2014), I. 5- 12.
`Liu et al.. Ascorbic Acid : Useful as a Buffer Agent and Rad iolytic
`Stabilizer for Metalloradiophannaceuticals, Bioconjug,1le
`hem,
`(2003), 14. 1052-1056.
`Liu et al ., Stabilization of 90Y-Labeled DOTA-Iliomolecule Con(cid:173)
`jugates Using Gentisic Acid and Ascorbic Acid, Bioconjugate
`Chem. (2001), 12. 554-558.
`Banerjee et al., Lutetium-177 Therapeutic Radiopharmaceuticals:
`Linking Chemistry, Radiochemistry, and Practical Applications,
`Chem Rev, (2015), 115, 2934-2974.
`Dec.laration for Grace Period filed in PCT/IB201 8/0574 15, dated
`Sep. 25, 2018.
`Declaration for Grace Period filed in PCT/IB2018/055575, Jul. 25,
`2018.
`Aslani et al., Lulelium-177 DOTATATE Production with and Auto(cid:173)
`mated Radio-pharmaceutical ynthcsis System, Asia Oceania Jour(cid:173)
`nal of uclcar Medicine & Biology. (2015). 3. 107-115.
`Lula.lhera, Advanced Accelerator Applications. 1-lighlighls of Pre(cid:173)
`scribing lnformation, .Jan. 2018.
`Lurathera, European Medicines Agency. EPAR Public Assessment
`Report, First Published Jan. 17, 20 18.
`( onti nucd)
`
`Primary Examiner - Michael G. Hartley
`Assistant Examiner - Melissa J Perreira
`(74) Aflorney. Agent, or Firm - Lian Ouyang
`
`ABSTRACT
`(57)
`The present invention relates to radionuclide complex solu(cid:173)
`tions o f high concentration and of high chemical stability,
`that allows their use as drug product for diasnostic and/or
`therapeutic purposes. The stability of tl1e drug product is
`achieved by at least one stabi lizer against radiolytic degra(cid:173)
`dation. The use of two stabil izers introduced during the
`manufacturing process at different stages was found to be of
`particu lar advantage.
`
`25
`
`laims, o Drawings
`
`Evergreen Ex. 1002
`1 of 20
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`Int. C l.
`A61K 51/00
`A61M 3(JIJ4
`A61K 51108
`A6JK 47112
`A6JK 47122
`A61K 47/18
`A61K 51112
`U.S. Cl.
`CP
`
`(2006.01)
`(2006.0J)
`(2006.01)
`(2006.0J)
`(2006.0J)
`(20 17.0l)
`(2006.01)
`
`A61K 51/083 (2013 .01); A61K 47112
`(2013.01); A61K 47/18 (2013.01); A61K 47122
`(20 13.01); A6IK 51/121 (2013.01); A61K
`51108 (2013 .01 )
`
`Field of Classification Search
`None
`ee application file for complete earcb bi tory.
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,753 ,627 A
`5,776,894 A
`5,804,157
`5.8~04 l A
`6,123,9 l6 A
`6,183,721 Bl
`6,277,356 B l
`2007/0269375 A l •
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`5/ l998
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`l 1/ 1998
`9/2000
`2/2001
`8/200 1
`ll/2007
`
`Albert el al.
`Albert et al.
`rin ivasan el al .
`rin i vasan et al.
`Kre.nning el al.
`Albert et al.
`Albert ct al.
`hen .... ............... . A6 1K 51/088
`424/ 1 .69
`
`

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`US 10,596,278 B2
`Page 2
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`(56)
`
`References Cited
`
`OT 1 R PUB I ATJONS
`
`Lutathera, European Medicines Agency. EPAR Product Informa(cid:173)
`tion, First Published Jan. 17, 2018, last updated Apr. 11, 2018.
`Lulathera. · uropean Medicines Agency, UMP ummary Positive
`Opinion, First Published Jul. 2 1. 2017.
