WO2022043556A1 - Composition pharmaceutique stable - Google Patents

Composition pharmaceutique stable Download PDF

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Publication number
WO2022043556A1
WO2022043556A1 PCT/EP2021/073897 EP2021073897W WO2022043556A1 WO 2022043556 A1 WO2022043556 A1 WO 2022043556A1 EP 2021073897 W EP2021073897 W EP 2021073897W WO 2022043556 A1 WO2022043556 A1 WO 2022043556A1
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Prior art keywords
pharmaceutical composition
salts
acid
mci
cas
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PCT/EP2021/073897
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English (en)
Inventor
Donato BARBATO
Lorenza Fugazza
Mattia TEDESCO
Elena CASTALDI
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Novartis Ag
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Publication of WO2022043556A1 publication Critical patent/WO2022043556A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds

Definitions

  • the present disclosure relates to pharmaceutical compositions with radiolabeled PSMA ligand of high concentration and of high chemical and radiochemical stability that allow their use as commercial drug products for diagnostic and/or therapeutic purposes.
  • Prostate cancer is one of the most widespread cancers in the US and in Europe.
  • metastatic prostate cancer mCRPC is associated with poor prognosis and diminished quality of life.
  • PSMA Proliferative a new development stream for treating prostate cancer is represented by the endoradiotherapy based on PSMA ligands, as PSMA is considered to be a suitable target for imaging and therapy due to its over-expression in primary cancer lesions and in soft- tissue/bone metastatic disease. Also, PSMA expression seems to be even higher in the most aggressive castration-resistant variants of the disease, which represents a patient population with high unmet medical need.
  • the urea-based low molecular weight agents have been the most extensively investigated ones. These agents were shown to be suitable for prostate cancer clinical assessment as well as for PRRT therapy (Kiess et aL, Q J Nucl Med Mol Imaging, 2015;59:241 -68). Some of these agents have glutamate-urea- lysine (GUL) as the targeting scaffold. A class of molecules was created following the strategy to attach a linker between the chelator and GUL moiety. This approach allows the urea to reach the binding site while keeping the metal chelated portion on the exterior of the binding site.
  • GUL glutamate-urea- lysine
  • the target cell receptor binding moiety is typically linked to a chelating agent which is able to form a strong complex with the metal ions of a radionuclide.
  • This radiopharmaceutical drug is then delivered 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.
  • radiolysis 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 form part of the drug product. This is often referred to as radiolysis or radiolytic degradation.
  • the radiolytic 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 drug product may be stored at low temperatures, or produced in high dilution, or stabilizers may be added.
  • 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-term elevated temperatures so that it can be produced on commercial scale and supplied as a ready-to-use radiopharmaceutical product.
  • a pharmaceutical composition comprising:
  • radionuclide is selected from 111 In, 133m ln, 99m Tc, 94m Tc, 67 Ga, 66 Ga, 68 Ga, 52 Fe, 169 Er, 7 2 As, 97 Ru, 203 Pb, 212 Pb, 62 Cu, 64 Cu, 67 Cu, 186 Re, 188 Re, 86 Y, 90 Y, 51 Cr, 52m Mn, 157 Gd, 1 77 Lu, 161 Tb, 169 Yb, 175 Yb, 105 Rh, 166 Dy, 166 Ho, 153 Sm, 149 Pm, 151 Pm, 172 Tm, 121 Sn, 1 17m Sn, 213 Bi, 212 Bi, 142 Pr, 143 Pr, 198 Au, 199 Au, 89 Zr, 225 Ac, 43 Sc, 44 Sc, 47 Sc, and 55 Co, preferably selected from 177 Lu and 68 Ga, more preferably is 177 Lu.
  • said chelating agent is selected from DOTA, DTPA, NTA, EDTA, DO3A, AAZTA, NODAGA, TETA and NOTA, preferably is DOTA.
  • Z is tetrazole or COOQ, preferably Z is COOQ;
  • Q is independently H or a protecting group, preferably Q is H; m is an integer selected from the group consisting of 1 , 2, 3, 4, and 5, preferably m is 4; q is an integer selected from the group consisting of 1 , 2, 3, 4, 5, and 6, preferably q is 1 ;
  • R is selected from the group consisting of C 6 -Ci 0 aryl and heteroaryl containing 5 to 10 ring atoms, said aryl and heteroaryl being substituted one or more times with X;
  • X is -Z 1 -Y
  • Z 1 is a bond or a Ci-C 6 alkylene, preferably Z 1 is a bond;
  • Y is a halogen
  • R 2 is H or C1-C4 alkyl, preferably R 2 is H; n is an integer selected from the group consisting of 1 , 2 and 3;
  • Ch is a chelating agent, preferably
  • said at least two stabilizer 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 ascorbate), methionine, histidine, melatonin, ethanol, and Se-methionine, preferably selected from gentisic acid or salts thereof and ascorbic acid or salts thereof.
  • the pharmaceutical composition according to any of embodiments 8 to 11 wherein said gentisic acid or salts thereof is present at a concentration between 600 pg/mL and 5000 pg/mL, preferably about 2800 pg/mL and ascorbic acid or salts thereof is present at a concentration between 3000 pg/mL and 15000 pg/mL, preferably about 8550 pg/mL.
  • said pharmaceutical formulation has a radiochemical purity higher than 95% up to 72 hours.
  • a process for manufacturing a pharmaceutical composition comprising: (a) a complex formed by
  • a process for manufacturing a pharmaceutical composition comprising:
  • cancer refers to cells having the capacity for autonomous growth, i.e., an abnormal state or condition characterized by rapidly proliferating cell growth.
  • Hyperproliferative and neoplastic disease states may be categorized as pathologic, i.e., characterizing or constituting a disease state, or may be categorized as non-pathologic, i.e., a deviation from normal but not associated with a disease state.
  • pathologic i.e., characterizing or constituting a disease state
  • non-pathologic i.e., a deviation from normal but not associated with a disease state.
  • the term is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness.
  • protecting group in reference to compounds of formula (I) refers to a chemical substituent which can be selectively removed by readily available reagents which do not attack the regenerated functional group or other functional groups in the molecule.
  • Suitable protecting groups are known in the art and continue to be developed. Suitable protecting groups may be found, for example in Wutz et al. ("Greene's Protective Groups in Organic Synthesis, Fourth Edition," Wiley- Interscience, 2007). Protecting groups for protection of the carboxyl group, as described by Wutz et al. (pages 533-643), are used in certain embodiments. In some embodiments, the protecting group is removable by treatment with acid.
  • protecting groups include, but are not limited to, benzyl, p- methoxybenzyl (PMB), tertiary butyl (t-Bu), methoxymethyl (MOM), methoxyethoxymethyl (MEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), benzyloxymethyl (BOM), trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBDMS), and triphenylmethyl (trityl, Tr).
  • PMB p- methoxybenzyl
  • t-Bu tertiary butyl
  • MEM methoxymethyl
  • MTM methoxyethoxymethyl
  • THF tetrahydrofuranyl
  • BOM benzyloxymethyl
  • TMS trimethylsilyl
  • TES triethylsilyl
  • TDMS t-
  • aryl refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring or multiple aromatic rings fused together, containing 6 to 10 ring atoms, wherein at least one ring is aromatic.
  • the aromatic ring may optionally include one to two additional rings (cycloalkyl, heterocyclyl or heteroaryl as defined herein) fused thereto.
  • Suitable aryl groups include phenyl, naphthyl and phenyl ring fused to a heterocyclyl, like benzopyranyl, benzodioxolyl, benzodioxanyl and the like.
  • alkyl refers to a linear or branched alkyl functional group having 1 to 6 carbon atoms. Suitable alkyl groups include methyl, ethyl, n-propyl, /-propyl, n-butyl, /-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g. n-pentyl, /so-pentyl), and hexyl and its isomers (e.g. n-hexyl, /so-hexyl).
  • alkylene refers to a divalent saturated, straight-chained or branched hydrocarbon group having 1 20 carbon atoms, preferably 1-12, more preferably 1- 6.
  • heteroalkyl refers to a linear or branched alkyl functional group having 1 to 6 carbon atoms and from one to three, heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
  • cycloalkyl refers to a saturated or unsaturated cyclic group having 3 to 6 carbon atoms. Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • halogen refers to a fluoro (-F), chloro (-CI), bromo (-Br), or iodo (-I) group.
  • alkoxy refers to a -O-alkyl group, wherein the alkyl group is a Ci- C 6 alkyl as defined herein. Suitable alkoxy groups include methoxy, ethoxy, propoxy.
  • heteroaryl refers to a polyunsaturated, aromatic ring system having a single ring or multiple aromatic rings fused together or linked covalently, containing 5 to 10 atoms, wherein at least one ring is aromatic and at least one ring atom is a heteroatom selected from N, O and S.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • Such rings may be fused to an aryl, cycloalkyl or heterocyclyl ring.
  • Non-limiting examples of such heteroaryl include: furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, purinyl, benzothiadiazolyl, quinolinyl
  • heterocyclyl or “heterocylcoalkyl” refer to a saturated or unsaturated cyclic group having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom selected from N, O and S.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • heterocycle examples include, but are not limited to, tetrahydropyridyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothienyl, piperazinyl, 1-azepanyl,imidazolinyl, 1 ,4-dioxanyl and the like.
  • % has herein the meaning of weight percent (wt%), also referred to as weight by weight percent (w/w%).
  • volumetric radioactivity expressed may vary for ⁇ 10%, preferably ⁇ 5%, even more preferably ⁇ 2%, even more preferably ⁇ 1%.
  • total concentration sum of one or more individual concentrations.
  • aqueous solution a solution of one or more solute in water.
  • the radionuclide metal ion is forming a non-covalent bond with the functional groups of the chelating agent, e.g. amines or carboxylic acids.
  • the chelating agent has at least two such complexing functional groups to be able to form a chelate complex.
  • Buffer for a pH from 4 to 6.0 may be an acetate buffer, citrate buffer (e.g. citrate + HCI or citric acid + Disodium hydrogenphosphate) or phosphate buffer (e.g. Sodium dihydrogenphosphate + Disodium hydrogenphosphate), preferably said buffer is an acetate buffer, preferably said acetate buffer is composed of acetic acid and sodium acetate.
  • citrate buffer e.g. citrate + HCI or citric acid + Disodium hydrogenphosphate
  • phosphate buffer e.g. Sodium dihydrogenphosphate + Disodium hydrogenphosphate
  • Radionuclide metal ions preferably DTPA: Diethylentriaminepentaacetic acid.
