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WO2008009444A1 - Utilisation de l'éthanol pour stabiliser une formulation liquide d'un peptide radiomarqué en flacon unique - Google Patents

Utilisation de l'éthanol pour stabiliser une formulation liquide d'un peptide radiomarqué en flacon unique Download PDF

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Publication number
WO2008009444A1
WO2008009444A1 PCT/EP2007/006405 EP2007006405W WO2008009444A1 WO 2008009444 A1 WO2008009444 A1 WO 2008009444A1 EP 2007006405 W EP2007006405 W EP 2007006405W WO 2008009444 A1 WO2008009444 A1 WO 2008009444A1
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peptide
labelled
ethanol
stabilizer
formulation
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Jack L. Erion
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/121—Solutions, i.e. homogeneous liquid formulation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to the use of ethanol in a single-vial liquid pharmaceutical formulation of a radiolabeled peptide, in a quantity sufficient to prevent radiolysis of said liquid formulation.
  • Radiolabelled peptides are generally stored and transported in the form of multi-vial kit formulations, wherein the radiolabelling component is separated from the peptide to be labeled, to prevent stability problems.
  • the contents of these vials are in a lyophilized or frozen condition.
  • the contents of these vials should be brought into solution and subsequently in a mutual reaction to produce the intended radiolabelled peptide. It is comfortable and also more safe for the pharmacists in a clinic or hospital not to have to perform all such handlings with radioactive material.
  • the term "vial" also includes injection syringe.
  • liquid formulation may be a mono- or multidose formulation, i.e. a dose for one patient or a multidose to be divided into a plurality of doses for administering to a number of patients.
  • the present invention relates to the use of ethanol as a first stabilizer in a single- vial liquid pharmaceutical formulation of a radiolabelled peptide, in a quantity sufficient to prevent radiolysis of said liquid formulation, wherein the formulation comprises in addition a second stabilizer, selected from inositol, ascorbic acid, gentisic acid, gentisyl alcohol, methionine and other suitable HS- or HSe-containing amino acids, and their derivatives, as well as combinations thereof, and wherein the peptide has been labelled with a detectable element, selected from gamma- or positron-emitting radionuclides, or with a therapeutic radionuclide, by using a chelating agent.
  • a detectable element selected from gamma- or positron-emitting radionuclides, or with a therapeutic radionuclide, by using a chelating agent.
  • ethanol as a quencher or stabilizer
  • literature - WO 2005/122712 (Socratech L.L.C. et al.; Dl) relates to the binding of a certain protein to Alzheimer's amyloid- ⁇ peptide.
  • the radioiodinated product is stabilized in ethanol as a quenching agent.
  • the product is purified and analysed, after which the purified product, apparently, is brought into a formulation suitable for infusion into the animal.
  • WO 03/000271 (Univ. of Alberta et al..; D3) relates to a method for the labelling of certain substrates, preferably nucleotides and nucleosides, steroids, or proteins such as antibodies, with radiohalogens.
  • substrates preferably nucleotides and nucleosides, steroids, or proteins such as antibodies, with radiohalogens.
  • the example and claims disclose the labelling of iododeoxuridine (IudR), a protein (polyclonal anti-TSH antibody) and a steroid (estradiol-6-CMO-histamine), all with 125 I.
  • an antioxidant preferably ethanol or vitamin D (ascorbic acid), or a mixture of both.
  • radioiodinated products are dissolved in ethanol (Example 3; steroid as substrate), in ethanol plus ascorbic acid (Example 1 ; IudR as substrate), or in BSA phosphate saline buffer stabilized with ascorbic acid (Example 2; antibody as substrate).
  • ethanol Example 3
  • ethanol plus ascorbic acid Example 1
  • BSA phosphate saline buffer stabilized with ascorbic acid Example 2; antibody as substrate
  • a combination of selenomethionine and ascorbic acid has shown to be superior as a stabilizer. Under optimised conditions this combination could stabilize a robust two-vial frozen formulation for preparing Lu-AMBA that could maintain an RCP (radiochemical purity) of over 90% for 5 days. It should be remarked, that ethanol apparently has not attracted the particular attention of the investigators.
