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WO2025068543A1 - Particules radiothérapeutiques polymères, suspensions et leurs procédés de production - Google Patents

Particules radiothérapeutiques polymères, suspensions et leurs procédés de production Download PDF

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Publication number
WO2025068543A1
WO2025068543A1 PCT/EP2024/077336 EP2024077336W WO2025068543A1 WO 2025068543 A1 WO2025068543 A1 WO 2025068543A1 EP 2024077336 W EP2024077336 W EP 2024077336W WO 2025068543 A1 WO2025068543 A1 WO 2025068543A1
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beta
alpha
particle
emitting radionuclide
resin
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Walter Cabri
Colin John STORY
Pietro Bubba BELLO
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Betaglue Technologies SpA
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Betaglue Technologies SpA
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    • 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
    • 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
    • A61K51/1213—Semi-solid forms, gels, hydrogels, ointments, fats and waxes that are solid at room temperature

Definitions

  • the present invention relates to polymeric radiotherapeutic particles, compositions and methods for producing same, wherein the radionuclide is an alpha and/or beta-emitting radionuclide.
  • the invention also relates to the use of said particle and compositions, in the treatment of cancer and their use in loco-regional radiotherapy, brachytherapy and transarterial radioembolization.
  • TARE transarterial radioembolization
  • SIRT selective internal radiation therapy
  • Such stable radiotherapeutic particles e.g., non-degradable glass spheres (TheraSphereTM) or resin based spheres (SIR-Spheres TM ) have been used for radioembolization for treating primary tumors and metastases to the liver.
  • TheraSphereTM non-degradable glass spheres
  • SIR-Spheres TM resin based spheres
  • the radiation emitted should be of high energy and short range, which is obtainable by alpha and/or beta radiation. Accordingly, radionuclides which have a high energy alpha and/or beta decay are highly preferred for such applications.
  • a clinical problem with the absorption of radionuclides on microparticles is the potential leaching of the radionuclides from the particles, which may cause inappropriate radiation of non-target tissues, and accumulation of daughters in unfavourable locations and tissues.
  • phosphate precipitation has been utilized in e.g., WO2015168726, which immobilizes the radionuclide on polymeric particles, by the precipitation of 90 Y as an insoluble phosphate salt onto the particles, thereby forming protrusions of phosphate salts on the surface of the particles, also leading to an inefficient utilization of the 90 Y raw materials.
  • the present invention relates to an alpha- and/or beta-emitting radionuclide labelled particle, wherein said particle comprises or consists of a polymeric resin conjugated with sulfonic acid and an ionically bound alpha- and/or beta-emitting radionuclide, such as e.g., alpha- and/or beta-emitting radionuclides selected from the group consisting of "Y, 225 Ac, 89 Sr, 153 Sm, 159 Gd, 18 F, 68 CU, 69 CU, 67 Ga, " m Tc, 201 Ti, 111 In, 161 Tb and 177 Lu, preferably selected from the groups consisting of 90 Y, 68 Cu, 69 Cu, 225 Ac, 212 Pb, 177 Lu, more preferably the radionuclide is "Y.
  • alpha- and/or beta-emitting radionuclides selected from the group consisting of "Y, 225 Ac, 89 Sr, 153 S
  • such radionuclide is preferably selected from radionuclides which emits no more than 10 % gamma radiation of the total decay radiation, and thereby preferably the primary decay is alpha and/or beta decay.
  • such radionuclides may have a decay half-life in the range of 1-300 hrs, such as between 30-100 hrs, or such as 50-70 hrs.
  • the particle may e.g., have a size in the range of 5-400 pm, such as a size in the range of 10-300 pm, 25-250 pm, 50-200 pm, 100-150 pm, such above 50 pm and below 200 pm.
  • such particles are spherical, with a smooth surface, such as a surface which lacks protrusions, with a low roughness. It is also preferred that such particles are essentially free of phosphate.
  • Particles described herein are preferably polymeric, formed from a polymeric resin, which e.g., comprises one or more elements selected from the group consisting of divinylbenzene, polystyrene, polyethylene glycol (PEG), Polycaprolactone (PCL), polyurethane (PU), Polyvinylpyrrolidone (PVP), poly(2-hydroxyethyl-methacrylate), polyglycolide, polylactide, polyhydroxobutyrate, chitosan and hyaluronic acid, it may also be a co-polymer, where multiple polymers makes up the polymeric particle, preferably, the polymeric resin is a styrene divinylbenzene copolymer.