  • the drug product e.g. a pharmaceutical aqueous solution
  • the drug product is able to obtain (preferably has obtained) marketing authorization by health authorities, e.g. US- FDA or EMA, by complying with all drug product quality and stability requirements as demanded by such health authorities, is able to be manufactured (preferably is manufactured) from or at a pharmaceutical production site at commercial scale followed by a quality control testing procedure, and is able to be supplied (preferably is supplied) to remotely located end users, e.g. hospitals or patients.
  • therapeutic agents in the combination can be administered concurrently with, prior to, or subsequent to, one or more other additional therapies or therapeutic agents.
  • the therapeutic agents or therapies can be administered in any order. In general, each therapeutic agent will be administered at a dose and/or using a regimen determined for that therapeutic agent. It will further be appreciated that the therapeutic agents utilized in this combination may be administered together in a single composition or administered separately in different compositions. In some embodiments, the therapeutic agents utilized in combination can be utilized at levels that do not exceed the levels at which they are typically utilized individually. In some embodiments, the levels of the therapeutic agents utilized in combination can be lower than those utilized individually.
  • the chelating agent in the context of the present disclosure may be
  • DOTA 1 ,4,7,10-Tetraazacyclododecane-1 ,4,7,10-tetraacetic acid
  • NTA Nitrilotriacetic acid
  • DO3A 1 ,4,7,10-Tetraazacyclododecane-1 ,4,7-triacetic acid
  • NOTA 1 ,4,7-Triazacyclononane-1 ,4,7-triacetic acid
  • NODAGA 1 ,4,7-triazacyclononane,1 -glutaric acid-4, 7-acetic acid
  • AAZTA 1 ,4-bis(carboxymethyl)-6-[bis(carboxymethyl)] amino- 6-methylperhydro-1 ,4-diazepine) or mixtures thereof, preferably is DOTA.
  • linking bond(s) is (are) either covalent or non-covalent bond(s) between the PSMA binding ligand (and the linker) and the chelating agent, preferably the bond(s) is (are) covalent.
  • “Stabilizer against radiolytic degradation” stabilizing agent which protects organic molecules against radiolytic degradation, e.g. when a gamma ray emitted from the radionuclide is cleaving a bond between the atoms of an organic molecules and radicals are formed, those radicals are then scavenged by the stabilizer which avoids the radicals undergoing any other chemical reactions which might lead to undesired, potentially ineffective or even toxic molecules. Therefore, those stabilizers are also referred to as “free radical scavengers” or in short “radical scavengers”. Other alternative terms for those stabilizers are “radiation stability enhancers”, “radiolytic stabilizers”, or simply “quenchers”.
  • the ratio between gentisic acid or salts thereof (GA) and ascorbic acid or salts thereof (AA)” is free acid concentration ratio (pg/mL:pg/mL), i.e. concentration ratio with respect to GA and AA as free acids wherein the concentration of counter-ions, such as sodium (Na), is not taken into calculation.
  • concentration of gentisic acid or salts thereof and ascorbic acid or salts thereof is expressed in pg/mL. When a concentration is given for gentisic acid or salts thereof and ascorbic acid or salts thereof, the concentration is intended to mean the free acid concentration. The person skilled in the art can readily determine the concentration of the corresponding salt.
  • Radiochemical purity is that percentage of the stated radionuclide that is present in the stated chemical or biological form. Radiochromatography methods, such as HPLC method or instant Thin Layer Chromatography method (iTLC), are the most commonly accepted methods for determining radiochemical purity in the nuclear pharmacy. “at room temperature”: is intended to mean a temperature between about 20°C and about 25°C.
  • the present disclosure concerns a pharmaceutical composition, in particular a radiopharmaceutical composition.
  • the pharmaceutical composition is for intravenous (IV) use/application/administration.
  • IV intravenous
  • the solution is stable, concentrated, and ready-to-use.
  • the PSMA binding ligand linked to a chelating agent is a molecule comprising a) a urea of 2 amino-acid residues, typically a glutamate-urea-lysine (GUL) moiety, and b) a chelating agent which can coordinate radioactive isotope.
  • GUL glutamate-urea-lysine
  • the PSMA binding ligand is a compound of formula (I):
  • Z is tetrazole or COOQ, preferably Z is COOQ;
  • R is selected from the group consisting of C 6 -Ci 0 aryl and heteroaryl containing 5 to
  • X is - Z 1 -Y
  • Z 1 is a bond or a Ci-C 6 alkylene, preferably Z 1 is a bond;
  • Y is a halogen
  • R 2 is H or C1-C4 alkyl, preferably R 2 is H; n is an integer selected from the group consisting of 1 , 2 and 3;
  • Ch is a chelating agent, preferably
  • Compounds of formula (I) include the stereoisomers of formulae (la), (lb), (Ic) and (Id):
  • R’, R” and R’ each may independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.
  • X is selected from Br and I.
  • Ch can be selected from the group consisting of:
  • m is 4, Z is COOQ, and Q is H.
  • the PSMA binding ligand is a compound of formula (II):
  • the compound of formula (II) can be referred to as PSMA-R2.
  • the PSMA binding ligand is a compound of formula (III):
  • the compound of formula (III) can be referred to as PSMA-Cpd2.
  • an aliphatic linker Boc-6-aminohexanoic acid can be coupled on the same e-Lys amine of 2, for example using a base (like N, IMdiisopropylethylamine) and a coupling agent (like N,N,N',N'-Tetramethyl-O-(N- succinimidyl)uronium tetrafluoroborate or 1 -[Bis(dimethylamino)methylene]-1 H-1 ,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate), to yield compound 3.
  • Compound 3 can then be deprotected to yield compound 4, for example using an acid like trifluoroacetic acid.
  • conjugation with commercially available DOTA-NHS ester can be performed to yield compound (II).
  • radiolabeled PSMA binding ligand linked to a chelating agent also called radiolabeledPSMA-R2
  • the radiolabeled PSMA binding ligand linked to a chelating agent can be manufactured both automatically, for example by using the MiniAIO synthesizer or other synthesizers known in the art for automated synthesis, and manually.
  • the present disclosure relates to a process for manufacturing a pharmaceutical composition
  • a process for manufacturing a pharmaceutical composition comprising:
  • the labelling step aims at forming a complex of the radionuclide and the PSMA binding ligand linked to a chelating agent.
  • this labelling step can be conducted by firstly providing an aqueous solution comprising an aqueous solution comprising the PSMA binding ligand linked to a chelating agent of formula (II), in the presence of at least one stabilizer against radiolytic degradation, for example gentisic acid.
  • the preparation can be done by adding a reaction solution to an aqueous solution containing the PSMA binding ligand linked to a chelating agent of formula (II).
  • the reaction solution comprises a stabilizer against radiolytic degradation. The stabilizer against radiolytic degradation protects the PSMA binding ligand linked to a chelating agent from radiolysis during the labelling step.
  • the stabilizer against radiolytic degradation is gentisic acid or salts thereof.
  • This gentisic acid or salts thereof can be added only during the labelling step, or, a part of this gentisic acid or salts thereof can be added during the labelling step and the other part can be added at the end of the process, during the formulation step.
  • the reaction solution comprises gentisic acid or salts thereof at a concentration of at least 600 pg/mL, preferably at least 1000 pg/mL, and more preferably at least 2000 pg/mL, typically between 600 pg/mL and 5000 pg/mL, preferably between 1500 Hg/mL and 3000 pg/mL, more preferably between 2000 and 3000 pg/mL, even more preferably between 2500 and 3000 pg/mL, even more preferably between 2600 and 3000 pg/mL, even more preferably about 2800 pg/mL.
  • the reaction solution comprises gentisic acid or salts thereof at a concentration between 50 pg/mL and 2000 pg/mL, preferably between 200 pg/mL and 1600 pg/mL, more preferably between 400 pg/mL and 1200 pg/mL, more preferably between 600 pg/mL and 1000 pg/mL, more preferably between 700 pg/mL and 900 pg/mL, more preferably about 800 pg/mL.
  • the reaction solution further comprises a buffer.
  • the buffer allows maintaining the labelling pH from 3.5 to 6.5, preferably from 3.5 to 5.0, more preferably from 3.5 to 4.5, even more preferably about 4.0.
  • the buffer is selected from acetate buffer, citrate buffer and phosphate buffer. More preferably the buffer is acetate buffer.
  • an aqueous solution comprising the radionuclide is provided.
  • This aqueous solution comprising the radionuclide is added and mixed to the aqueous solution containing PSMA binding ligand linked to a chelating agent in the presence of at least one stabilizer against radiolytic degradation previously obtained thereby obtaining a complex solution.
  • the radionuclide is selected from 111 In, 133m ln, 99m Tc, 94m Tc, 67 Ga, 66 Ga, 68 Ga, 52 Fe, 169 Er, 72 As, 97 Ru, 203 Pb, 212 Pb, 62 Cu, 64 Cu, 67 Cu, 186 Re, 188 Re, 86 Y, 90 Y, 51 Cr, 52m Mn, 157 Gd, 177 Lu, 161 Tb, 169 Yb, 175 Yb, 105 Rh, 166 Dy, 166 Ho, 153 Sm, 149 Pm, 151 Pm, 172 Tm, 121 Sn, 117m Sn, 213 Bi, 212 Bi, 142 Pr, 143 Pr, 198 Au, 199 Au, 89 Zr, 225 Ac, 43 Sc, 44 Sc, 47 Sc, and 55 Co, preferably selected from 177 Lu and 68 Ga, and more preferably is 177 Lu.
  • the aqueous solution comprises 177 Lu as the radionuclide and HCL
  • the radionuclide 177 Lu is present in complexed form 177 LuCI 3 .
  • the radionuclide is present at a concentration so that it provides a volumetric radioactivity of at least 0.1 mCi/mL, preferably from 0.1 mCi/mL to 100 mCi/mL, more preferably from 0.1 mCi/mL to 30 mCi/mL, more preferably from 0.1 mCi/mL to 20 mCi/mL, more preferably from 1 mCi/mL to 20 mCi/mL, more preferably from 2 mCi/mL to 20 mCi/mL, more preferably from 5 mCi/mL to 15 mCi/mL, more preferably from 7 mCi/mL to 13 mCi/mL, more preferably from 8 mCi/mL to 12 mCi/mL, more preferably from 9 mCi/mL to 11 mCi/mL, even more preferably of about 10 mCi/mL.
