WO2014030993A1 - Microsphères marquées au 153sm et activées par des neutrons - Google Patents

Microsphères marquées au 153sm et activées par des neutrons Download PDF

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Publication number
WO2014030993A1
WO2014030993A1 PCT/MY2013/000147 MY2013000147W WO2014030993A1 WO 2014030993 A1 WO2014030993 A1 WO 2014030993A1 MY 2013000147 W MY2013000147 W MY 2013000147W WO 2014030993 A1 WO2014030993 A1 WO 2014030993A1
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WO
WIPO (PCT)
Prior art keywords
microspheres
labelled
compound
incorporated
insoluble
Prior art date
Application number
PCT/MY2013/000147
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English (en)
Inventor
Basri Johan Jeet ABDULLAH
Chai Hong YEONG
Lip Yong Chung
Kwan Hoong NG
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Universiti Malaya (Um)
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Application filed by Universiti Malaya (Um) filed Critical Universiti Malaya (Um)
Publication of WO2014030993A1 publication Critical patent/WO2014030993A1/fr

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Classifications

    • 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
    • A61K51/1241—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 particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
    • A61K51/1244—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 particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles
    • A61K51/1251—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 particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles micro- or nanospheres, micro- or nanobeads, micro- or nanocapsules
    • G—PHYSICS
    • G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
    • G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
    • G21G1/00—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes
    • G21G1/04—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes outside nuclear reactors or particle accelerators
    • G21G1/06—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes outside nuclear reactors or particle accelerators by neutron irradiation
    • G—PHYSICS
    • G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
    • G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
    • G21G4/00—Radioactive sources
    • G21G4/04—Radioactive sources other than neutron sources
    • G21G4/06—Radioactive sources other than neutron sources characterised by constructional features
    • G21G4/08—Radioactive sources other than neutron sources characterised by constructional features specially adapted for medical application