  • the present invention also relates to pharmaceutical compositions comprising a particle as disclosed herein.
  • Such pharmaceutical compositions may e.g., further comprise a diluent, carrier, surfactant, and/or excipient, and/or a bioglue component, such as e.g., an albumin, such as e.g., bovine serum albumin, and/or glutaraldehyde, and/or a buffering agent, such as e.g., acetate, citrate, or glutamate.
  • the pharmaceutical composition preferably comprises with an amount of radionuclide that is 1 kBq to 10GBq per dosing, or with an amount of radionuclide that is 50 MBq to 1000 GBq suitable for multidose industrial scale production.
  • said pharmaceutical composition is suitable for intravenous, intratumor, and/or intracavitary injection.
  • the present invention also relates to the use of particles and/or pharmaceutical compositions disclosed herein, preferably as a medicament, such as for use in the treatment or amelioration of cancer, such as head and neck squamous cell carcinoma, metastatic melanoma, sarcoma, non-small cell lung cancer, colorectal cancer, primary and secondary hepatocellular carcinoma, pancreatic ductal adenocarcinoma, renal cell carcinoma, ovarian cancer, muscle invasive bladder cancer, prostate cancer, and/or osteosarcoma, preferably, unresectable hepatocellular carcinoma and/or locally-advanced borderline-resectable pancreatic ductal adenocarcinoma, e.g., by single or repeated dosing.
  • cancer such as head and neck squamous cell carcinoma, metastatic melanoma, sarcoma, non-small cell lung cancer, colorectal cancer, primary and secondary hepatocellular carcinoma, pancreatic ductal adeno
  • the particles and/or composition disclosed herein are also suitable for use in intracavitary therapy, or radiosynovectomy, radioembolization, such as transarterial radioembolization (TARE) and intratumor injection, preferably in hepatocellular carcinoma, but also in other cancers disclosed herein.
  • Particles as compositions as disclosed herein may also be suitable for radionuclide imaging.
  • the present invention further relates to a method of treatment of cancer comprising administering an effective dose of an alpha- and/or beta-emitting radionuclide labelled particle as disclosed herein.
  • the present invention further relates to methods for producing an alpha- and/or beta-emitting radionuclide labelled particle or pharmaceutical composition as disclosed herein.
  • Said method e.g., comprises; providing an alpha- and/or beta-emitting radionuclide or a salt thereof; providing a particle with a sulfonic acid conjugated polymeric resin; mixing said alpha- and/or beta-emitting radionuclide and said particle in an aqueous solution at a pH in the range of pH 6.5-9.5; and isolating an alpha and/or a beta-emitting radionuclide labelled particle from said aqueous solution.
  • the mixing and isolation step is not separated by more than 60 minutes, such as no more than 30 minutes, such as no more than 15 minutes.
  • the aqueous solution has a pH in the range of pH 7-9, preferably less than pH 8.5, such as less than pH 7.5, such as about pH 7.4. It is preferred that the method does not comprise immobilizing said radionuclide on said particle by phosphate precipitation.
  • the present invention also relates to a kit comprising; unlabelled particles comprising or consisting of a polymeric resin conjugated with sulfonic acid; optionally reagents for preparing an alpha- and/or beta-emitting radionuclide labelled particle, or a pharmaceutical composition as disclosed herein; and optionally instructions for preparing said particle or pharmaceutical composition.
  • Said kit may further comprise, aqueous solution comprising an uncured curable biocompatible adhesive and/or non-polymerized hydrogel in an aqueous solution and an aqueous solution comprising a curing and/or polymerizing agent, preferably, said curable biocompatible adhesive is an albumin, preferable bovine serum albumin, and said curing and/or polymerizing agent is an amide cross linking agent, preferably glutaraldehyde.
  • the present invention further relates to a method of preparing a cured 90 Y radiotherapeutic composition
  • a method of preparing a cured 90 Y radiotherapeutic composition comprising; providing a 90 Y labelled particle suspension, an uncured biocompatible adhesive and/or non-polymerized hydrogel in an aqueous solution, and a curing and/or polymerizing agent which upon mixture of said glue or hydrogel induces curing of said biocompatible adhesive and/or polymerization of said hydrogel; thereafter mixing said components to obtain a cured "Y radiotherapeutic composition, comprising biocompatible adhesive and/or hydrogel embedded "Y radiotherapeutic particles.