  • the radionuclide is present at a concentration so that it provides a volumetric radioactivity of at least 0.1 mCi/mL, preferably from 0.1 mCi/mL to 400 mCi/mL, more preferably from 0.1 mCi/mL to 120 mCi/mL, more preferably from 0.1 mCi/mL to 80 mCi/mL, more preferably from 20 mCi/mL to 80 mCi/mL, more preferably from 25 mCi/mL to 60 mCi/mL, more preferably from 30 mCi/mL to 50 mCi/mL, more preferably from 35 mCi/mL to 45 mCi/mL, even more preferably of about 40 mCi/mL.
  • the molar ratio between the PSMA binding ligand linked to a chelating agent and the radionuclide, preferably 177 Lu is at least 1.25, preferably at least 1.5, preferably from 1 .25 to 6, more preferably from 1 .5 to 5, even more preferably from 1 .5 to 4.
  • the labelling step can be conducted at a room temperature or at a temperature of from 65°C to 99 °C, preferably from 70°C to 95 °C, and more preferably about 95°C, for from 1 to 59 min, preferably about 2 to 30 min, more preferably about 2 to 20 min, even more preferably about 2 to 15 min, even more preferably about 5 to 15 min or 5 to 12 min, and even more preferably about 5 min.
  • the formulation step aims at diluting the complex solution obtained at the end of the labelling step in order to obtain the desired volumetric radioactivity.
  • this formulation step can be conducted by firstly providing an aqueous dilution solution comprising at least one stabilizer against radiolytic degradation selected from the group consisting of ascorbic acid or salts thereof and gentisic acid or salts thereof.
  • the salt of ascorbic acid is sodium ascorbate.
  • the aqueous dilution solution comprises only one stabilizer against radiolytic degradation which is ascorbic acid or salts thereof.
  • the aqueous dilution solution comprises ascorbic acid or salts thereof at a concentration of at least 3000 pg/mL, preferably 6000 pg/mL, more preferably at least 8000 pg/mL, typically between 3000 pg/mL and 15000 pg/mL, preferably between 6000 pg/mL and 12000 pg/mL, more preferably between 7500 pg/mL and 9000 pg/mL, even more preferably between 8000 pg/mL and 9000 pg/mL, even more preferably about 8500 pg/mL and 9000 pg/mL, even more preferably about 8550 pg/mL.
  • the aqueous dilution solution comprises ascorbic acid or salts thereof at a concentration of at least 3000 pg/mL, preferably 6000 pg/mL, more preferably at least 8000 pg/mL, typically between 3000 pg/mL and 15000 pg/mL, preferably between 6000 pg/mL and 12000 pg/mL, more preferably between 7500 pg/mL and 9000 pg/mL, even more preferably between 8000 pg/mL and 9000 pg/mL, even more preferably about 8500 pg/mL.
  • gentisic acid or salts thereof in a concentration between 500 pg/mL and 4000 pg/mL , preferably between 1000 pg/mL and 3000 pg/mL, more preferably between 1400 pg/mL and 2600 pg/mL, more preferably between 1600 pg/mL and 2400 pg/mL, more preferably between 1800 pg/mL and 2200 pg/mL, more preferably about 2000 pg/mL.
  • the aqueous dilution solution further comprises a sequestering agent, preferably diethylentriaminepentaacetic acid (DTPA) or a salt thereof.
  • DTPA or a salt thereof is present at a concentration between 50 pg/mL and 300 pg/mL, preferably between 100 pg/mL and 200 pg/mL, more preferably about 150 pg/mL.
  • the aqueous dilution solution further comprises a pH adjuster.
  • the pH adjuster is NaOH and/or HCI, more preferably NaOH and HCI.
  • NaOH is present at a concentration of between 0.5 mg/mL and 2 mg/mL, preferably between 1 mg/mL and 1 ,5mg/mL, more preferably about 1.35 mg/mL; and HCI is present at a concentration of between 1 mg/mL and 3mg/mL, preferably between 1.5 mg/mL and 2.5 mg/mL, more preferably about 1 .95 mg/mL.
  • the aqueous dilution solution further comprises a solvent.
  • the solvent is water for injection and/or saline solution, more preferably solvent is water for injection and saline solution.
  • the saline solution comprises 0.9% of sodium chloride (NaCI).
  • Such dilution solution is mixed to the complex solution obtained at the end of the labelling step, thereby obtaining the pharmaceutical composition
  • the pharmaceutical composition comprising:
  • the pharmaceutical composition can be filtered for sterilization for safe injection to the patient.
  • the filtration is done by using a filter with a membrane filter cutoff threshold of 0.2 pm, more preferably by using Pall Supor AEF 0.2 pm.
  • This filter has a polyethersulfone membrane with low chemical binding properties, as well as broad chemical and temperature resistance.
  • the pharmaceutical composition is produced at commercial scale manufacturing, in particular is produced at a batch size of at least 18.5GBq (0.5 Ci), for example at least 18.5 GBq (0.5 Ci), at least 37 GBq (1 Ci), or at least 55.5 GBq (1.5 Ci) and not more than 148 GBq (4 Ci), 129.5 GBq (3.5 Ci), 111 GBq (3 Ci), 92.5 GBq (2.5 Ci) or 74 GBq (2 Ci).
  • it is produced at a batch size between 18.5 GBq (0.5 Ci) and 148 GBq (4 Ci).
  • the pharmaceutical composition is for commercial use.
  • the radiolabeled PSMA binding ligand linked to a chelating agent has the tendency to degrade over time ending with radiochemical purity below the specifications at the end of the target shelf life (72 hours) which is a problem for formulating the pharmaceutical composition.
  • the stability of the solution is ascertained by the use of stabilizers against radiolytic degradation.
  • the stabilizers used in accordance with the present disclosure 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, and Se-methionine.
  • Preferred stabilizers are selected from gentisic acid or salts thereof and ascorbic acid or salts thereof.
  • the pharmaceutical composition of the present disclosure is substantially free of alcohol such as methanol, ethanol, propanol, butanol or mixtures thereof, e.g. less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.05%, or less than 10ppm, preferably less than 2%, more preferably less than 1% in the final pharmaceutical composition which is foreseen to be injected or infused to a subject.
  • alcohol such as methanol, ethanol, propanol, butanol or mixtures thereof, e.g. less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.05%, or less than 10ppm, preferably less than 2%, more preferably less than 1% in the final pharmaceutical composition which is foreseen to be injected or infused to a subject.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a radiolabeled PSMA binding ligand linked to a chelating agent as described herein, and at least two stabilizers against radiolytic degradation.
  • said at least two stabilizer can 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, and Se- methionine, preferably selected from gentisic acid or salts thereof and ascorbic acid or salts thereof.
  • Said at least two stabilizers can be gentisic acid or salts thereof and ascorbic acid or salts thereof.
  • the inventors unexpectedly found that adding both ascorbic acid and gentisic acid in specific amounts in a pharmaceutical composition of a radiolabeled PSMA binding ligand linked to a chelating agent compound enables a radiochemical purity of said composition over 95% after 72 hours after synthesis.
  • the molar ratio between the PSMA binding ligand linked to a chelating agent and the radionuclide, preferably 177 Lu can be at least 1.25, preferably at least 1.5, preferably from 1 .25 to 6, more preferably from 1 .5 to 5, even more preferably from 1 .5 to 4.
  • the ratio between gentisic acid or salts thereof and ascorbic acid or salts thereof is between 1 :32 and 1 :1 , preferably between 1 :16 and 1 :2, more preferably between 1 :4 and 2:5.
  • said gentisic acid or salts thereof can be present in a concentration of least 600 pg/mL, preferably at least 1000 pg/mL, and more preferably at least 2000 pg/mL, preferably between 600 pg/mL and 5000 pg/mL, more preferably between 1500 pg/mL and 3000 pg/mL, more preferably between 2000 pg/mL and 3000 pg/mL, even more preferably between 2500 pg/mL and 3000 pg/mL, even more preferably between 2600 pg/mL and 3000 pg/mL, even more preferably about 2800 pg/mL.
  • said gentisic acid or salts thereof is present in a concentration between 600 pg/mL and 5000 pg/mL, preferably between 1500 pg/mL and 3000 pg/mL, more preferably between 2000 pg/mL and 3000 pg/mL, even more preferably between 2500 pg/mL and 3000 pg/mL, even more preferably between 2600 pg/mL and 3000 pg/mL, even more preferably about 2800 pg/mL and ascorbic acid or salts thereof can be present at a concentration between 3000 pg/mL and 15000 pg/mL, preferably between 6000 pg/mL and 12000 pg/mL, more preferably between 7500 pg/mL and 9000 pg/mL, even more preferably between 8000 pg/mL and 9000 pg/mL, more preferably between 8500 pg/mL and 9000
  • the radiopharmaceutical composition comprises, as stabilizers against radiolytic degradation, both gentisic acid and ascorbic acid, at the respective concentrations of about 2800 pg/mL and 8550 pg/mL.
  • the pharmaceutical composition has radiochemical purity higher than 95% up to 72 hours at room temperature, preferably equal to or higher than 97% up to 72h.
  • the pH of the pharmaceutical composition as described herein can be from 3.5 to 6.5 preferably from 3.5 to 5.0, more preferably from 3.5 to 4.5, even more preferably about 4.0.
  • the radiolabeled PSMA binding ligand linked to a chelating agent can be present in a concentration providing a volumetric radioactivity of at least 0.1 mCi/mL (at EOP), preferably from 0.1 mCi/mL to 100 mCi/mL, more preferably from 0.1 mCi/mL to 30 mCi/mL, even more preferably from 0.1 mCi/mL to 20 mCi/mL, even more preferably from 1 mCi/mL to 20 mCi/mL, even more preferably from 2 mCi/mL to 20 mCi/mL, even more preferably from 5 mCi/mL to 15 mCi/mL, even more preferably from 7 mCi/mL to 13 mCi/mL, even more preferably from 8 mCi/mL to 12 mCi/mL, even more preferably from 9 mCi/mL to 11 mCi/
  • the radionuclide can be present at a concentration so that it provides a volumetric radioactivity of at least 0.1 mCi/mL (at EOP), preferably from 0.1 mCi/mL to 400 mCi/mL, more preferably from 0.1 mCi/mL to 120 mCi/mL, even more preferably from 0.1 mCi/mL to 80 mCi/mL, even more preferably from 20 mCi/mL to 80 mCi/mL, even more preferably from 25 mCi/mL to 60 mCi/mL, even more preferably from 30 mCi/mL to 50 mCi/mL, even more preferably from 35 mCi/mL to 45 mCi/mL, even more preferably of about 40 mCi/mL.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a radiolabeled PSMA binding ligand linked to a chelating agent as described herein, at least two stabilizers against radiolytic degradation and at least one other pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient can be any of those conventionally used, and is limited only by physico-chemical considerations, such as solubility and lack of reactivity with the active compound(s).