  • the stabilized radiolabeled products of documents 1,2,3 and 4 are not ready for use, with the exception of the radioiodinated protein of Example 2 of D3; this product, however, could not be stabilized with a mixture of ascorbic acid and ethanol. Further, there is not any indication, neither in D3 nor in D4, that a mixture of ethanol with e.g. ascorbic acid could have superior radiostabilizing properties over other combinations or over the separate stabilizers.
  • ethanol in combination with a second stabilizer, stabilizes a liquid formulation of said radiolabelled peptides so superbly, that such a formulation can be protected completely against deterioration during the desired storage and transport period. It is indeed beyond expectation, that ethanol has a generally superior stabilizing effect on radiolabelled peptide solutions, stabilized with well-known stabilizers such as gentisic acid, ascorbic acid and methionine or combinations thereof, compared with these stabilizers or combinations as such.
  • stabilizers such as gentisic acid, ascorbic acid and methionine or combinations thereof
  • the radiolabelled peptide to be stabilized according to the invention can be characterized in more detail as a product destined for tumour localization and therapy (see in this connection the review article of Reubi: Endocrine Reviews 24(4), 389-427 (2003)).
  • Suitable peptides for this purpose - after labelling - are: CCK, gastrin, substance P, bombesine, VIP, PACAP, NPY, neurotensine and somatostatin, as well as derivatives and analogues of these peptides.
  • octreotides and octreotates Eight amino acid moieties containing somatostatin derivatives or analogues, so-called octreotides and octreotates, have attracted the most interest of the scientific world to date, and are, after radiolabelling, pre-eminently suitable substrates to be stabilized according to the present invention. More in particular, the peptide to be stabilized according to the present invention has been labelled by use of a chelating agent with a detectable element selected from gamma- or positron-emitting radionuclides, or with a therapeutic radionuclide.
  • Suitable chelating agents are selected from: (i) N 2 S 2 -, N 3 S- and N 4 -tetradentate ring structure containing agents, (ii) isocyanate, carbonyl, formyl, diazonium, isothiocyanate and alkoxycarbimidoyl containing agents, (iii) agents derived from N-containing di- and polyacetic acids and their derivatives, and (iv) 2-iminothiolane and 2-iminothiacyclohexane containing agents.
  • the peptide to be stabilized may be labelled with a detectable element such as "" 1 Tc, 203 Pb, 66 Ga, 67 Ga, 68 Ga, 72 As, 111 In, 11301 In, 97 Ru, 62 Cu, 64 Cu, 52 Fe, 51 Cr, 24 Na, 157 Gd, 52ra Mn, 162 Dy and 201 Tl.
  • detectable elements are: ' 11 In, " 111 Tc, 67 Ga and 68 Ga.
  • the present invention relates in particular to the use of ethanol in liquid formulations comprising a peptide labelled with a therapeutic radionuclide.
  • Suitable therapeutically active radionuclides are: 186 Re, 188 Re, 77 As, 90 Y, 67 Cu, 169 Er, 121 Sn,
  • Preferred radionuclides are: 67 Cu, 177 Lu, 153 Sm, 90 Y and 166 Ho.
  • compositions can generally be stabilized adequately by ethanol as a first stabilizer, if used in a quantity sufficient to prevent radiolysis, if this formulation comprises in addition a second stabilizer, such as: inositol, ascorbic acid, gentisic acid, gentisyl alcohol, methionine and other suitable HS- and HSe-containing amino acids, and their derivatives, as well as combinations of two or more of these second stabilizers.
  • a second stabilizer such as: inositol, ascorbic acid, gentisic acid, gentisyl alcohol, methionine and other suitable HS- and HSe-containing amino acids, and their derivatives, as well as combinations of two or more of these second stabilizers.
  • the present invention further relates to a stabilized single- vial liquid formulation of a radiolabelled peptide comprising ethanol in a quantity sufficient to prevent radiolysis of said formulation, in combination with a second stabilizer as defined above.