  • FIGURE 1 A first figure.
  • EDS Energy-dispersive-X-ray-spectroscope
  • the present inventors have identified a treatment of cancer with less risk for off-target side effects based on a focal therapy using short-ranging alpha- and/or beta- emitters, especially suitable for loco-regional radiotherapy such as brachytherapy and transarterial radioembolization.
  • One object of the present invention relates to a particle a comprising a polymeric resin which allows adhesion of an alpha and/or beta-emitting radionuclide, wherein the leaching of said radionuclide from the particle is sufficiently low to make the particle suitable for use in cancer therapy.
  • a particle may be obtained by conjugating a polymeric particle with one or more suitable functional groups which enables strong binding of the radionuclide to the particle.
  • suitable functional groups which enables strong binding of the radionuclide to the particle.
  • strong cationic functional groups capable of strong binding of metal ions are e.g., sulfonic acid and phosphoric acid, which are commonly used in cation exchange resins, such as the Lewatit® TP 260, AG® 50W and AG® MP-50 cation exchange resins.
  • an aspect of the invention relates to an alpha- and/or beta-emitting radionuclide labelled particle, wherein said particle comprises or consists of a polymeric resin conjugated with sulfonic acid and an ionically bound alpha- and/or beta-emitting radionuclide.
  • the particle is labelled by cation exchange, where the alpha- and/or beta-emitting radionuclide is provided as a soluble salt, preferably a chloride salt, but may also be provided with an alternative anion such as e.g., bromide, iodide, sulphate, sulphite, nitrate, acetate, phosphate, carbonate, or oxide, or other suitable alternative anions known to the skilled person.
  • a soluble salt preferably a chloride salt
  • an alternative anion such as e.g., bromide, iodide, sulphate, sulphite, nitrate, acetate, phosphate, carbonate, or oxide, or other suitable alternative anions known to the skilled person.
  • the cation exchange is enabled by the sulfonic acid group on the polymeric resin, which may be pre-loaded with a counter ion, such as Na + , H + , Fe 2+ or similar counter ion.
  • a counter ion such as Na + , H + , Fe 2+ or similar counter ion.
  • the functional group is preferably loaded with Na + prior to the cation exchange with the salt of the alpha- and/or beta-emitting radionuclide.
  • Example 1 exemplifies the preparation of an yttrium (Y) labelled particle, wherein the cation exchange is performed by exchanging the Na + ion bound by SOa' functional group with the Y 3+ ion released from the Cl", thus producing NaCI and particle bound yttrium.
  • Example 1 thus shows an example of how an alpha- and/or beta-emitting radionuclide may be absorbed on the surface of a suitable particle, in order to produce an alpha- and/or beta-emitting radionuclide labelled particle as described herein.
  • the particles prepared as described herein are generally smoother and have less protrusions than particles prepared using precipitation, as is respectively shown in figure 2 and in figure 3.
  • a smooth surface is characterized by its even and regular texture, lacking any prominent irregularities or protruding features. Such surfaces are in context of the present invention generally spherical and provide a uniform and continuous contact area.
  • a surface with protrusions features raised or uneven elements, creating variations in height and texture.
  • These protrusions can take various forms, from small bumps to more complex structures. Surfaces with protrusions are often designed for specific purposes like providing grip, such as in the arteries of patients.
  • the protrusions of a surface can be quantified.
  • Surface protrusions (or roughness) is a function of the length scale it is measured at and the frequency response function of the instrument used to acquire data. Scanning or measuring the surface of the particle using two- and three-dimensional probes identify the protrusions with various tip widths and radii. These can be quantified and compared.
  • a particle with a smooth surface with little or no protrusions is defined as a particle with less than ten protrusions of minimum 1 m height as determined by a scanning electron microscope (SEM).
  • a particle with a smooth surface with little or no protrusions is defined as a particle with less than ten protrusions of minimum 1 m height as determined by a scanning electron microscope (SEM). In one or more exemplary embodiments of the present invention, a particle with a smooth surface with little or no protrusions is defined as a particle with less than ten protrusions of minimum 2 m height as determined by a scanning electron microscope (SEM). In one or more exemplary embodiments of the present invention, a particle with a smooth surface with little or no protrusions is defined as a particle with less than 50 protrusions of minimum 1 m height as determined by a scanning electron microscope (SEM). In one or more exemplary embodiments of the present invention, a particle with a smooth surface with little or no protrusions is defined as a particle with less than 5 protrusions of minimum 2 m height as determined by a scanning electron microscope (SEM).