  • the at least other pharmaceutically acceptable excipient can be selected from buffer, solvent, sequestering agent, pH adjuster and mixtures thereof.
  • Buffer includes acetate buffer, citrate buffer and phosphate buffer.
  • said buffer is acetate buffer.
  • said solvent is water for injection and/or saline solution.
  • said sequestering agent is diethylentriaminepentaacetic acid (DTPA) or a salt thereof.
  • said DTPA is present at a concentration between 50 pg/mL and 300 pg/mL, preferably between 100 pg/mL and 200 pg/mL, more preferably about 150 pg/mL.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • gentisic acid or salts thereof and ascorbic acid or salts thereof gentisic acid or salts thereof and ascorbic acid or salts thereof; a buffer, typically acetate buffer; a sequestering agent, typically DTPA; water for injection and saline solution; HCI and NaOH.
  • said gentisic acid or salts thereof is present at a concentration between 600 pg/mL and 5000 pg/mL, preferably between 1500 pg/mL and 3000 pg/mL, more preferably between 2000 pg/mL and 3000 pg/mL, even more preferably between 2500 pg/mL and 3000 pg/mL, even more preferably between 2600 pg/mL and 3000 pg/mL, even more preferably about 2800 pg/mL and said ascorbic acid or salts thereof is present at a concentration between 3000 pg/mL and 15000 pg/mL, preferably between 6000 pg/mL and 12000 pg/mL, more preferably between 7500 pg/mL and 9000 pg/mL, more preferably between 8000 pg/mL and 9000 pg/mL, more preferably about 8500 pg/mL and 9000 pg/m
  • the disclosure also relates to the pharmaceutical composition as described above for use in treating or preventing cancer, typically prostate cancer.
  • the pharmaceutical composition is produced at commercial scale manufacturing, in particular is produced at a batch size of at least 18.5 GBq (0.5 Ci), at least 37 GBq (1 Ci), or at least 55.5 GBq (1.5 Ci) and not more than 148 GBq (4 Ci), 129.5 GBq (3.5 Ci), 11 1 GBs (3 Ci), 92.5 GBq (2.5 Ci) or 74 GBq (2 Ci). Typically, it is produced at a batch size between 18.5 GBq (0.5 Ci) and 148 GBq (4 Ci).
  • the pharmaceutical composition is for commercial use.
  • the disclosure also relates a pharmaceutical composition
  • a pharmaceutical composition comprising a radiolabeled PSMA binding ligand linked to a chelating agent, typically 177 Lu-PSMA binding ligand linked to a chelating agent, also called 177 Lu-PSMA-R2, for use in treating or preventing cancer in a subject in need thereof, wherein said pharmaceutical composition is formulated with stabilizers as described in any of the previous embodiments, and is administered to said subject at a therapeutically efficient amount comprised between 0.5 mCi and 1000mCi, preferably between 50 mCi and 400mCi, typically with a radiochemical purity (RCP) superior to 95% at the time of administration.
  • RCP radiochemical purity
  • a therapeutically efficient amount of the composition is administered to said subject 1 to 8 times per treatment, preferably 3 times per treatment.
  • a human patient may be treated with said pharmaceutical composition comprising a radiolabeled PSMA binding ligand linked to a chelating agent, specifically 177 Lu- PSMA binding ligand linked to a chelating agent, also called 177 Lu-PSMA-R2, administered intravenously in 2 to 8 cycles of a 0.5 mCi to 1000 mCi each, typically with radiochemical purity (RCP) superior to 95% at the time of administration.
  • a radiolabeled PSMA binding ligand linked to a chelating agent specifically 177 Lu- PSMA binding ligand linked to a chelating agent, also called 177 Lu-PSMA-R2
  • RCP radiochemical purity
  • the pharmaceutical composition of the present invention are used in combination with other therapeutic agents, such as other anti-cancer agents, anti-allergic agents, anti-nausea agents, anti-emetic agents, pain relievers, cytoprotective agents, and mixtures thereof.
  • other therapeutic agents such as other anti-cancer agents, anti-allergic agents, anti-nausea agents, anti-emetic agents, pain relievers, cytoprotective agents, and mixtures thereof.
  • anastrozole (Arimidex®) bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC- Dome®), dacarbazine (DTIC- Dome®), dacarbazin
  • Tyrosine kinase inhibitors Erlotinib hydrochloride (Tarceva®); Linifanib (N-[4-(3-amino-1 H- indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, also known as ABT 869, available from Genentech); Sunitinib malate (Sutent®); Bosutinib (4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1 -yl)propoxy]quinoline-3- carbonitrile, also known as SKI-606, and described in US Patent No.
  • VEGF receptor inhibitors Bevacizumab (Avastin®), axitinib (Inlyta®); Brivanib alaninate (BMS-582664, (S)-((F?)-1 -(4-(4-Fluoro-2-methyl-1 H-indol- 5-yloxy)-5-methylpyrrolo[2,1 -f
  • Sorafenib (Nexavar®); Pazopanib (Votrient®); Sunitinib malate (Sutent®); Cediranib (AZD2171 , CAS 288383-20-1 ); Vargatef (BIBF1120, CAS 928326-83-4); Foretinib (GSK1363089); Telatinib (BAY57-9352, CAS 332012-40-5); Apatinib (YN968D1 , CAS 811803-05-1); Imatinib (Gleevec®); Ponatinib (AP24534, CAS 943319-70-8); Tivozanib (AV951 , CAS 475108-18-0); Regorafenib (BAY73-4506, CAS 755037-03-7); Vatalanib dihydrochloride (PTK787, CAS 212141 -51-0); Brivanib (BMS-540215, CAS 649735-46-6); Vand
  • PDGF receptor inhibitors Imatinib (Gleevec®); Linifanib (N- [4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, also known as ABT 869, available from Genentech); Sunitinib malate (Sutent®); Quizartinib (AC220, CAS 950769-58-1); Pazopanib (Votrient®); Axitinib (Inlyta®); Sorafenib (Nexavar®); Vargatef (BIBF1120, CAS 928326-83-4); Telatinib (BAY57-9352, CAS 332012-40-5); Vatalanib dihydrochloride (PTK787, CAS 212141-51-0); and Motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2,3-di
  • FGFR Fibroblast Growth Factor Receptor
  • BMS-582664 Brivanib alaninate
  • S (S)- ((F?)-1 -(4-(4-Fluoro-2-methyl-1 H-indol-5-yloxy)-5-methylpyrrolo[2, 1 -f
  • Vargatef BIBF1120, CAS 928326-83-4
  • Dovitinib dilactic acid TKI258, CAS 852433-84-2
  • BGJ398, CAS 872511 -34- 7 Danusertib
  • Aurora kinase inhibitors Danusertib (PHA-739358); /V-[4-[[6-Methoxy-7-[3-(4- morpholinyl)propoxy]-4-quinazolinyl]amino]phenyl]benzamide (ZM447439, CAS 331771 -20- 1); 4-(2-Amino-4 -methyl-5-thiazolyl)-N-[4-(4-morpholinyl)phenyl]-2-pyrimidinamine (CYC116, CAS 693228-63-6); Tozasertib (VX680 or MK-0457, CAS 639089-54-6); Alisertib (MLN8237); (N- ⁇ 2-[6-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidine-2-ylamino)-(1 S,4R)- 1 ,2,3,4-tetrahydro-1 ,4-epiazano-na
  • Cyclin-Dependent Kinase (CDK) inhibitors Aloisine A; Alvocidib (also known as flavopiridol or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1 -methyl-4-piperidinyl]- 4-chromenone, and described in US Patent No.
  • CHK inhibitors 7-Hydroxystaurosporine (UCN-01 ); 6-Bromo-3-(1 - methyl-1 /-/-pyrazol-4-yl)-5-(3F?)-3-piperidinyl-pyrazolo[1 ,5-a]pyrimidin-7-amine (SCH900776, CAS 891494-63-6); 5-(3-Fluorophenyl)-3-ureidothiophene-2-carboxylic acid N-[(S)-piperidin- 3-yl]amide (AZD7762, CAS 860352-01 -8); 4-[((3S)-1 -Azabicyclo[2.2.2]oct-3-yl)amino]-3-(1 H- benzimidazol-2-yl)-6-chloroquinolin-2(1 H)-one (CHIR 124, CAS 405168-58-3); 7- Aminodactinomycin (7-A
  • 3-Phosphoinositide-dependent kinase-1 (PDK1 or PDPK1) inhibitors 7-2-Amino-/V-[4-[5-(2- phenanthrenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]phenyl]-acetamide (OSU-03012, CAS 742112-33-0); Pyrrolidine-1 -carboxylic acid (3- ⁇ 5-bromo-4-[2-(1 H-imidazol-4-yl)-ethylamino]- pyrimidin-2-ylamino ⁇ -phenyl)-amide (BX912, CAS 702674-56-4); and 4- Dodecyl- /V-1 ,3,4- thiadiazol-2-yl-benzenesulfonamide (PHT-427, CAS 1 191951 -57-1 ).
  • PDK Pyruvate Dehydrogenase Kinase inhibitors: (+)-Dehydroabietylamine; Dichloroacetic acid (DCA); and Leelamine.
  • PKT Protein Kinase B
  • AKT inhibitors 8-[4-(1 -Aminocyclobutyl)phenyl]-9-phenyl-1 ,2,4- triazolo[3,4-/][1 ,6]naphthyridin-3(2/-/)-one (MK-2206, CAS 1032349-93-1 ); Perifosine (KRX0401 ); 4- Dodecyl- /V-1 ,3,4-thiadiazol-2-yl-benzenesulfonamide (PHT-427, CAS 1191951 -57-1 ); 4-[2-(4-Amino-1 ,2,5-oxadiazol-3-yl)-1 -ethyl-7-[(3S)-3-piperidinylmethoxy]-1 H- imidazo[4,5-c]pyridin-4-yl]-2-methyl-3-butyn-2-ol (GSK690693, CAS 937174-76-0
  • PKC Protein Kinase C activators: Bryostatin I (bryo-1 ) and Sotrastaurin (AEB071 ).