`Luna-GuLierrez el al., Freeze-Dried multi-dose kits for the fast
`preparation of I 77Lu-Tyr3-ocLreotide and I 77Lu-PSMA(inhibitor)
`under GMP conditions, J Rarlioanal
`ucl
`hem. (2017), 314,
`2181-2188.
`freeze(cid:173)
`Das et al.. Preparation of DO A-TATE and DOTA-NO
`dried kit for formulation of patient doses of I 77Lu-labeled agents
`and their comparison for pepLide receptor radionuclide therapy
`applicaLion, J Radioanal Nucl Chem. 20 14) 299, 1389-1398.
`de Blois et al., Elfectivene s of Quenchers to Reduce Radiolysis of
`11 l ln-or 177-Lu-Labelled Methionine . ntainingRegulatory Pepi ides.
`Maintaining Radiochemical Purity as Measured by HPLC, Current
`Topics in Med hem, (20 12), 12, 2677-2685.
`
`Wild el al., DOTA-NOC. a high-affi nity ligand of somatostatin
`receptor subtypes 2, 3 and 5 for labelling with various rad iometals,
`Eur J Nucl Med Mol Imaging, (2003). 30, 1338-1347.
`Kwekkeboom et al., ( 177-Lu-DOTA0. Tyr3 Joctreotate: comparison
`with ( LI l ln-DTPA0)octreotide in patients, Eur J Nucl Med Mol
`Imaging, (2001), 28, 1319- 1325.
`Das et al.. Preparation of Therapeutic Dose of 177Lu-DOTA-TATE
`Using a ovel Single Vial Freeze-dried Kit A omparison with
`· In-situ' Preparation at Hospital Radiopharmacy,
`urrenl
`Radiopharmaceuticals, (2014) 7. 12-19.
`Mathur el al., Bulk Scale Formulation of Therapeutic Dosed of
`linical Grade Ready-to-Use 177Lu-DOTA-TATE: The Intricate
`Radiochemistry Aspects aocer Biotherapy and Radiophannaceuticals,
`(2017). 32. 7. 266-273 .
`Advanced Accelerator Appl ications Announces European Approval
`of Lutetium ( l77Lu) Oxo rlot reotide ( ut alhera ) for
`Gastroeoteropancrcatic Neuroendocrinc (G P-NET) Tumors, Press
`Release Sep. 29.2017.
`Advanced Accelerator Applications Receives US FDA Approval for
`Lulathera
`for Treatment of Gastroenteropancreatic euroendocrine
`Tumors, Press Release Jan, 26, 2018.
`
`* cited by examiner
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`1
`STABLE, CONCENTRATED RADIONUCLIDE
`COMPLEX SOLUTIONS
`
`RELATED APPLICATIONS
`
`This application is a continuation application of U.S.
`application Ser. No. 16/140,962 filed Sep. 25, 2018, which
`is a continuation-in-part ofU.S. application Ser. No. 16/045,
`484 filed Jul. 25, 2018 and claims priority to, and the benefit
`of International Application No. PCI/1B2018/055575 filed
`Jul. 25. 2018, the contents of each of which are hereby
`incorporated by reference in their entireties.
`
`FIELD OF THE INVENTION
`
`TI1e present invention relates to radionuclide complex
`solutions of high concentration and of high chemical and
`radiochemical stability, that allows their use as co=ercial
`drug product for diagnostic and/or therapeutic purposes.
`
`BACKGROUND OF THE INVENTION
`
`5
`
`2
`Radioanal Nucl Chem 2014, 299, 1389-1398; Das et al.
`Current Radiophar111ace11ticals 2014, 7, 12-19; Llllla-Guti(cid:173)
`errez et al. J Radioanal Nucf Chem 20 17, 314. 2181-2 188).
`However, those kits are not "ready-to-use" as they require
`the reconstitution step and in addition further processing
`steps (e.g. applying heat for the complexation reaction) as
`well as purification and sterilization steps before the drug
`can be finally administered.