  • SEM scanning electron microscope
  • a particle with a smooth surface with little or no protrusions is a particle of the present invention, wherein the smooth surface with little or no protrusions is defined by a particle surface that has less protrusion than the same particle which has been labelled using phosphate precipitation.
  • Phosphate precipitation of radionuclides onto particles, as described herein, are well-known in the art.
  • Example 2 shows the process wherein 100-times the amount of Y was used in the preparation of the particles, using both the new process disclosed herein and the previous phosphate precipitation method.
  • figure 5 particles prepared by the novel process
  • figure 7 particles prepared by the previous phosphate precipitation process
  • the high amount of Y used in the preparation of the particles leads to formation of multiple salt precipitate layers on the particles ( Figure 7), which may lead to flaking from the particles of the Y containing phosphate salts, leading to unwanted migration of potentially radioactive material from the particles.
  • Example 3 further shows that the amount of 90 Y absorbed on the particles exceeds 85%, in particular exceeds 96% of the initial radioactivity amount provided initially in the solution, thereby greatly optimizing the amount of Y transferred to the particles, thereby dramatically reducing the radioactive waste from the production of the particles.
  • Example 4 further shows that the particles only have a very limited leakage of less than 1% following various temperature stresses.
  • the polymeric particle may be made up of any suitable polymer or co-polymer known to the skilled person which enables its use as a resin for the functional group capable of binding the radionuclide, as described herein.
  • the particle presented in examples 1-3 are produced with a styrene divinylbenzene copolymer resin, which is activated by conjugation of sulphate, as described above.
  • Alternative polymeric materials are e.g., Cellulose based resins, Sepharose, polyacrylate resins, polystyrene and silica gels.
  • the particles comprise styrene.
  • the particles comprise divinylbenzene.
  • the polymeric resin making up the particle is a styrene divinylbenzene copolymer.
  • lattice refers to a three-dimensional arrangement of polymeric components within the particle, which is preferably a spherical particle comprising crosslinked polymeric molecules, as disclosed herein. This arrangement may involve formation of a lattice structure from a single type of polymeric molecules or formation of a lattice structure from multiple different types of polymeric molecules by e.g., crosslinking or covalent inter- or intra- molecular binding of the polymers to provide spherical or substantially spherical particles. The components making up the lattice structure will impact the properties of the particle.
  • the particle preferably comprises a crosslinked styrene divinylbenzene copolymer lattice, which is produced as a spherical particle, with a specific size profile and properties, as disclosed herein.
  • the lattice structure is preferably conjugated, with functional groups, such as e.g., sulphonic or phosphoric acid, which allows for binding of the radionuclides as disclosed herein.
  • polymeric molecules of the particle may comprise a crosslinked polymeric lattice.
  • the crosslinking degree of the crosslinked polymeric lattice is about 2%-10%, such as 3-7%, such as 4%, 6% or 8% preferably about 4%.
  • resin refers to a polymerized structure of polymers, formulated as a particle or a bead to achieve desired properties such as e.g., hardness, chemical resistance, thermal stability, pore size and particle size.
  • the resin is preferably formulated as spherical particles, with a specific size profile, as disclosed herein, combined with particular functional groups, such as sulphonic or phosphoric acid, which allows for binding of the radionuclides as disclosed herein.
  • functional groups such as sulphonic or phosphoric acid
  • the resin is a polystyrene-divinylbenzene sulfonic acid resin.
  • the resins of the present invention may have lattice structure.
  • the polymeric particle lattice of the present invention may refer to polymeric resin. These terms can be used interchangeably.
  • resin making up the particle is a styrene divinylbenzene copolymer
  • the resin may be styrene divinylbenzene copolymer lattice.
  • one example of these types of resins is a polystyrene-divinylbenzene sulfonic acid resin.
  • the particle has a size in the range of 5-400 pm, such as 25-250 pm, such as 50-200 pm, such as 100-150 pm, such above 60 pm and below 150 pm. In embodiments, the particle is having a size in the range of 70-150 pm. In preferred embodiments, the particle has a size in the range of 20-50 pm, more preferably 30-35 pm. In embodiments, the particle has a size in the range of 5-400 pm, with a mean particle size of 20-50 pm, preferably a mean particle size of 30-35 pm.