  • B-RAF inhibitors Regorafenib (BAY73-4506, CAS 755037-03-7); Tuvizanib (AV951 , CAS 475108-18-0); Vemurafenib (Zelboraf®, PLX-4032, CAS 918504-65-1 ); 5-[l-(2- Hydroxyethyl)-3-(pyridin-4-yl)-lH-pyrazol-4-yl]-2,3-dihydroinden-l-one oxime (GDC-0879, CAS 905281 -76-7); 5-[2-[4-[2-(Dimethylamino)ethoxy]phenyl]-5-(4-pyridinyl)-1 H-imidazol-4- yl]-2,3-dihydro-1 H-lnden-1 -one oxime (GSK2118436 or SB590885); (+/-)-Methyl (5-(2-(5- chloro-2-methylphenyl)
  • C-RAF Inhibitors Sorafenib (Nexavar®); 3-(Dimethylamino)-/V-[3-[(4-hydroxybenzoyl)amino]- 4-methylphenyl]-benzamide (ZM336372, CAS 208260-29-1); and 3-(1-cyano-1 -methylethyl)- /V-[3-[(3,4-dihydro-3-methyl-4-oxo-6-quinazolinyl)amino]-4-methylphenyl]-benzamide (AZ628, CAS 1007871 -84-2).
  • G-CSF modulators Human Granulocyte colony-stimulating factor (G-CSF) modulators: Filgrastim (Neupogen®); Sunitinib malate (Sutent®); Pegilgrastim (Neulasta®) and Quizartinib (AC220, CAS 950769- 58-1).
  • c-KIT Inhibitors Pazopanib (Votrient®); Dovitinib dilactic acid (TKI258, CAS 852433-84-2); Motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1 H-indol- 6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide, described in PCT Publication No.
  • WO 02/066470 Masitinib (Masivet®); Regorafenib (BAY73-4506, CAS 755037-03-7); Tivozanib (AV951 , CAS 475108-18-0); Vatalanib dihydrochloride (PTK787, CAS 212141-51 - 0); Telatinib (BAY57-9352, CAS 332012-40-5); Foretinib (GSK1363089, formerly XL880, CAS 849217-64-7); Sunitinib malate (Sutent®); Quizartinib (AC220, CAS 950769-58-1); Axitinib (Inlyta®); Dasatinib (BMS-345825); and Sorafenib (Nexavar®).
  • Masitinib Mosivet®
  • Regorafenib BAY73-4506, CAS 755037-03-7
  • Bcr/Abl kinase inhibitors Imatinib (Gleevec®); Inilotinib hydrochloride; Nilotinib (Tasigna®); Dasatinib (BMS-345825); Bosutinib (SKI-606); Ponatinib (AP24534); Bafetinib (INNQ406); Danusertib (PHA-739358), AT9283 (CAS 1133385-83-7); Saracatinib (AZD0530); and N-[2- [(1 S,4F?)-6-[[4-(Cyclobutylamino)-5-(trifluoromethyl)-2-pyrimidinyl]amino]-1 ,2,3,4- tetrahydronaphthalen-1 ,4-imin-9-yl]-2-oxoethyl]-acetamide (PF-03814735, CAS 942487-16- 3).
  • IGF-1R inhibitors Linsitnib (OSI-906); [7-[frans-3-[(Azetidin-1 -yl)methyl]cyclobutyl]-5-(3- benzyloxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine (AEW541 , CAS 475488-34-7); [5-(3- Benzyloxyphenyl)-7-[frans-3-[(pyrrolidin-1 -yl)methyl]cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4- yl]amine (ADW742 or GSK552602A, CAS 475488-23-4); (2-[[3-Bromo-5-(1 ,1 -dimethylethyl)-
  • IGF-1R antibodies Figitumumab (CP751871 ); Cixutumumab (IMC-A12); Ganitumab (AMG- 479); Robatumumab (SCH-717454); Dalotuzumab (MK0646) R1507 (available from Roche); BIIB022 (available from Biogen); and MEDI-573 (available from Medlmmune).
  • PIM Kinase inhibitors 1 ,10-Dihydropyrrolo[2,3-a]carbazole-3-carbaldehyde (DHPCC-9); /V- [(1 -Methyl-4-piperidinyl)methyl]-3-[3-(trifluoromethoxy)phenyl]- lmidazo[1 ,2-b]pyridazin-6- amine sulfate (SGI-1776, CAS 1 173928-26-1 ); and CX-6258 (described in ACS Med. Chem. Lett., 2012, 3 (2), pp 135-139).
  • RESULTS 1000873-98-2 RESULTS 1000873-98-2
  • AMG 458 Cryzotinib (Xalkori®, PF-02341066); (3Z)-
  • HER2 receptor Human Epidermal Growth Factor Receptor 2 (HER2 receptor) (also known as Neu, ErbB-2, CD340, or p 185) inhibitors: Trastuzumab (Herceptin®); Pertuzumab (Omnitarg®); Neratinib (HKI-272, (2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7- ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide, and described PCT Publication No.
  • WO 05/028443 Lapatinib or Lapatinib ditosylate (Tykerb®); (3R,4R)-4-amino-1-((4-((3- methoxyphenyl)amino)pyrrolo[2,1 -f][1 ,2,4]triazin-5-yl)methyl)piperidin-3-ol (BMS690514); (2E)-/V-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-
  • mTOR inhibitors Temsirolimus (Torisel®); Ridaforolimus (formally known as deferolimus, (1 F?,2F?,4S)-4-[(2F?)-2 [(1 R,9S,12S,15R,16E,18R,19R,21 R, 23S,24E,26E,28Z,30S,32S,35R)-
  • Phosphoinositide 3-kinase (PI3K) inhibitors 4-[2-(1 H-lndazol-4-yl)-6-[[4-
  • BCL-2 inhibitors 4-[4-[[2-(4-Chlorophenyl)-5,5-dimethyl-1 -cyclohexen-1 -yl]methyl]-1 - piperazinyl]-N-[[4-[[(1 R)-3-(4-morpholinyl)-1 -[(phenylthio)methyl]propyl]amino]-3- [(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (also known as ABT-263 and described in PCT Publication No.
  • Mitogen -activated protein kinase (MEK) inhibitors include GDC-0973, Cas No. 1029872-29-4, available from ACC Corp.); Selumetinib (5-[(4-bromo-2- chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1 -methyl-1 H-benzimidazole-6- carboxamide, also known as AZD6244 or ARRY 142886, described in PCT Publication No.
  • P38 MAPK inhibitors Orantinib (TSU-68, CAS 252916-29-3); Dilmapimod (SB681323, CAS 444606-18-2); 6-[(Aminocarbonyl)(2,6-difluorophenyl)amino]-2-(2,4-difluorophenyl)- 3- pyridinecarboxamide (VX702); 8-Phenyl-2-(morpholin-4-yl)-chromen-4-one (LY294002, CAS 154447-36-6); 4-[4-(4-fluorophenyl)-2-[4-(methylsulfinyl)phenyl]-1 /-/-imidazol-5-yl]-pyridine (SB203580, CAS 152121 -47-6); 4-[4-(4-Fluorophenyl)-2-[4-(methylsulfinyl)phenyl]-1 H- imidazol-5-yl]-pyridine (
  • JAK inhibitors Ruxolitinib (Jakafi®); Tofacitinib (CP690550); Axitinib (AG013736, CAS 319460-85-0); 5-Chloro- A ⁇ -[(1 S)-1 -(5-fluoro-2-pyrimidinyl)ethyl]-/V 4 -(5-methyl-1 H-pyrazol-3- y)-l2,4-pyrimidinediamine (AZD1480, CAS 935666-88-9); and (9£ -15-[2-(1 - Pyrrolidinyl)ethoxy]- 7,12,26-Trioxa-19,21 ,24-triazatetracyclo[18.3.1 .1 25 .1 14 ’ 18 ]-hexacosa- 1 (24),2,4,9,14,16,18(25),20,22-nonaene (SB-1578, CAS 937273-04-6); Momelotinib (CY
  • Alkylating agents Oxaliplatin (Eloxatin®); Temozolomide (Temodar® and Temodal®); Dactinomycin (also known as actinomycin-D, Cosmegen®); Melphalan (also known as L- PAM, L-sarcolysin, and phenylalanine mustard, Alkeran®);Altretamine (also known as hexamethylmelamine (HMM), Hexalen®); Carmustine (BiCNU®); Bendamustine (Treanda®); Busulfan (Busulfex® and Myleran®); Carboplatin (Paraplatin®); Lomustine (also known as CCNU, CeeNU®); Cisplatin (also known as CDDP, Platinol® and Platinol®-AQ); Chlorambucil (Leukeran®); Cyclophosphamide (Cytoxan® and Neosar®); dacarbazine (also known as DTIC, DIC and
  • Topoisomerase I inhibitors Irinotecan (Camptosar®); Topotecan hydrochloride (Hycamtin®); and 7-Ethyl-10-hydroxycampothecin (SN38).
  • Topoisomerase II inhibitors Etoposide (VP-16 and Etoposide phosphate, Toposar®, VePesid® and Etopophos®); Teniposide (VM-26, Vumon®); and Tafluposide .
  • DNA Synthesis inhibitors Capecitabine (Xeloda®); Gemcitabine hydrochloride (Gemzar®); Nelarabine ((2F?,3S,4F?,5F?)-2-(2-amino-6-methoxy-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4- diol, Arranon® and Atriance®); and Sapacitabine (1 -(2-cyano-2-deoxy-p-D- arabinofuranosyl)-4-(palmitoylamino)pyrimidin-2(1 H)-one).
  • Folate Antagonists or Antifolates Trimetrexate glucuronate (Neutrexin®); Piritrexim isethionate (BW201 U); Pemetrexed (LY231514); Raltitrexed (Tomudex®); and Methotrexate (Rheumatrex®, Trexal®).
  • Immunomodulators Afutuzumab (available from Roche®); Pegfilgrastim (Neulasta®); Lenalidomide (CC-5013, Revlimid®); Thalidomide (Thalomid®), Actimid (CC4047); and IRX- 2 (mixture of human cytokines including interleukin 1 , interleukin 2, and interferon y, CAS 951209-71 -5, available from IRX Therapeutics).