  • such a composition comprises a radiolabelled peptide to be used for tumour localization or therapy. More in particular, such a peptide is labelled by use of a chelating agent with a detectable element selected from gamma- or positron-emitting radionuclides, or with a therapeutic radionuclide. Suitable chelating agents and radionuclides are listed hereinbefore. Preferred therapeutic radionuclides are selected from 67 Cu, 177 Lu, 153 Sm, 90 Y and 166 Ho, which have superior characteristics as labels for therapeutic application. During the last decade there is a growing interest in radiolabeled peptides, such as somatostatin derivatives and analogs, for diagnostic purposes as well as for tumor therapy.
  • Suitable somatostatin analogs that are in the centre of interest are octapeptides having a high somatostatin receptor affinity, generally called octreotides and octreotates.
  • octreotides having a high somatostatin receptor affinity
  • octreotates having a high somatostatin receptor affinity
  • Such octapeptides may be represented by the general formula
  • n O or 1
  • a 0 is optionally halogenated Tyr or Phe, or wherein
  • a 0 is a trifunctional amino acid residue to which an additional peptide part, comprising 3 to 12 amino acid residues which form at least once the Arg-Gly-Asp sequence, is covalently linked,
  • a 1 is optionally halogenated Tyr, or optionally halogenated or methylated Phe or NaI,
  • a 3 is Tyr, Phe, NaI or benzothienylalanyl
  • a 4 is Trp, optionally N-methylated in its side-chain,
  • a 5 is Lys, optionally N-methylated in its side-chain
  • a 6 is Thr, VaI, Ser, Phe or He, and
  • a 8 is Thr, Trp or NaI, wherein the terminal carboxy group may be modified to an alcohol or an , optionally C1-C3 alkylated, amide group.
  • the present invention relates even more preferably to a composition as described hereinbefore, wherein the radiolabeled peptide is an octreotide or octreotate, as defined above, labelled with a suitable metal radionuclide by use of a chelating agent selected from ethylenediamine tetraacetic acid (EDTA), diethylenetriamine pentaacetic acid (DTPA), ethyleneglycol-O,O'-bis(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA), N 1 N'- bis(hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED), triethylenetetramine hexaacetic acid (TTHA), substituted EDTA or DTPA, 1, 4,7,1 O-tetraazacyclododecane- N,N',N",N'"-tetraacetic acid (DOTA), l,4,7-triaza
  • the present invention relates to a stabilized liquid formulation which is ready for use, i.e. which can be administered as such to the patient, e.g. intravenously (as an infusion fluid). If necessary or desired, this liquid formulation can be diluted with a physiologically acceptable liquid, e.g. buffered saline.
  • a stabilized formulation comprises, in addition to a radiolabelled peptide and a second stabilizer, both as defined hereinbefore, a stabilizing quantity of ethanol as a first stabilizer, which quantity is physiologically acceptable to the human body.
  • the quantity of ethanol in the injection liquid is 1 to 20 % v/v, preferably approx. 5 to 20% v/v.
  • the second stabilizer is used in a usual molar quantity, dependent on the character of the peptide to be stabilized. Normally approx. 1 to 100 mM of second stabilizer (including stabilizer combination) per mL liquid to be stabilized is sufficient. It will be obvious, that the volume of the liquid depends strongly on the purpose of the radiolabelled peptide formulation. For diagnostic purposes in general a few millilitres are sufficient, e.g. to be administered by injection; for therapeutic purposes approx. 100 mL per treatment is frequently necessary, to be administered by infusion.
  • treatment means the administration of the liquid to a human being of approx. 70 kg of body weight.
  • second stabilizer (including stabilizer combination), of course, also depends on the radioactivity of the liquid to be stabilized. In general 0.1 to 40 mM second stabilizer is sufficient per 100 MBq activity.
  • Example 1 A concentrated labelled peptide solution is prepared in a manner known per se, e.g. as described for 111 In labelled DTPA-octreotide in EP 0600992, viz. by diluting a frozen formulation of the chelated peptide, stabilized with a mixture of ascorbic acid and gentisic acid salts, as delivered by the producer, with buffered saline, followed by labelling with a 177 Lu solution ("kit labelling").
  • the second stabilizer combination is present in the same amount as in commercially available kit formulation, viz. 1 mM for both ascorbic and gentisic acid.