Definitions

  • the present invention relates to a method of preparation and use of 153 Sm labelled microspheres.
  • Non-invasive imaging techniques are important clinical diagnostic tools in the investigation of gastrointestinal (GI) motility and transit.
  • GI gastrointestinal
  • Several radiological and endoscopic techniques have been developed and are practised in clinical settings (Lin HC, Prather C, Fisher RS, Meyer JH, Summers RW, Pimentel M, et al.: Measurement of gastrointestinal transit. Dig Dis Sci 2005).
  • gamma scintigraphy is one of the most favoured diagnostic methods because it combines quantitative assessment and visual information from sequential image data.
  • this methodology does not involve dense contrast agents such as barium which may alter the GI physiology during the examination.
  • Radionuclides are also gaining increasing importance by providing palliative and curative treatment in an increasing number of malignant diseases. Most radionuclides used in radionuclide therapy emit beta particles, which have a low range of tissue penetration. A few emit auger electrons and alpha particles, and several also emit gamma rays and X-rays during their decay. The most successful metabolic radionuclide for thyroid therapy uses Iodine- 131 ( l 31 I) as the nuclide for the treatment of benign hyperthyroid conditions and thyroid carcinoma.
  • Non-resectable primary and metastatic liver cancers carried a bleak prognosis with limited treatment options until recently. Encouraging results of several recent trials suggest radioembolization using Y-90 is achieving the previously elusive goal of destroying hepatic tumor cells while sparing surrounding tissue. The procedure has been approved in the United States for more than a decade, but the past year has witnessed a surge in utilization. Two commercially available agents are FDA-approved for the treatment of liver cancer. TheraSphere, made by MDS Nordion Inc, was approved in late 1999 as a humanitarian use device for hepatocellular carcinoma (HCC), while SIR-Spheres, made by Sirtex Medical Ltd, were sanctioned as a first-line therapy for colorectal liver metastases in 2002.
  • HCC hepatocellular carcinoma
  • Microspheres target liver tumors by taking advantage of their hypervascularity. Metastatic liver tumors larger than 3 mm receive 80% to 100% of their blood supply from the hepatic artery while normal liver tissue is predominantly fed by the portal vein.
  • the microspheres are delivered via a fluoroscopic embolization procedure in which millions of 30-micron beads are infused through a catheter into the hepatic artery. The beads become embedded in the liver, and the therapeutic dose is delivered over a period of about two weeks.
  • the beads are bonded with 90 Y, a beta-emitting radionuclide that acts locally because its relatively low energy means the beta particles travel at most 1 1 mm in the liver. This allows the beads to embed in and irradiate the tumor while sparing healthy liver tissue.
  • 153 Sm is most commonly known as a therapeutic agent for bone metastasis pain release in the form of radiopharmaceutical, l 53 Sm-EDTMP.
  • 153 Sm has also been widely used as a radiotracer in pharmacoscintigraphic studies (Ahrabi et al., 2000, Ahrabi et al., 1999a, Ahrabi et al., 1999b, Awang et al., 1993, Marvola et al., 2004, Marvola et al., 2008, Waaler et al., 1997, Waaler et al., 1999a, Waaler et al., 1999b, Watts et al., 1991 , Watts et al., 1993a, Watts et al., 1993b).
  • 153 Sm-PHYP Samarium-153 particulate hydroxyapatite
  • 153 Sm-PHYP is injected intra-articularly to the joint space and flushed through with a mixture of xylocaine and triamcinolone acetonide.
  • the injected radioactivity is absorbed by phagocytic lining cells along the synovial surface.
  • 153 Sm-PHYP is stable and remains tightly bound in vivo.
  • the extra-articular whole body radiation (unwanted) dose is approximately 3.8 mSv, which is no more than the estimated dose from an isotope bone scan (3.7 to 6 mSv) (Shields RA, Lawson RS. Effective dose equivalent. Nucl Med Commun 1987;8:851-5).
  • the dose is significantly lower than the dose estimated from 90 Y synovectomy and similar to the dose after intra-articular dysprosium- 165 macroaggregates. There is no evidence for an increase in chromosome-type damage after 153 Sm-PHYP therapy (Deutsch E, Brodack JW, Deutsch F. Radiation synovectomy revisited. Eur J Nucl Med 1993;20: 1 1 13-27).
  • the present invention provides a method of preparation of l 53 Sm labelled microspheres, preferably resin or glass beads microspheres to be used for diagnostic imaging in GI motility and transit, and as a therapeutic agent for tumors and inflammatory joint disease.
  • Figure 1 Gamma spectra of neutron activated l 53 Sm-labelled sample.
  • SGF simulated gastric fluid
  • SIF simulated intestinal fluid.
  • the present invention provides a method of preparation of 153 Sm microspheres, comprising the steps of incorporating l 52 SmCl 3 or a hydrate thereof into insoluble microspheres and subsequently performing neutron activation of the incorporated samarium.
  • the present invention further provides radioactivemicsopheres containing 153 SmCl 3 or a hydrate thereof.
  • the present invention also encompasses the use of the 153 Sm labelled microspheres for the diagnostics of gastrointestinal (GI) motility and transit, and as a therapeutic agent for tumors and inflammatory joint disease.
  • GI gastrointestinal
  • the present invention provides a method of preparation of 153 Sm labelled microspheres of varying sizes and in various formulations, comprising the steps of incorporating l 52 SmCl 3 or a hydrate thereof into insoluble ion-exchange microspheres and subsequently performing neutron acti vation of the incorporated samarium.
  • the incorporated compound is 152 SmCl 3 .6H 2 0.
  • the micsopheres are insoluble ion-exchange resin or glass beads, more preferably is a cation-exchange (H*) resin or a styrene-divinylbenzene gel type resin with sulfonic acid (H 2 S0 4 ) functionality.
  • H* cation-exchange