  • the particle is essentially phosphate free.
  • essentially phosphate free is meant that the preparation of the particles preferably does not involve a step of phosphate precipitation of the radionuclide in order to immobilize the particle on the particle. The omission of the phosphate precipitation step is essential in order to obtain a smooth particle, with little or no protrusions, otherwise resulting from the phosphate precipitation.
  • the term “essentially” means that the amount of phosphate is less than for particles that have been prepared using phosphate precipitation.
  • one or more embodiments of the present invention relates to the particle of the present invention where the amount of phosphate is less than 100 ppm.
  • one or more embodiments of the present invention relates to the particle of the present invention where the amount of phosphate is less than 10 ppm.
  • one or more embodiments of the present invention relates to the particle of the present invention where the amount of phosphate is less than 1 ppm.
  • the new method of absorbing Y-90 via ionic binding rather than phosphate precipitation allow the product to be more stable over Temperature stress conditions reducing the percentage of Y-90 leacing.
  • the particle is in particular embodiments composed of a divinylbenzene copolymer.
  • the divinylbenzene copolymer has a crosslinking degree of 2%-10%, such as 3-7%, such as 4%, 6% or 8% preferably about 4%.
  • the radionuclides of the present invention can be any alpha- and/or beta-emitting radionuclide.
  • alpha and/or beta particle emitting compounds in local therapy in e.g., the liver is the shorter range, typically less than 0.1 mm for alpha emitters such as 212 Bi and 212 Pb and mm to cm ranges for beta-particles from medical beta-emitters such as 90 Y, 82 Br and 201 TI, compared to gamma emitting particles such as " m Tc, 111 ln and 18 F.
  • alpha-emitters and beta-emitters would in an intratumoral setting reduce risk for toxicity due to irradiation of non-target regions such as adjacent healthy tissue including blood vessels or even other proximal internal organs.
  • the decay of said alpha-, and/or beta-emitting radionuclide is primarily alpha and/or beta decay.
  • the alpha- and/or beta-emitting radionuclide is selected from the group consisting of 90 Y, 225 Ac, 89 Sr, 153 Sm, 159 Gd, 18 F, 68 Cu, 69 Cu, 67 Ga, " m Tc, 201 Ti, 111 ln, 161 Tb, 212 Pb and 177 Lu. More preferably, the alpha- and/or beta-emitting radionuclide is selected from the group consisting of "Y, 68 Cu, 69 Cu, 225 Ac, 177 Lu. Most preferable, the beta-emitting radionuclide is "Y.
  • Y is preferred due to its release of high amounts of beta radiation (2.2 MeV) and low tissue penetration length (up to 11 mm) (Barrio et. al.), making it especially suitable for tumour directed radiotherapy, such as local-regional radiotherapy, brachytherapy or radioembolization.
  • Y is a radioactive isotope of yttrium with 39 protons and 51 neutrons, giving it an atomic mass of 90.
  • Y is a beta-emitter, that primarily decays by emission of beta radiation and decays into stable 90 Zr, with a half-life of 64.4 hrs.
  • the emission of gamma radiation is critical for the clinical application of the particles as mentioned herein since a high dose of gamma radiation would irradiate both the patient and the person preparing and/or providing the therapy. Accordingly, it is preferred that the alpha, and/or beta-emitting radionuclide emits no more than 10%, such as less than 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less than 0.1 % gamma radiation of the total decay radiation.
  • the half-life of the radionuclide is also of great importance, and it is preferred that the decay of the particle is in a range which allows for fast administration of the desired dosage of radiation, while also allowing the practitioner to prepare and administer the treatment. Accordingly, in embodiments, the alpha- and/or betaemitting radionuclide has a decay half-life in the range of 1-300 hrs, such as between 10-100 hrs, or such as 50-70 hrs.
  • the amount of 90 Y used per patient dosage may be in the range of 1 kBq to 10 GBq, depending on the type of cancer to treat.
  • liver cancer such as hepatocellular carcinoma a dose in the range of 20 MBq to 1 GBq.