`To reduce radiolysis of radiopbarmaceutical drug prod-
`10 ucts and thus improve stability, various strategies have been
`explored with more or less success: The drug product may
`be stored at low temperarures, or produced in high dilu1ion,
`or stabilizers may be added.
`Adding stabilizers however may be problematic as those
`15 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 ~O 2008/
`009444). While ethanol might not have a negative impact on
`20 the complexation or a solubility issue, higher amounts of
`ethanol in an in: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 has the
`25 disadvantage that large volumes of infusion solutions need
`to be admjnistered to patients. For the convenience of
`patients and for drug tolerability reasons it would be highly
`desirable to provide the radiopharmaceutical drug product in
`a high concentration. Those highly concentrated solutions
`30 however are in particular prone to radiolysis. Therefore,
`there are contradictory positions between, on the one hand,
`avoiding radiolysis by dilution of the drug product but, on
`the o ther band. avoiding patient discomfort during treatment
`by providing a concentrated drug solution. In Mathur et al.
`35 Cancer Biotherapy and Radiophan11aceuticals. 20) 7. 32(7),
`266-273 a product of high concentration has be 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
`radiophanuaceutical dn1g product which can be produced at
`commercial scale and delivered as a suflicieotly s1able and
`sterile solution in a high concentration which leads to a for
`patiem convenient small inf-t1sion volume and which has a
`45 composition of high physiological tolerability (e.g. a com(cid:173)
`position which does not contain ethanol).
`
`The concept of targeted drug delivery is based on cell
`receptors which are overexpresscd in the target cell in
`contrast to the not-to-be-targeted cells. If a dn1g 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 other
`cells, which are not of interested, unaffected. For example,
`if tumor cells arc characterized by an ovcrcxpression of a
`specific cell receptor. a drug with binding aftinity to said
`receptor will after intravenous infi.1sion acetmrnlate in high
`concentration in the tumor tissue while leaving the normal
`tissue tu1a Erected.
`This targeted drug 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 Ilic target cell receptor
`binding moiety is typically linked 10 a chelating agent which
`is able to fonn a strong complex with the metal ions of a 40
`radionuclide. This radiopham1aceutical 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 ga=a rays at the target site.
`One technical problem with those radiopham1aceutical
`drug products is that the decay of the radionuclide occurs
`constantly, e.g. also during the mam1facturing and during
`storage of the drug product, and the released high energy
`emissions induce the cleavage of the chemical bonds of the
`molecules which form part of the drng product. This is often 50
`The present inventors have now found a way to design
`referred to as radiolysis or radiolytic degradation. The
`and produce a highly concentrated radionuclide complex
`solution which is chemically and radiochemically very
`radiolytic degradation of the receptor binding moiety of t11e
`stable even if stored at ambient or short term elevated
`drug may lead to a decrease in its efficacy to act as a
`temperatures so that it can be produced on commercial scale
`diagnostic and/or therapeutic.
`111e poor stability of those radiopbamiaceutical drug 55
`and supplied as ready-to-use radiophannaceutical product.
`products and their lack of any significant shelf-life required
`The present invention is provided in various aspects as
`that those drugs have so far to be manufactured as an
`outlined in the following:
`A pharmaceutical aqueous solution comprising
`individual patient's dose unit in the laboratories at the
`hospital and administered immediately to t11e patient who
`(a) a complex fom1ed by
`had to be present at that hospital already awaiting the 60
`(ai) a radionuclide, and
`(aii) a cell receptor binding organic moiety linked to a
`radiological treannent. To faci litate such drug preparation in
`the hospital laboratories, "cold" (i.e. non-radioactive)
`chelating agent; and
`freeze-dried kits have been developed which comprise the
`(b) at least one stabilizer against radiolytic degradation;
`cell receptor binding moiety linked to a chelating agent
`wherein
`without the radionuclide. The freeze-dried content of those 65 said radionuclide is present in a concentration that it pro(cid:173)
`vides a volumetric radioactivity of at least 100 MBq/m.L,
`kit vials is t11e11 to be reconstituted wit11 an solution of t11e
`radionuclide short before administration (Das et al. J
`preferably of at least 250 MBq/mL.