  • the stability of the ethanol containing solutions is compared with that of solutions of radiolabelled peptides, comprising in addition second radiostabilizers, selected from gentisic acid and ascorbic acid as salts, and methionine, as well as mixtures thereof, instead of ethanol as a stabilizer.
  • the liquid formulations (solutions) are stored at room temperature (21-22° C) during a certain period. At regular time intervals the radiochemical purity (RCP) is determined. The results are presented in the graphs appended as figures 1-3.
  • n 'in-labelled peptides are prepared by labelling these peptides with 111 In at different specific activities and concentrations of radioactivity (up to 100MBq per nmol in lOO ⁇ L), while varying t, T and stabilizers.
  • the peptides used are DOTA- octreotate [DOTA-DF-C- Y-D W-K-T-C-T], DTPA-octreotide [DTPA-DF-C-F-DW-K-T-C- T(ol)], DTPA-bombesine [DTPA-P-Q-R-Y-G-N-W-A-V-G-H-L-M-NH 2 ] and DOTA-MGl 1 [DOTA-DGIu-A-Y-G-W-M-D-NH 2 ]; the two last compounds have a methionin amino acid moiety in their molecules.
  • the RCP of the radiopeptides prepared varied between 97% for DTPA-octreotide (highest) and 93% for DOTA-MGl 1 (lowest).
  • the stability of the radiopeptide solutions in buffered saline is measured by HPLC, in the presence / absence of a number of stabilizers, viz. ethanol, ascorbic acid, gentisic acid and methionin, in different combinations. Under optimised conditions and by adding 10% v/v ethanol and 1 mM ascorbic acid, the RCP could be maintained at between 85% and 93% for all radiolabeled peptides up to 7 days.
  • DOTA-MGl 1 [DOTA-DGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NHJ, including methionin-sulfoxide
  • DOTA-CCK [DOTA-DAsp-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH 2 ;
  • FIG. 4 shows the C 18 HPLC chromatograms of l x 1 In-DOTA-MG 11 at 24 h after radiolabelling, without (chromatogram A) and with stabilizers. Addition of 10% v/v ethanol, 4 mM L-methionin and 4 mM ascorbic acid, resp. does not show satisfactory improvement: chromatograms B,C and D respectively. Enhancement of the methionin and ascorbic acid concentrations up to 50 mM does not improve the chromatographic results, shown in C and D, substantially.
  • the chromatograms, shown as E and F, are obtained after addition of 10% v/v ethanol and 10% ethanol v/v plus 50 mM L-methionin, respectively.
  • the RCP of A and F are 60% and 94% respectively, 94% being also the RCP of the radiolabeled peptide in the presence of these stabilizers immediately after radiolabelling: 5 min. at 80° C in the presence of ascorbate, methionin and ethanol. Similar results are obtained with DOTA-CCK.
  • Demogastrin 2 is labelled with 99mTc to the labelled peptide up to a specific activity of 250 MBq per nmol, with a RCP of approx 83%.
  • a combination of ascorbic acid and ethanol stabilizes this product adequately against radiolysis: no significant reduction of radiolabeled peptide according to RCP during storage.

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Abstract

L'invention concerne l'utilisation de l'éthanol comme premier stabilisant dans une formulation pharmaceutique liquide en flacon unique d'un peptide radiomarqué, dans une quantité suffisante pour empêcher la radiolyse de la formulation liquide. La formulation comprend, de plus, un deuxième stabilisant, sélectionné parmi l'inositol, l'acide ascorbique, l'acide gentisique, l'alcool gentisylique, la méthionine et autres amino-acides appropriés contenant HS ou HSe, et leurs dérivés, ainsi que des combinaisons de ceci. Le peptide a été marqué avec un élément détectable sélectionné parmi des radionucléides émetteurs de gammas ou de positrons ou avec un radionucléide thérapeutique au moyen d'un agent de chélation.