  • the particle as disclosed herein may be prepared with a dose in the range of 1 kBq to 10 GBq, such as between 100- 500 MBq, such as about 10 MBq, 20 MBq, 30 MBq, 40 MBq, 50 MBq, 60 MBq, 70 MBq, 80 MBq, 90 MBq, 100 MBq, 110 MBq, 120 MBq, 130 MBq, 140 MBq, 150 MBq, 160 MBq, 170 MBq, 180 MBq, 190 MBq, 200 MBq, 210 MBq, 220 MBq, 230 MBq, 240 MBq, 250 MBq, 260
  • MBq 360 MBq, 370 MBq, 380 MBq, 390 MBq, 400 MBq, 410 MBq, 420 MBq, 430 MBq, 440
  • MBq, 450 MBq, 460 MBq, 470 MBq, 480 MBq, 490 MBq or such as about 500 MBq may be considered suitable. Dosages generally depends on the size of the tumour.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a particle as disclosed herein.
  • composition may be a particle suspension comprising monodisperse or polydisperse particles labelled with an alpha- and/or beta-emitting radionuclide.
  • the composition is preferably an aqueous composition.
  • said composition comprises particles as disclosed herein and a diluent, carrier, surfactant, deflocculant and/or excipient.
  • Acceptable carriers and pharmaceutical carriers include but are not limited to non-toxic buffers, fillers, isotonic solutions, solvents and co-solvents, anti-microbial preservatives, anti- oxidants, wetting agents, antifoaming agents and thickening agents etc. More specifically, the pharmaceutical carrier can be but are not limited to normal saline (0.9 %), half-normal saline, Ringer’s lactate, dissolved sucrose, dextrose, e.g. 3.3 % Dextrose/0.3 % Saline, water for injection (WFI).
  • the physiologically acceptable carrier can contain a radiolytic stabilizer, e.g. ascorbic acid, human serum albumin, which protect the integrity of the radiopharmaceutical during storage and shipment.
  • the pharmaceutical compositions can comprise a multitude of particles. These can be the same or different.
  • the pharmaceutical composition a particle suspension comprising monodisperse or polydisperse particles labelled with an alpha- and/or beta-emitting radionuclide.
  • a composition comprising the particles as disclosed herein comprises a curable adhesive and/or a polymerizable hydrogel.
  • said adhesive or hydrogel is biocompatible, such that the adhesive or hydrogel component in the composition does not induce any adverse effects upon administration.
  • a hydrogel is a three-dimensional network of hydrophilic polymer chains that has the ability to absorb and retain water or biological fluids while maintaining its structural integrity. These materials are highly biocompatible, meaning they are well-tolerated by living organisms and can interact with biological systems without causing harm or adverse reactions to the tissue into which they are applied or administered.
  • the hydrogels may be polymerized to form an adhesive structure, in which the radioactive particles are embedded.
  • polymerized hydrogels are formed through cross-linking polymer chains, resulting in a stable, three-dimensional network structure. These hydrogels are solid or gel-like materials, maintaining their shape and integrity in the presence of moisture or biological fluids. In contrast, unpolymerized hydrogels are in a liquid or semi-liquid state and lack the cross-linked structure of their polymerized counterparts. Such hydrogels are often used as injectable biomaterials, allowing for in-situ polymerization at the application site, making them suitable for minimally invasive medical procedures, such as intratumorally administration via image assisted administration.
  • Biocompatible curable adhesives/glue designs are specifically formulated adhesives that bond biological materials together while safeguarding their integrity and biocompatibility, the curing process, typically initiated by UV light, controlled heat, or by addition of a curing agent, offers precise control over bonding strength and speed, minimizing damage to sensitive biological tissue.
  • biocompatible adhesives are e.g., BIOGLUE®, composed of bovine serum albumin which is cured using glutaraldehyde crosslinking; and fibrin glue comprising the protein fibrinogen and the protein curing agent thrombin.
  • suitable alternatives are known to the skilled person, such as collagen-based adhesives, alginate adhesives and gelatine adhesives.
  • a biocompatible adhesive is to be understood as an adhesive which is a specialized bonding material designed to adhere to biological tissues or medical devices while minimizing adverse reactions or harm to living organisms.
  • This type of adhesive is formulated to be substantially non-toxic, non-irritating, and compatible with the human body or other biological systems.