  • H 2 S0 4 styrene-divinylbenzene gel type resin with sulfonic acid
  • the size of the microspheres is smaller than 1 mm.
  • the step of incorporating l 52 SmCl 3 or a hydrate thereof into microspheres is performed by dissolving l 52 SmCl 3 or a hydrate thereof in water, adding the insoluble ion-exchange resin or glass beads and mixing, and then drying the resulting mixture at a temperature of 30 to 80°C.
  • the step of performing neutron activation of the incorporated samarium is performed by irradiating of the final dosage form, such as a capsule, preferably a gelatine capsule, filled with the microspheres with incorporated samarium, using a nuclear reactor.
  • the microspheres with incorporated samarium are irradiated using a thermal nuclear reactor.
  • the recommended neutron flux is between lO 10 to 10 14 n.cm'V.
  • the neutron relevant in the activation process is thermal neutron constitutes energy in the range of 0 to 0.55 eV.
  • the samples are irradiated in the neutron flux for a period of time depending on the neutron flux.
  • the activity of the neutron activated sample can be calculated through the following equation:
  • This process in which first a 152 Sm compound is incorporated into microspheres and subsequently the 152 Sm is activated by neutrons to form l 53 Sm, avoids the lengthy manipulation with an activated radionuclide during preparation of the administration form and thus decreases the radiation safety of the personnel. Another advantage is that the method is safe, robust and reproducible.
  • the present invention further provides radioactive microspehres containing 153 SmCl 3 or a hydrate thereof.
  • the present invention also encompasses the use of the 153 Sm labelled microspheres for the diagnostics of gastrointestinal (GI) motility and transit, and as a therapeutic agent for tumors and inflammatory joint disease.
  • the radiolabeled microspheres can be administered within the gelatin capsule, or it can be emptied from the capsule for incorporation into a suitable meal or oral formulation.
  • the radiolabelledmicrospheres can be filled into syringes for injection and delivered in this form.
  • the present invention brings namely the following advantages. It allows for incorporation of inactivated 152 Sm into microspheres of different sizes and formulations with stability for long term storage off the shelf base product. It also enables rapid delivery and local manufacture, activation of several different fixed quantities of samarium to required activity i.e. varying activity and not changing quantity of inactivated samarium used. The fact that there is no need to manipulate dose once activated leads to better safety for the personnel. Furthermore, various administration forms, such as capsules, tablets or syringes, can be prepared, delivered, activated and used.
  • Example 1 Preparation of 152 Sm labelled resin beads
  • the stable nuclide samarium- 152 (III) chloride hexahydrate ( 152 SmCl 3 .6H20, molecular weight 364.81 g/mol, assay purity >99%) was incorporated into the cation-exchange resin.
  • the resin is a gel type strongly acidic cation exchange resin of the sulfonated polystyrene type.
  • the chemical structure of the resin is as following:
  • PC polymer chain
  • XL cross-link
  • ES exchange site
  • EI exchangeable ion
  • the mean size of the resin beads ranged from 0.62 to 0.83 mm.
  • the total exchange capacity of the resin was >1.80 eq.L -1 (H + form), and the moisture holding capacity was 53-58% (H + form).
  • Example 2 Neutron activation The sample was activated using a thermal research reactor. Before irradiation, each capsule was heat-sealed into a polyethylene vial. The vial was then packed into a polyethylene ampoule (commonly known as the 'rabbit'). The ampoule was delivered to the reactor core by a pneumatic transport system (PTS). The sample was irradiated in a neutron flux of lxlO 13 cm -2 s ⁇ " for 100 s to achieve a nominal radioactivity of 5 MBq at 66 h after neutron activation.
  • PTS pneumatic transport system
  • Gamma spectroscopy was carried out to detect any radioactive impurities 24 and 48 h after neutron activation using a coaxial, p-type, germanium detector and D Dspectrum analysis software.
  • the safety requirement is that any net ⁇ peak area not originating from I S3 Sm should not exceed 0.3% of the 153 Sm main peak at 103 keV and that the total net peak areas not originating from l53 Sm should not exceed 1% of the 153 Sm main peak.
  • the capsule was kept in a radioactive storage room for minimum 48 h to allow for decay of the unwanted short-lived activated by-products, primarily sodium-24 ( 24 Na).
  • Example 3 Testing for labelling efficiency 153 Sm-radiolabelled resins were weighed and assayed for radioactivity to derive the specific activity. Mean labelling efficiency of 91% was obtained by determining the activity bound to the resin after washing for 5 min with distilled water. Retention of the radioactivity bound to resins over time was measured as described below. Stability of radiolabeled resins in simulated gastric and intestinal fluid:
  • the stability of the activated 153 Sm-resin was measured in vitro over a period of 24 h. Artificial gastric juice (pH 1.03) and simulated intestinal fluid (pH 6.8) with enzyme incorporation were prepared according to the recommendation in the British Pharmacopoeia, 2007.
  • the activated 153 Sm-resins were emptied from the capsule and transferred to glass tubes containing either 10 ml of artificial gastric juice or 10 ml of simulated intestinal fluid.
  • the initial activities of all the samples were measured using a dose calibrator and recorded.
  • the tubes were then placed on a tilt and mix rollerand rolled constantly at 50 rpm for 1 h.
  • the tubes were then transferred to a centrifuge and rotated at 1200 rpm for 5min to separate the resin beads and fluid.
  • the net gamma peak area not originating from 153 Sm did not exceed 0.3% of the 153 Sm main peak at 103 keV, and the total net peaks areas not originating from 153 Sm did not exceed 1 % of the 153 Sm main peak.