`
`SUMMARY OF THE lNVENTJON
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`one stabilizer during complex formation and another stabi(cid:173)
`lizer added after the complex fonnation 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 enhances the protecting effect 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 tJ1e potential interference of that stabilizer with
`to the complexation reaction) and after complexation a large
`amount of a stabilizer combination is present (which
`strengthens the protective power of the stabilizers for the
`following dmg product storage time period).
`TI1is sequential application of two stabilizers also reduces
`the overall tl1emrnl stress oftl1ose stabilizers as one of them
`is not present when the complexation reaction. which
`involves high temperatures, 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.
`111e composition of the radiopharmacemical solution does
`25 not require the presence of ethanol. The solution is suffi(cid:173)
`ciently stable without e thanol. TI1e abse11ce of ethanol is of
`advantage with respect to the physiological tolerability of
`the solution.
`A shelf-life of at least 3 days is required to allow a
`radiopbanuaceutical drug product to be manufactured from
`a centralized phannaceutical production site and to com(cid:173)
`mercialize it as a ready-to-use drug product.
`ll1erefore, due to the h.igb stability (72 h at 25° C.) the
`present inventio11 allows centralized phanuaceutical produc(cid:173)
`tion a t 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 drug product in numerous dose units, e.g.
`enough dose units for the treatment of l Oto 20 patients at the
`same ti.me.
`Further. due to the high stability, there is sufficient time
`for the present inveution to be sl:Lipped from a centralized
`phannaceutical productioD site to re mote clinical centers.
`Even further, due to the high stability, the present inven(cid:173)
`tion can be provided as a ready-to-use infusion solution
`45 which can be inunediately aruninistered to the patient with(cid:173)
`out a need for the clinical staff to perform any preparatory
`work before administration.
`The present iJwentiou 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-1 77 with its specific
`radioactivity characteristics.
`
`15
`
`3
`Said stabilizer(s), component (b), is (are) present in a total
`concentration of at least 0.2 mg/mL, preferably at least 0.S
`mg/mL, more preferably at least 1.0 mg/mL, even more
`preferably at least 2.7 mg/mL.
`A pham1aceutical aqueous solution, comprising
`(a) a complex fonned by
`(ai) the radionuclide 177Lutetium (Lu-177), present in a
`concentration that it provides a volumetric radioac(cid:173)
`tivity of from 2S0 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 1 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 S.0 mg/mL.
`A process for manufacturing said phamiaceutical aqueous
`solution as defined above, comprising the process steps: 20
`(l) Forming a complex of the radionuclide and the
`chelating agent linked cell receptor binding organic
`moiety by
`(1.1) preparing an aqueous solmion comprising the
`radionuclide;
`(I .2) preparing an aqueous solution compnsmg the
`chelating agent linked cell receptor binding organic
`moiety, a first stabilizer. optionally a second stabi(cid:173)
`lizer: and
`(J.3) mixing the solutio ns obtained in steps ( I.I ) and 30
`( 1.2) and heating the resulting mixture:
`(2) Diluting the complex solution obtained by step ( 1) by
`(2.l) preparing an aqueous dilution solution optionally
`comprising a second stabilizer; aud
`(2.2.) mixing the complex solution obtained by step (1) 35
`with the dilution solution obtained by the step (2.1).
`The present invention provide the following advantages:
`111e high 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 of 7.4 GBq can be provided in a small 40
`volume of 20.5 to 25.0 mL which allows the JV infusion
`administration to be completed within about 20 to 30
`minutes.
`The use of suitable stabilizer(s), according to the present
`invention as described, herein ensures high stability, at least
`9S%, 96%, 97%. 98%, 99% or l 00% chemical stab ii ity with
`respect to the chemical purity for the cell receptor-binding
`molecule after 72 hours at 2S° C., even if this molecule is a
`sensitive peptide molecule. E.g. for DOTA-TATE 100%
`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 l 2 hand 2S0 for
`60 h) such high stability was found with respect to chemical
`purity.