  • Biocompatible adhesives are commonly used in medical applications such as wound closure, tissue grafting, and the assembly of implantable devices, where it provides a secure and durable bond without causing inflammation, toxicity, or other negative biological responses. Accordingly, it is preferred that the biocompatible adhesive as disclosed herein is minimally toxic or irritating to the surrounding tissue, when such tissue is non-cancerous.
  • the composition comprises a one part of a two-component adhesive, such as e.g., BIOGLUE® (Artivion Inc.; Atlanta, GA), which comprises a first component, being bovine serum albumin, and a second component being glutaraldehyde.
  • a two-component adhesive such as e.g., BIOGLUE® (Artivion Inc.; Atlanta, GA)
  • BIOGLUE® Articleivion Inc.; Atlanta, GA
  • a first component being bovine serum albumin
  • glutaraldehyde glutaraldehyde
  • the composition comprises an 90 Y labelled particle with a divinylbenzene copolymer resin.
  • the composition further comprises bovine serum albumin and/or glutaraldehyde.
  • composition of as disclosed herein is a pharmaceutical composition, injectable composition, or a pharmaceutical formulation.
  • the pharmaceutical composition prepared with an amount of radionuclide that is 1 kBq to 10 GBq per dosing.
  • the pharmaceutical composition prepared with an amount of radionuclide that is suitable for multidose industrial scale production e.g., 50 MBq to 1000 GBq.
  • a method for producing a radionuclide labelled particle e.g., 50 MBq to 1000 GBq.
  • the present invention also relates to a method for producing an alpha- and/or beta-emitting radionuclide labelled particle.
  • an alpha- and/or beta-emitter is provided e.g., as a salt or in an aqueous solution, such as e.g., an aqueous solution comprising 90 Y or a powder comprising "YCh, or another alpha- and/or beta-emitting radionuclide, or a salt thereof as disclosed herein.
  • an aqueous solution such as e.g., an aqueous solution comprising 90 Y or a powder comprising "YCh, or another alpha- and/or beta-emitting radionuclide, or a salt thereof as disclosed herein.
  • the alpha- and/or beta-emitter is mixed with a particle suspension, comprising particles which are functionalized to bind to e.g., the 90 Y ions in the solution.
  • a particle suspension comprising particles which are functionalized to bind to e.g., the 90 Y ions in the solution.
  • Such functional groups may e.g., be phosphoric acid or sulphonic acid or a combination of such.
  • Essential is that the functional group should be capable of binding the alpha- and/or beta-emitter in an aqueous solution with a pH in a physiological range.
  • the suspension is preferable left for a period of time i.e., labelling time, which allows for the radionuclide to be bound by the particles, e.g., by cation exchange of an ion bound functional group on the particles, and the cationic radionuclide, this may e.g., be for a duration of about 60 minutes, such as no more than 30 minutes, such as no more than 15 minutes after step.
  • labelling time i.e., labelling time
  • this may e.g., be for a duration of about 60 minutes, such as no more than 30 minutes, such as no more than 15 minutes after step.
  • the mixing of the particles and the alpha- and/or beta-emitter is often followed by an isolation step, which may also comprise several washing steps.
  • the mixing may e.g., be done in a reaction vessel, such as a chromatographic column, or a tube containing a filter suitable for isolating the particles and the aqueous solution containing unbound radionuclide, such as e.g., a polypropylene fitted disc, column or similar.
  • the isolation and washing may e.g., be done via centrifugation, where the particles and the aqueous solution are separated into a liquid-liquid and a particle-liquid phase.
  • isolation methods for isolating the labelled particle and the unconjugated radionuclide are well known to the skilled person.
  • the optimal time to allow binding will depend on the specific radionuclide, and its binding kinetics with the particles.
  • the half-life of the specific radionuclide is essential, where it follows that the shorter the half-life of the radionuclide, the shorter the process step should be, in order to maintain as high a radioactivity dose as possible.
  • the methods as provided herein provides for a faster and more efficient labelling method of the particles, compare to the available methods, which otherwise also includes a step of ion immobilization by precipitation, a process which is both time consuming and reduces the overall recovery of the alpha- and/or beta-emitting radionuclide, since more ions will detach from the particles in the precipitation step.
  • the methods presented herein for producing a radioactive particle produces less waste and consumes less raw materials, than particles produced according to the current available methods.
  • the precipitation such as e.g., performed by rapid pH adjustments by addition of phosphate salts, such as sodium phosphate, creates protrusions on the surface of the particles, which may lead to unintended flaking of the alpha- and/or beta-emitting radionuclide phosphate salts from the particles. Accordingly, by the use of phosphate precipitation, the amount of radioactivity per particle becomes restricted to an amount which does not result in flaking.