  • Proapoptotic receptor agonists including DR4 (TRAILR1) and DR5 (TRAILR2): Dulanermin (AMG-951 , RhApo2L/TRAIL); Mapatumumab (HRS-ETR1 , CAS 658052-09-6); Lexatumumab (HGS-ETR2, CAS 845816-02-6); Apomab (Apomab®); Conatumumab (AMG655, CAS 896731-82-1); and Tigatuzumab (CS1008, CAS 946415-34-5, available from Daiichi Sankyo).
  • PARAs Proapoptotic receptor agonists
  • DR4 DR4
  • TRAILR2 DR5
  • Dulanermin AMG-951 , RhApo2L/TRAIL
  • Mapatumumab HRS-ETR1 , CAS 658052-09-6
  • Lexatumumab HS-ETR2, CAS 845816
  • Phospholipase A2 (PLA 2 ) inhibitors Manoalide; E-(3-Acetamide-1 -benzyl-2-ethylindolyl-5- oxy)propane sulfonic acid (LY311727); Anagrelide (Agrylin®); Methyl arachidonyl fluorophosphonate (MAFP); Arachidonyl trifluoromethyl ketone (AACOCF 3 ); (E)-6-(1- bromoethyle)tetrahydro-3-(1-naphthalenyl)-2/-/-pyran-2-one (Bromoenol lactone or BEL); R- Bromoenol lactone (R-BEL); S-Bromoenol lactone (S-BEL); Diisopropylfluorophosphate (DFP); Phenylmethylsulfonylfluoride (PMSF); and Pefabloc (CAS 34284-75-8, 4-[2- aminoeth
  • SRC inhibitors Dasatinib (Sprycel®); Saracatinib (AZD0530, CAS 379231 -04-6); Bosutinib (SKI-606, CAS 380843-75-4); 5-[4-[2-(4-Morpholinyl)ethoxy]phenyl]-/V-(phenylmethyl)- 2- pyridineacetamide (KX2-391 , CAS 897016-82-9); and 4-(2-Chloro-5-methoxyanilino)-6- methoxy-7-(1 -methylpiperidin-4-ylmethoxy)quinazoline (AZM475271 , CAS 476159-98-5).
  • Osteoclastic bone resorption inhibitors Zoledronate (Zometa®); Ibandronate (Boniva®); Alendronate (Fosamax®); Risedronate (Actonel®, Atelvia®, and Benet®); and Mineral trioxide aggregate (MTA).
  • G-Protein-coupled Somatostain receptors Inhibitors Octreotide (also known as octreotide acetate, Sandostatin® and Sandostatin LAR®); Lanreotide acetate (CAS 127984-74-1); Seglitide (MK678); Vapreotide acetate (Sanvar®); and Cyclo(D-Trp-Lys-Abu-Phe-MeAla- Tyr)( BIM23027).
  • Interleukin-11 and Synthetic lnterleukin-11 (IL-11): Oprelvekin (Neumega®).
  • Erythropoietin and Synthetic erythropoietin Erythropoietin (Epogen® and Procrit®); Darbepoetin alfa (Aranesp®); Peginesatide (Hematide®); and EPO covalently linked to polyethylene glycol (Micera®).
  • Receptor Activator for Nuclear Factor K B (RANK) inhibitors Denosumab (Prolia® and Xgeva®).
  • Thrombopoietin mimetic peptibodies Romiplostim (Nplate®).
  • Cell growth stimulators Palifermin (Kepivance®); Erythropoietin (Epogen® and Procrit®); Darbepoetin alfa (Aranesp®); Peginesatide (Hematide®); and EPO covalently linked to polyethylene glycol (Micera®).
  • Chlamydocin (S)-Cyclic(2-methylalanyl-L-phenylalanyl-D-prolyl-r
  • Biologic response modifiers include therapeutics such as interferons, interleukins, colonystimulating factors, monoclonal antibodies, vaccines (therapeutic and prophylactic), gene therapy, and nonspecific immunomodulating agents.
  • Interferon alpha Intron®, Roferson®- A
  • Interferon beta Interferon gamma
  • lnterleukin-2 IL-2 or aldesleukin, Proleukin®
  • Filgrastim Neuropogen®
  • Sargramostim Leukine®
  • Erythropoietin epoetin
  • Interleukin-11 oprelvekin
  • Imiquimod Aldara®
  • Lenalidomide Revlimid®
  • Rituximab Rituximab
  • Trastuzumab Herceptin®
  • Bacillus calmette-guerin theraCys® and TICE® BCG
  • Levamisole Ergamisol®
  • Anti-tumor antibiotics Doxorubicin (Adriamycin® and Rubex®); Bleomycin (lenoxane®); Daunorubicin (dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, Cerubidine®); Daunorubicin liposomal (daunorubicin citrate liposome, DaunoXome®); Mitoxantrone (DHAD, Novantrone®); Epirubicin (EllenceTM); Idarubicin (Idamycin®, Idamycin PFS®); Mitomycin C (Mutamycin®); Geldanamycin; Herbimycin; Ravidomycin; and Desacetylravidomycin.
  • Anti-microtubule or Anit-mitotic agents Vinca Alkaloids (such as Vinorelbine tartrate (Navelbine®), Vincristine (Oncovin®), and Vindesine (Eldisine®)); Taxanes (such as paclitaxel and docetaxel); and Estramustine (Emcyl® or Estracyt®);
  • Vinca Alkaloids such as Vinorelbine tartrate (Navelbine®), Vincristine (Oncovin®), and Vindesine (Eldisine®)
  • Taxanes such as paclitaxel and docetaxel
  • Estramustine Emcyl® or Estracyt®
  • Plant Alkaloids Paclitaxel (Taxol and OnxalTM); Paclitaxel protein-bound (Abraxane®); Vinblastine (also known as vinblastine sulfate, vincaleukoblastine and VLB, Alkaban-AQ® and Velban®); Vincristine (also known as vincristine sulfate, LCR, and VCR, Oncovin® and Vincasar Pfs®); and Vinorelbine (Navelbine®).
  • Paclitaxel Texol and OnxalTM
  • Paclitaxel protein-bound Abraxane®
  • Vinblastine also known as vinblastine sulfate, vincaleukoblastine and VLB, Alkaban-AQ® and Velban®
  • Vincristine also known as vincristine sulfate, LCR, and VCR, Oncovin® and Vincasar Pfs®
  • Vinorelbine® Vinorelbine®
  • Cathepsin K inhibitors Odanacatib (MK-0822, /V-(1 -cyanocyclopropyl)-4-fluoro-/ ⁇ - ⁇ (1 S)- 2,2,2-trifluoro-1-[4'-(methylsulfonyl)biphenyl-4-yl]ethyl ⁇ -L-leucinamide and described in PCT Publication no.
  • Epothilone B analogs Ixabepilone (Lxempra®); Patupilone (EP0906); Sagopilone (CAS 305841-29-6); and 21-Aminoepothilone B (BMS-310705, CAS 280578-49-6).
  • HSP Heat Shock Protein
  • Thrombopoietin (TpoR) agonists Eltrombopag (SB497115, Promacta® and Revolade®); and Romiplostim (Nplate®).
  • Kinesis Spindle Protein (KSP) inhibitors also known as Eg5 inhibitors: Monastrol (Ethyl 4- (3-hydroxyphenyl)-6-methyl-2-sulfanylidene-3,4-dihydro-1 H-pyrimidine-5-carboxylate);
  • Polo-like kinase (Plk) inhibitors (R)-4-[(8-Cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6- oxo-2-pteridinyl)amino]-3-methoxy-N-(1 -methyl-4-piperidinyl)benzamide (BI2536, CAS 755038-02-9); Wortmannin; Morin; Quercetin; Volasertib (BI6727); 8-Phenyl-2-(morpholin- 4-yl)-chromen-4-one (LY294002); 5-[6-[(4-Methylpiperazin-1-yl)methyl]-1 H-benzimidazol-1- yl]-3-[[(1 R)-1 -[2-(trifluoromethyl)phenyl]ethyl]oxy]-thiophene-2-carboxamide (GSK461364); (E)-4-[2-[2-[
  • Adrenal steroid inhibitors Aminoglutethimide (Cytadren®); Trilostane (Modrenal® or Vetoryl®); and Mitotane (Lysodren®).
  • Anti-androgens Nilutamide (Nilandron® and Anandron®); Bicalutamide (Casodex®); Megestrol (Megace®); Cyproterone acetate (Cyprostat®, Androcur®, or Cyproterone®), and Flutamide (FulexinTM or Eulexin®); Leuprolide (Lupron®, Viadur® or Eligard®); Foserelin (Zoladex®); Triptorelin (Trelstar Depot®); Abarelix (Plenaxis®) and Finasteride (Andozac® or MK-906).
  • Anabolic Steroids Fluoxymesterone (Halotestin®); OxymethoIone (Anadrol 50®); Oxandrolone (Oxandrin)®; and Stanozolol (Winstrol®).
  • Marizomib (NPI-0052); Ixazomib citrate (M LN-9708); Delanzomib (CEP-18770); and O- Methyl-/V-[(2-methyl-5-thiazolyl)carbonyl]-L-seryl-0-methyl-/V-[(1 S)-2-[(2F?)-2-methyl-2- oxiranyl]-2-oxo-1 -(phenylmethyl)ethyl]- L-serinamide (ONX-0912).
  • Gonadotropin-releasing hormone (GnRH) receptor agonists Leuprolide or leuprolide acetate (Viadure®, Eligard® and Lupron®); Buserelin (Suprefact® or Suprecor®); Nafarelin (Synarel®); Histrelin (Supprelin LA® or Vantas®); Goserelin (Zoladex®); Deslorelin (Suprelorin® or Ovuplant®); Degarelix (Firmagon®); and Triptorelin (Decapeptyl®, Diphereline®, Goapeptyl®, Trelstart® or Variopeptyl® 0.1 ).
  • HPV vaccines Human papilloma virus (HPV) vaccine (Cervarix® (ATC code J07BM02), and Gardasil® (ATC code J07BM01).
  • Iron Chelating agents Silybin; Curcumin; Ethylene diamine tetraacetic acid (EDTA); Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone); Di-2-pyridylketone thiosemicarbazon ; Di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone; Desferrioxamine; and Deferasinox (Exjade®).
  • Demethylating agents 5-Azacitidine (Vidaza®); and Decitabine (Dacogen®).