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  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Engineering & Computer Science (AREA)
  • High Energy & Nuclear Physics (AREA)
  • Nanotechnology (AREA)
  • Medicinal Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Optics & Photonics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un procédé d'élaboration de microsphères marquées au 153Sm, qui comprend les étapes consistant à incorporer un composé de 152Sm dans une résine échangeuse d'ions insoluble ou dans des billes de verre, et à mettre en oeuvre ultérieurement une activation neutronique des microsphères de samarium incorporées. L'invention concerne en outre des microsphères radioactives contenant 153SmCI3 ou un hydrate de ce composé, ainsi que l'utilisation clinique de telles microsphères radiomarquées.
PCT/MY2013/000147 2012-07-18 2013-08-16 Microsphères marquées au 153sm et activées par des neutrons WO2014030993A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
MYPI2012700480 2012-07-18
MYPI2012700480 MY150861A (en) 2012-07-18 2012-07-18 Neutron activated 153sm labelled microspheres

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WO2014030993A1 true WO2014030993A1 (fr) 2014-02-27

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2793955A4 (fr) * 2011-12-21 2016-01-06 Iso Therapeutics Group Llc Compositions radioactives et procédés pour leur utilisation thérapeutique
EP3645058A4 (fr) * 2017-06-28 2021-05-12 The Regents of The University of California Billes d'embolisation composites

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5342283A (en) * 1990-08-13 1994-08-30 Good Roger R Endocurietherapy
WO1994026755A1 (fr) * 1993-05-06 1994-11-24 The Dow Chemical Company Complexes d'acides bicyclopolyazamacrocyclophosphoniques, conjugues de ces derniers, procede de preparation associe et d'utilisation en tant que produits radiopharmaceutiques
US20110165070A1 (en) * 2008-04-24 2011-07-07 The Australian National University Methods for radiolabeling synthetic polymers

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5342283A (en) * 1990-08-13 1994-08-30 Good Roger R Endocurietherapy
WO1994026755A1 (fr) * 1993-05-06 1994-11-24 The Dow Chemical Company Complexes d'acides bicyclopolyazamacrocyclophosphoniques, conjugues de ces derniers, procede de preparation associe et d'utilisation en tant que produits radiopharmaceutiques
US20110165070A1 (en) * 2008-04-24 2011-07-07 The Australian National University Methods for radiolabeling synthetic polymers

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2793955A4 (fr) * 2011-12-21 2016-01-06 Iso Therapeutics Group Llc Compositions radioactives et procédés pour leur utilisation thérapeutique
US9687574B2 (en) 2011-12-21 2017-06-27 Isotherapeutics Group Llc Radioactive compositions and methods for their therapeutic use
US10918746B2 (en) 2011-12-21 2021-02-16 Isotherapeutics Group Llc Radioactive compositions and methods for their therapeutic use
EP3645058A4 (fr) * 2017-06-28 2021-05-12 The Regents of The University of California Billes d'embolisation composites

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