`Further. the use of suitable stabilizer(s), according to the 55
`present invention as described, herein ensures high stability.
`at least 9S% 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 h and 2S0 for 60 h)
`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 65
`fow1d to be of particular suitability in stabilizing sensitive
`radiophannaceutical solutions. In particular, the presence of
`
`DETAJLED DESCRIPTlON OF THE
`lNVENTION
`
`Herein after, the present invention is described in further
`detail and is exemplified.
`ln general. the present invention is concemed about a
`pham1aceutical aqueous solutiou, in particular a radiophar(cid:173)
`maceutical aqueous solution. The solution is for intravenous
`OV) use/application/administration. The solution is stable,
`concentrated, and ready-to-use.
`111e stability of the solution ascertained by the use of
`stabilizers against radiolytic degradation.
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`5
`In general, the stabilizers used in accordance with the
`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). me1hioni11e. histidine, melatonine, ethanol, and 5
`Se-methionine. Preferred stabilizers are selected from gen(cid:173)
`tisic acid or salts 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 ideaJly avoid!;.'() in the 10
`solutions of the present invention (in other words: free of
`ethanol), at ]east the amounl of ethanol in the s0Ju1ions of the
`present invention should be limited, e.g. less than 5%,
`preferably less than 2%, more preferably less than 1 % in the
`final solution wh.ich is foreseen to be injected/infused. Even 15
`more preferably, the solution is free of ethanol.
`In accordance with the present invention the fo llowing
`embodiments are provided:
`I . A phamrnceutical 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. Tue pharmaceutical aqueous solution according to
`embodiment J ,
`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. more 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 sa.id radio(cid:173)
`nuclide is present in a concentration that it provides a
`volumetric radioactivity of from 100 to 1000 MBq/mL,
`preferably from 250 to 500 MBq/m L.
`4. The pharmaceutical aqueous solution according to any 40
`one of the preceding embodiments, wherein said
`stabilizer(s) is (are) present in a total concentration of
`from 0.2 to 20.0 mg/mL, preferably from 0.5 to 10.0
`mg/mL. more preferably from 1 .0 to 5.0 mglmL. even
`more preferably from 2.7 to 4.1 mg/mL.
`5. The pharmaceutical aqueous solution according to any
`one of the precedi11g embodimems,
`wherein the component (b) is only one stabilizers against
`radiolylic 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) arc at least two stabilizers
`against radiolytic degradation. i.e. at least a first and a
`second stabilizer, preferably only two stabilizers. i.e.
`only a first and a second stabilizer.
`7. The pharmaceutical aqueous solmion 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/mL,
`preferably from 0.5 to 5 mg/ml, more preferably from 0.5
`to 2 mg/mL. even more preferably from 0.5 to I 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 IO 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 prefer.ibly from 2.2 to
`3.4 mg/mL.
`
`45
`
`55
`
`6
`9. Tue pharmaceutical aqueous solution according to any
`one of the preceding embodiments. wherein
`the
`stabilizer(s) is (are) selected from gentisic acid (2,5-
`dihydroxybenzoic acid) or salts thereof, ascorbic acid
`(l-ascorbic acid, vitamin C) or salts thereof (e.g. sodium
`ascoorbate), methionine, histidine, ruelatonine, ethanol,
`and Se-methionine, preferably selected from gentisic acid
`or salts thereof and ascorbic acid or salts thereof.
`10. 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 Grst stabilizer is gentisic acid.
`I I. The pharmaceutical aqueous solution according to any
`one of the embodiments 6 to JO, 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
`I :3 to I :7, preferably from I :4 10 I :5.
`13. The pharmaceutical aqueous solution according to any
`one of the preceding embodiments, wherein the radionu(cid:173)
`c lide is selected from 177Lu, 68Ga. 18F, 99"'Tc, 211 At, 82Rb,
`t3 'I. s9zr, 9oy, preferably
`166Ho. 22sAc, 1111n. 123),
`selected from 177Lu and 68Ga, more preferably is 177Lu.