PCT/EP2007/006405 2006-07-19 2007-07-18 Utilisation de l'éthanol pour stabiliser une formulation liquide d'un peptide radiomarqué en flacon unique Ceased WO2008009444A1 (fr)

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EP06076439 2006-07-19

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2234636A4 (fr) * 2007-12-21 2013-05-15 Lyotropic Therapeutics Inc Formulations de peptides et de protéines stabilisées
EP2579902B1 (fr) 2010-06-04 2017-07-12 Piramal Imaging SA Procédé de production de ligands de l'amyloïde bêta marqués au 18f
WO2018081860A1 (fr) * 2016-11-04 2018-05-11 Clarity Pharmaceuticals Pty Ltd Formulations pour radiothérapie et imagerie diagnostique
WO2020021310A1 (fr) * 2018-07-25 2020-01-30 Advanced Accelerator Applications (Italy) Srl Solutions complexes de radionucléides, stables, concentrées
WO2020021322A1 (fr) 2018-07-25 2020-01-30 Advanced Accelerator Applications (Italy) Srl Solutions complexes concentrées stables de radionucléides
WO2020021465A1 (fr) * 2018-07-25 2020-01-30 Advanced Accelerator Applications (Italy) S.R.L. Procédé de traitement de tumeurs neuroendocrines
US10596276B2 (en) 2018-07-25 2020-03-24 Advanced Accelerator Applications (Italy) S.R.L. Stable, concentrated radionuclide complex solutions
US10596278B2 (en) 2018-07-25 2020-03-24 Advanced Accelerator Applications (Italy) S.R.L. Stable, concentrated radionuclide complex solutions
WO2020237290A1 (fr) * 2019-05-24 2020-12-03 The University Of Melbourne Formulations d'agents d'imagerie psma
WO2021033530A1 (fr) * 2019-08-21 2021-02-25 日本メジフィジックス株式会社 Procédé de production de complexe métallique radioactif
WO2021052960A1 (fr) 2019-09-16 2021-03-25 Advanced Accelerator Applications (Italy) Srl Composition radiopharmaceutique concentrée, stable
WO2022043556A1 (fr) 2020-08-31 2022-03-03 Novartis Ag Composition pharmaceutique stable
WO2022156907A1 (fr) * 2021-01-25 2022-07-28 Vrije Universiteit Brussel Procédé et kit pour marquer une biomolécule avec un ou plusieurs marqueurs détectables, comprenant un marqueur radioactif
CN114796532A (zh) * 2022-04-20 2022-07-29 北京先通国际医药科技股份有限公司 放射性标记的伊文思蓝衍生物药物水溶液及其用途
CN115015441A (zh) * 2022-07-14 2022-09-06 原子高科股份有限公司 一种测定镥[177Lu]氧奥曲肽注射液中稳定剂含量的方法
RU2788581C2 (ru) * 2016-11-04 2023-01-23 Клэрити Фармасьютикалз Лтд Составы для радиотерапии и диагностической визуализации
WO2023100852A1 (fr) * 2021-11-30 2023-06-08 日本メジフィジックス株式会社 Composition radiopharmaceutique stabilisée
WO2023150738A2 (fr) 2022-02-04 2023-08-10 Westinghouse Electric Company Llc Procédé et dispositif de production directe de produits pharmaceutiques de traitement du cancer à base de radio-isotopes
US12144873B2 (en) 2018-07-25 2024-11-19 Advanced Accelerator Applications Sa Stable, concentrated radionuclide complex solutions

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WO2003000271A2 (fr) * 2001-06-22 2003-01-03 The University Of Alberta, The University Of British Columbia, Carleton University, Simon Fraser University And The University Of Victoria, Collectively Doing Business As Triumf Systeme et procede d'etiquetage a grande echelle de composes a radiohalogenes
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Cited By (68)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2234636A4 (fr) * 2007-12-21 2013-05-15 Lyotropic Therapeutics Inc Formulations de peptides et de protéines stabilisées
EP2579902B2 (fr) † 2010-06-04 2019-08-14 Piramal Imaging SA Procédé de production de ligands de l'amyloïde bêta marqués au 18f
EP2579902B1 (fr) 2010-06-04 2017-07-12 Piramal Imaging SA Procédé de production de ligands de l'amyloïde bêta marqués au 18f
JP2019533728A (ja) * 2016-11-04 2019-11-21 クラリティー・ファーマシューティカルズ・プロプライエタリー・リミテッド 放射線治療及び画像診断のための製剤
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