  • Cytokines lnterleukin-2 (also known as aldesleukin and IL-2, Proleukin®); Interleukin-11 (also known as oprevelkin, Neumega®); and Alpha interferon alfa (also known as IFN-alpha, Intron® A, and Roferon-A®).
  • Retinoids Alitretinoin (9-c/s-retinoic acid, Panretin®); Tretinoin (a ⁇ -trans retinoic acid, also known as ATRA, Vesanoid®); Isotretinoin (13-c/s-retinoic acid, Accutane®, Amnesteem®, Claravis®, Clarus®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®); Bexarotene (Targretin®), Liposomal retinoic acid; Tazarotene (Tazorac®, Avage® or Zorac®); a ⁇ -trans retinol; a ⁇ -trans retinaldehyde (also known as a ⁇ -trans retinal); a ⁇ -trans 4- oxo retinoic acid; retinyl palmitate; and retinyl acetate.
  • Estrogen receptor downregulators Fulvestrant (Faslodex®).
  • Anti-estrogens Tamoxifen (Novaldex®); Toremifene (Fareston®); and Fulvestrant (Faslodex®).
  • SERMs selective estrogen receptor modulators: Raloxifene (Evista®); Bazedoxifene; Tamoxifen (Nolvadex®); and Toremifene (Fareston®).
  • LHRH Leutinizing hormone releasing hormone agonists: Goserelin (Zoladex®); and Leuprolide acetate (Eligard® or Lupron®).
  • Megestrol also known as megestrol acetate, Megace®.
  • CYP17A1 17 a-hydroxylase/C17,20 lyase (CYP17A1) inhibitors: Abiraterone acetate (Zyitga®).
  • Miscellaneous cytotoxic agents Arsenic trioxide (Trisenox®); Asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, Elspar® and Kidrolase®); and Asparaginase Erwinia Chrysanthemi (Erwinaze®).
  • Asparaginase also known as L-asparaginase, Erwinia L-asparaginase, Elspar® and Kidrolase®
  • Asparaginase Erwinia Chrysanthemi Erwinaze®
  • C-C Chemokine receptor 4 (CCR4) Antibody Mogamulizumab (Potelligent®) CD20 antibodies: Rituximab (Riuxan® and MabThera®); and Tositumomab (Bexxar®); and Ofatumumab (Arzerra®).
  • CD20 Antibody Drug Conjugates Ibritumomab tiuxetan (Zevalin®); and Tositumomab,
  • CD22 Antibody Drug Conjugates Inotuzumab ozogamicin (also referred to as CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd.)
  • CD30 mAb-cytotoxin Conjugates Brentuximab vedotin (Adcetrix®);
  • CD33 Antibody Drug Conjugates Gemtuzumab ozogamicin (Mylotarg®),
  • CD40 antibodies Dacetuzumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc),
  • CD52 antibodies Alemtuzumab (Campath®)
  • Anti-CS1 antibodies Elotuzumab (HuLuc63, CAS No. 915296-00-3)
  • CTLA-4 inhibitor antibodies Tremelimumab (lgG2 monoclonal antibody available from Pfizer, formerly known as ticilimumab, CP-675,206); and Ipilimumab (CTLA-4 antibody, also known as MDX-010, CAS No. 477202-00-9).
  • TPH inhibitors telotristat
  • PARP poly ADP ribose polymerase inhibitors: olaparib (Lynparza), rucaparib (Rubraca), Niraparib (Ze fonda), Talazoparib, Veliparib.
  • PD-1 Inhibitors Spartalizumab (PDR001 , Novartis), Nivolumab (Bristol-Myers Squibb), Pembrolizumab (Merck & Co), Pidilizumab (CureTech), MEDI0680 (Medimmune), REGN2810 (Regeneron), TSR-042 (Tesaro), PF-06801591 (Pfizer), BGB-A317 (Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), or AMP-224 (Amplimmune).
  • PD-L1 inhibitors Durvalumab, Atezolizumab, Avelumab Radio-sensitizers: Idronoxil (Veyonda, also known as NOX-66), Sodium glycididazole, Nimorazole, NBTXR3 (also known as PEP503), [89Zr]AGulX, Lucanthone, Telomelysin (OBP-301 ), lonidamine, nimorazole, panobinostat, celecoxib, cilengitide, entinostat, etanidazole, ganetespib (STA-9090).
  • a pharmaceutical composition comprising:
  • radionuclide is present at a concentration so that it provides a volumetric radioactivity of at least 0.1 mCi/mL, preferably from 0.1 mCi/mL to 100 mCi/mL, more preferably from 0.1 mCi/mL to 30 mCi/mL, more preferably from 0.1 mCi/mL to 20 mCi/mL, more preferably from 1 mCi/mL to 20 mCi/mL, more preferably from 2 mCi/mL to 20 mCi/mL, more preferably from 5 mCi/mL to 15 mCi/mL, more preferably from 7 mCi/mL to 13 mCi/mL, more preferably from 8 mCi/mL to 12 mCi/mL, more preferably from 9 mCi/mL to 11 mCi/mL, even more preferably of about 10
  • Z 1 is a bond or a Ci-C 6 alkylene, preferably Z 1 is a bond;
  • Y is a halogen
  • compositions wherein said at least two stabilizers are gentisic acid or salts thereof and ascorbic acid or salts thereof.
  • composition according to embodiment 9 to 1 1 wherein said ascorbic acid or salts thereof is present at a concentration of at least 3000 pg/mL, preferably at least 6000 pg/mL, more preferably at least 8000 pg/mL, preferably between 3000 pg/mL and 15000 pg/mL, preferably between 6000 pg/mL and 12000 pg/mL, more preferably between 7500 pg/mL and 9000 pg/mL, more preferably between 8000 pg/mL and 9000 pg/mL, more preferably between 8500 pg/mL and 9000 pg/mL, even more preferably about 8550 pg/mL.
  • the pharmaceutical composition according to any of the preceding embodiments wherein said pharmaceutical formulation has a radiochemical purity higher than 95% up to 72 hours.
  • the pharmaceutical composition according to any of the preceding embodiments wherein the molar ratio between the (ii) PSMA binding ligand linked to a chelating agent and the (i) radionuclide, preferably 177 Lu, is at least 1 .25, preferably at least 1 .5, preferably from 1 .25 to 6, more preferably from 1 .5 to 5, even more preferably from 1.5 to 4.
  • composition (b) gentisic acid or salts thereof and ascorbic acid or salts thereof.
  • the buffer is selected from acetate buffer, citrate buffer and phosphate buffer, preferably acetate buffer.
  • a sequestering agent typically DTPA
  • 2800 pg/mL and ascorbic acid or salts thereof is present at a concentration between 3000 ng/mL and 15000 pg/mL, preferably between 6000 pg/mL and 12000 pg/mL, more preferably between 7500 pg/mL and 9000 pg/mL, more preferably between 8000 pg/mL and 9000 pg/mL, more preferably about 8500 pg/mL and 9000 pg/mL, even more preferably about 8550 pg/mL.
  • composition according to any of the preceding embodiments wherein the pharmaceutical composition consists of less than 10% ethanol, preferably less than 5% ethanol, more preferably less than 2% ethanol, even more preferably less than 1% ethanol, even more preferably the composition is free of ethanol.
  • composition according to any of the preceding embodiments for use in treating or preventing cancer, typically prostate cancer.
  • a process for manufacturing a pharmaceutical composition comprising:
  • step (2.2) mixing the complex solution obtained by step (1) with the aqueous dilution solution obtained in step (2.1) to obtain the pharmaceutical composition of embodiment 1 , and optionally filtering the pharmaceutical composition obtained in step (2.2) to produce the pharmaceutical composition of any of embodiments 1 to 28.
  • the aqueous solution prepared in step (1 .2) comprises only one stabilizer which is gentisic acid or salts thereof at a concentration of at least 600 pg/mL, preferably at least 1000 pg/mL, and more preferably at least 2000 pg/mL, typically between 600 pg/mL and 5000 pg/mL, preferably between 1500 pg/mL and 3000 pg/mL, more preferably between 2000 and 3000 pg/mL, more preferably between 2500 and 3000 pg/mL, more preferably between 2600 and 3000 pg/mL, even more preferably about 2800 pg/mL or at a concentration between 50 pg/mL and 2000 pg/mL, preferably between 200 pg/mL and 1600 pg/mL, more preferably between 400 pg/mL and 1200 pg/mL, more preferably between 600 pg/
  • PSMA binding ligand linked to a chelating agent is of formula (I): wherein:
  • Z is tetrazole or COOQ, preferably Z is COOQ;
  • Q is independently H or a protecting group, preferably Q is H; m is an integer selected from the group consisting of 1 , 2, 3, 4, and 5, preferably m is 4; q is an integer selected from the group consisting of 1 , 2, 3, 4, 5, and 6, preferably q is 1 ;
  • Z 1 is a bond or a Ci-C 6 alkylene, preferably Z 1 is a bond;
  • Y is a halogen
  • R 2 is H or C1-C4 alkyl, preferably R 2 is H; n is an integer selected from the group consisting of 1 , 2 and 3; Ch is a chelating agent, preferably
  • aqueous dilution solution prepared in step (2.1) comprises at least one stabilizer selected from the group consisting of ascorbic acid or salts thereof at a concentration of at least 3000 pg/mL, preferably 6000 pg/mL, more preferably at least 8000 pg/mL, typically between 3000 pg/mL and 15000 pg/mL, preferably between 6000 pg/mL and 12000 pg/mL, more preferably between 7500 pg/mL and 9000 pg/mL, more preferably between 8000 pg/mL and 9000 pg/mL, more preferably about 85 pg/mL and 9000 pg/mL, even more preferably about 8550 pg/mL and gentisic acid or salts thereof in a concentration between 500 pg/mL and 4000 pg/mL , preferably between 1000 pg/
  • step (1 .3) the resulting mixture is heated to a temperature of from 65 to 99 °C, preferably from 70 to 95 °C, more preferably about 70 °C, for from 1 to 59 min, preferably from 2 to 15 min, more preferably about 5 min. 40.
  • the aqueous dilution solution of step (2.1) further comprises a sequestering agent, preferably diethylentriaminepentaacetic acid (DTPA) or a salt thereof.
  • DTPA diethylentriaminepentaacetic acid
  • aqueous dilution solution of step (2.1) further comprises a pH adjuster, preferably NaOH and/or HCI.
  • aqueous dilution solution of step (2.1) further comprises a solvent, preferably water for injection and/or saline solution.