`14. The pharmaceutical aqueous solution according to any
`one of the preceding embodiments, wherein tl1e 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,
`D03A, NOC and NOTA, preferably is DOTA.
`J 6. TI1e pharmaceutical aqueous solution according to any
`one of tbe preceding embodiments, wherein tbe cell
`receptor binding moiety and the chelating agent form
`together molecules selected from DOTA-OC, DOTA(cid:173)
`TOC (edotreotide). DOTA-NOC. DOTA-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.
`17. The pharmaceutical aqueous solution according to any
`one of the preceding embodiments, wherein the radionu(cid:173)
`clide, the celJ receptor binding moiety and the cbelating
`agent form together the complex 177Lu-DOTA-TOC
`(177Lu-edotreotide) or 177Lu-DOTA-TATE (177Lu-oxodo(cid:173)
`treotide). preferably 177lu-00TA-TATE.
`18. TI1e pharmaceutical aqueous solution according to any
`one of the preceding embodiments, further comprising a
`bufter, preferably said buffer is an acetate buffer. prefer(cid:173)
`ably in an amount to result in a concentration 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 pharmaceutical aqueous solution according to any
`one of tbe preceding embodin1ents, further 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 0.01 to 0 .10 mg/ml (preferably about 0.05
`mg/mL).
`
`Evergreen Ex. 1002
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`us 10,596,278 8 2
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`25
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`7
`20. The pharmaceutical aqueous solution according to any
`one of the preceding embodiments, which has a shelf life
`of at least 24 hours (b) at s25° C., at least 48 bat s25° C.,
`at least 72 bat s25° C., of from 24 h to l 20 bat s25° C.,
`from 24 h to 96 h at s 25° C .. from 24 h to 84 b at s25° s
`C., fro1n 24 h 10 72 bat s25° C., in particular has a shelf
`life of 72 b at s25° C.
`21. The pharmaceutical 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
`)east 50 GBq, at least 70 GBq.
`22a. The pharmaceutical aqueous solution according to any
`one of the preceding embodiments, which is ready-to-use.
`22b. The pharmaceutical aqueous solution according to any 15
`one of the preceding embodiments. which is for commer(cid:173)
`cial use.
`23. A pharmacemical aqueous solution, comprising
`(a) a complex fonned by
`(ai) the radionuclide 177Lutetium (Lu-l 77), present in a 20
`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
`binging organic moiety OOTA-TATE (oxodot-
`reotide) or DOTA-TOC (edotreotide);
`(bi) gentisic acid or a salt thereof as the first stabilizer
`against radiolyl'ic degradation present in a concentra(cid:173)
`tion of from 0.5 to 1 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 mg/mL.
`24. T he 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 mg/mL. 35
`25. The pharmaceutical aqueous solution according to
`embodiments 23 or 24. further comprising:
`(d) acetic acid in a concentration of from 0.3 to 0.7
`mg/mL 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 formation of components (ai) and (aii).
`27. The phannaceutical aqueous solution according to any 45
`one of embodiments 5 to 26 wherein only the first
`stabilizer is present during the complex fonnatfon of
`components (ai) and (aii), preferably iJ1 an amount to
`result in a concentration of from 0.5 to 5 rug/mL, more
`preferably from 0.5 to 2 rug/mL, even more preferably 50
`from 0.5 to 1 mg/m.L. even more preferably from 0.5 to
`0.7 mg/mL, in the fina l solution.
`28. The phannaceutical 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 55
`during the complex fonnation of components (ai) and (aii)
`and another part of the amount of the second stabilizer is
`added after the complex fom1ation of components (ai) and
`(aii).
`29. ll1e 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 formation of components (ai) and
`(aii), preferably in an amount to result in a concentration
`
`40
`
`8
`of from 0.5 to 10 mg/mL, more preferably from 1.0 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 mg/mL. 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 0.01
`t