  • composition of embodiments 1 to 29 for its use in combination with another therapeutic agent selected in the group consisting of anti-cancer agents, anti-allergic agents, anti-nausea agents, anti-emetic agents, pain relievers, cytoprotective agents, and mixtures thereof.
  • compositions of embodiments 1 to 29 for its use in combination with another therapeutic agent selected in the group consisting of general chemotherapeutic agents, Tyrosine kinase inhibitors, Vascular Endothelial Growth Factor (VEGF) receptor inhibitors, Platelet-derived Growth Factor (PDGF) receptor inhibitors, Fibroblast Growth Factor Receptor (FGFR) Inhibitors, Aurora kinase inhibitors, Cyclin-Dependent Kinase (CDK) inhibitors, Checkpoint Kinase (CHK) inhibitors, 3-Phosphoinositide-dependent kinase-1 (PDK1 or PDPK1) inhibitors, Pyruvate Dehydrogenase Kinase (PDK) inhibitors, Protein Kinase B (PKB) or AKT inhibitors, Protein Kinase C (PKC) activators, B-RAF inhibitors, C-RAF Inhibitors, Human Granulocyte colony-stimulating factor (G-CSF) modulators, RET Inhibitors, F
  • the 177 LuCls may be obtained from commercial sources, e.g. LD.B. Holland BV. All other components of the drug product are commercially available from various sources.
  • the target characteristics which have been set for the development of 177 Lu-PSMA-R2 formulation are the following:
  • Lu-PSMA-R2 manufacturing is performed both automatically, by using the MiniAIO synthesizer, and manually.
  • the synthesis procedure has been developed as follows:
  • reaction buffer is composed of sodium acetate buffer and gentisic acid.
  • the acetate buffer allows to maintain the labelling pH between 4-5, while gentisic acid protects the PSMA-R2 from radiolysis during the labelling step;
  • the dilution solution is composed of ascorbic acid and/or gentisic acid (stabilizers against radiolytic degradation), DTPA (sequestering agent), NaOH (pH adjuster) and saline solution (tonicity agent).
  • Example 1 Effect of the molar ratio between PSMA-R2 and 177 Lu on the radiochemical purity
  • PSMA-R2 has a molecular weight of 987.89 g/mol and the following formula (II):
  • SA The specific activity
  • 177 LuCI 3 solution used as precursor for the radiolabelling contains also 176 Lu and 175 Lu isotopes. So, in this case, SA corresponds to the ratio between the radioactivity and the sum of all the Lu isotopes present in solution. Since all these isotopes compete together for complexation with the DOTA-moiety, it is important to define the maximum amount of ( 177+17 5+ 17 6)
  • Ascorbic acid and gentisic acid were tested in order to protect the labelled molecules from radiolytic degradation.
  • Reaction buffer Acetic acid/acetate buffer.
  • the radiolabelling tests have been carried out both manually and automatically by using the MiniAIO synthesizer.
  • the synthesis procedure has been developed as follows:
  • reaction buffer is composed of sodium acetate buffer and gentisic acid.
  • the acetate buffer allows to maintain the labelling pH between 4-5, while gentisic acid protects the PSMA-R2 from radiolysis during the labelling step;
  • Reaction buffer Acetic acid/acetate buffer.
  • the amount of ascorbic acid was fixed at 8000 pg/mL.
  • the synthesis was performed under the following conditions:
  • Reaction buffer Acetic acid/acetate buffer.
  • the radiolabelling has been carried out automatically by using the MiniAIO synthesizer.
  • the synthesis procedure has been performed as follows:
  • reaction buffer is composed of sodium acetate buffer and gentisic acid.
  • the acetate buffer allows to maintain the labelling pH between 4-5, while the gentisic acid protects the PSMA-R2 from radiolysis during the labelling step;
  • the dilution solution is composed of ascorbic acid (stabilizer against radiolytic degradation), DTPA (sequestering agent), NaOH (pH adjuster) and saline solution.
  • Scales up batches are manufactured during the process-development and optimization stage of the drugs.
  • the batch size is generally similar to the routine manufacturing and marketing of the product.
  • Production-scale batches are also useful to assist in the evaluation and definition of critical quality attributes (CQAs).
  • CQAs critical quality attributes
  • the 177 LuPSMA-R2 scale-up study has been designed with the aim of moving from the activities tested at R&D lab-scale (up to 200 mCi) to different batch sizes applicable at industrial level:
  • Reaction buffer Acetic acid/acetate buffer
  • the radiolysis can be reduced protecting the molecule with a suitable amount of radical scavengers.
  • gentisic acid or ascorbic acid were selected.
  • the oxidative degradation can be prevented by decreasing the amount of atmospheric O 2 into the vial, either by filling the 30 mL vial with the liquid formulation as much as possible (e.g. with 25 mL of solution), or by storing the finished product under nitrogen atmosphere.
  • the thermal degradation can be reduced by lowering the storage temperature of the finished product.
  • the synthesis module is used to prepare the Drug Substance (Mother Solution) containing the 177 Lu-labelled molecule.
  • the automatic synthesis process was developed to produce the radioactive Drug Substance as a sterile, aqueous concentrate mother solution.
  • Drug Substance synthesis steps were set up in the MiniAIO (TRASIS) synthesizer module, a self-contained closed-system synthesis module which is automated and remotely controlled by GMP compliant software with monitoring and recording of the process parameters.
  • MiniAIO TRASIS
  • Mini AIO radiosynthesizer module is widely used in the radiopharmaceutical industry for manufacture of PET radiopharmaceuticals. This module incorporates a disposable fluid path which is preferred over fixed fluid path devices since it ensures a sterile and pyrogen free fluid path and eliminates the possibility of a cross-contamination between batches.
  • the synthesis module is placed in a lead-shielded hot cell providing supply of Grade C HEPA filtered air.
  • the isolator is inside a clean Grade C laboratory room.
  • PSMA-R2 net amount 1 mg
  • Table 12 summarizes the radiochemical purity results obtained for the 177 LuPSMA-R2 1 Ci scale-up batch. As it can be noted, the radiochemical purity of the product at to meets the target specification being > 97%.
  • samples with final volume of 25 mL and 5 mL filled with air were placed both at 5°C and at room temperatures (samples 1-4).
  • Table 16 are described the characteristics and storage conditions for the dispensed samples.
  • Table 16 Samples characteristics and storage conditions Table 17 summarizes the stability results obtained for the 2 Ci batch. As shown, the radiochemical purity of the product at the end of the synthesis meets the specification (RCP% > 97%). No free 177Lu3+ was observed in HPLC radiochromatogram profile.
  • Table 20 are described the target formulation characteristics selected for the manufacturing of the 4 Ci batch size. Table 20 - Target formulation characteristics
  • Table 21 summarizes relevant parameters for the in process controls carried out on during the manufacturing of 4 Ci 177 LuPSMA scale up batch.
  • Ci batch allowed to dispense 22 samples that were subjected to different physicochemical conditions during the stability assessment of finished drug product.
  • samples with volume of 25 mL and 5 mL filled with air were placed at both 5°C and room temperature.
  • no supplemental gentisic acid was added at the formulation step (gentisic acid concentration 700 pg/mL).
  • the final gentisic acid concentration was doubled (about 1400 pg/mL), and they were stored at room temperature and at 40°C.
  • Samples 19-20 were dispensed with volume of 25 mL and 5 mL and stored at room temperature.
  • the gentisic acid concentration was also in this case around 700 pg/mL and the final pH was moved above 7 with 1 mL of NaOH 0.1 N.
  • samples 21 and 22 were both dispensed in a volume of 10 mL and then respectively diluted 1 :2 (final volumetric radioactivity 5 mCi/mL) and 2:3 (final volumetric radioactivity 6.66 mCi/mL) with saline solution. These samples were stored at room temperature. The gentisic acid concentration was about 700 pg/mL. The aim of these tests was to understand if there is correlation between the volumetric radioactivity and the stability of the drug substance.
  • Table 22 are described the characteristics and storage conditions of the samples dispensed during the 4 Ci production.
  • Sample 5 and 6 shows both a RCP% at the end of shelf life over 95%.
  • the pH of these samples is, respectively 5.33 and 5.36.
  • the improvement observed in these conditions should be due to the presence of the extraamount of stabilizer against radiolytic degradation compared to the previous samples.
  • the samples 13 and 14 (formulation with 2800 pg/mL of gentisic acid) stored at room temperature show both a RCP% at the end of shelf life over 95%.
  • the pH of these samples is, respectively 5.23 and 5.38.
  • the sample 18 was formulated with 700 p g/mL of gentisic acid and the final pH was adjusted around 4 with 1 mL of HCI 0.1 N.
  • the radiochemical purity after 3 days is 96.0 % and the pH measured is 3.80.
  • Example 7 Final formulation with 177 LuSR-VI-71 and detailed composition
  • a final formulation comprising 177 LuSR-VI-71 is prepared for an amount of 1 Ci according to Table 27.

Abstract

La présente invention concerne une composition pharmaceutique de concentration élevée et de stabilité chimique élevée, permettant une utilisation en tant que produit médicamenteux à des fins diagnostiques et/ou thérapeutiques. La stabilité du produit médicamenteux est obtenue au moyen d'au moins deux stabilisants contre la dégradation radiolytique. L'utilisation de deux stabilisants introduits pendant le procédé de fabrication s'est avérée comme étant particulièrement avantageuse. En particulier, la présente invention concerne une composition pharmaceutique comprenant : (a) un complexe formé par (i) un radionucléide, et (ii) un ligand de liaison à PSMA lié à un agent chélatant ; et (b) au moins deux stabilisants contre la dégradation radiolytique.
PCT/EP2021/073897 2020-08-31 2021-08-30 Composition pharmaceutique stable WO2022043556A1 (fr)

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WO2023219582A1 (fr) * 2022-05-13 2023-11-16 Eczacibaşi Monrol Nükleer Ürünler Sanayi̇ Ve Ti̇caret Anoni̇m Şi̇rketi̇ Produits radiopharmaceutiques à haute stabilité et efficacité de radiomarquage et kit théranostique comprenant lesdits produits radiopharmaceutiques

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023219582A1 (fr) * 2022-05-13 2023-11-16 Eczacibaşi Monrol Nükleer Ürünler Sanayi̇ Ve Ti̇caret Anoni̇m Şi̇rketi̇ Produits radiopharmaceutiques à haute stabilité et efficacité de radiomarquage et kit théranostique comprenant lesdits produits radiopharmaceutiques

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