  • the method does not comprise immobilizing said radionuclide on said particle by phosphate precipitation. Accordingly, the present method enables the preparation of alpha- and/or beta-emitting radionuclide labelled particles which are essentially phosphate free.
  • the invention also relates to a method for producing an alpha- and/or beta-emitting radionuclide labelled particle as disclosed herein and/or or a pharmaceutical composition disclosed herein.
  • the method comprises:
  • Providing an alpha- and/or beta-emitting radionuclide or a salt thereof Providing a particle with a sulfonic acid and/or phosphonic acid, preferably a sulfonic acid conjugated polymeric resin,
  • the method disclosed herein may comprise providing a salt of a nuclide, preferable 90 Y, such as “YCI3 or 90 Y2(SO4)3, 90 Y3(CH3CO2)3, Y(NOs)3 or other salts.
  • the particles provided for said method are preferably conjugated with sulphuric acid, and preferably comprises of a co-polymeric styrene divinylbenzene.
  • particles suitable for preparing the alpha- and/or beta-emitting radionuclide labelled particle are e.g., AG® 50W or AP® MP-50 or Aminex 50W- X4, X6resins (BioRad), Sulfopropyl SepharoseTM resins (GELifescience), and other sulphopropyl or sulphate conjugated agarose, dextran or similar resins.
  • the invention relates to a method for producing an alpha- and/or beta-emitting radionuclide labelled particle as disclosed herein and/or or a pharmaceutical composition disclosed herein, comprising:
  • the mixing and isolation step is performed no more than 60 minutes, such as no more than 30 minutes, such as no more than 15 minutes within each other.
  • the pH is may be essential for some applications for several reasons, such as suitability for injection, where pH ranges far beyond physiological pH might induce unwanted tissue irritation, for example, if the pH is greater than 9, this may result in irritation of the blood vessels when the suspension is injected into the artery during TARE (SIRT) procedure.
  • the pH is preferably in the range of pH 7-9, preferably less than pH 8.5, such as less than pH 7.5, such as about pH 7.4.
  • the methods disclosed herein enables the labelling of particles with different ratios between the radioactive nuclides and the particles, and also at radionuclide: particle ratios which introduces flaking from the particles when phosphate precipitation is used.
  • the weight ratio between the radionuclide and the particle is in the range of 1 :40-1 :6000 (mg/mg), such as in the range of 1 :100-1 :6000, such as in the range of 1 :1000-1 :6000, such as about 1 :5000.
  • the weight ratio of radionuclide to particle may be in the range of 1 :40 to 1 :6000, such as in the range of 1 :50 to 1 :5000, or such as in the range of 1 :60 to 1 :4000.
  • Suitable sub-ranges within the broad range include, but are not limited to 1 :50 to 1 :3000, 1 :75 to 1 :2500, 1 :100 to 1 :2000, 1 :150 to 1 :1500, and 1 :200 to 1 :1000, with further exemplary sub-ranges being 1 :45 to 1 :100, 1 :100 to 1 :1000, and 1 :1000 to 1 :6000.
  • the weight ratio between the radionuclide and the particle is about 1 :5800.
  • the weight ratio between the radionuclide and the particle is more than 1 :5800, such as more than 1 :5000, 1 :4000, 1 :3000, 1 :2000, 1 :1000, 1 :500, 1 :250, 1 :100 or such as more than 1 :75.
  • the weight ratio between the radionuclide and the particle is in the range of 1 :40-1 :1000, such as in the range of 1 :50-1 :100, 1 :45-1 :75, such as about 1 :50. In embodiments, the weight ratio between the radionuclide and the particle is about 1 :53.
  • the labelled particles for administration, it might be preferred to prepare the labelled particles in an aqueous suspension, wherein such an aqueous suspension may e.g., in addition to water for injection (WFI), comprise a buffering agent, such as e.g., acetate, phosphate, citrate, or glutamate.
  • a buffering agent such as e.g., acetate, phosphate, citrate, or glutamate.
  • the particle suspension consists essentially of the alpha- and/or beta-emitting radionuclide labelled particles and water for injection (WFI).
  • said method may also comprise combining the alpha- and/or beta-emitting radionuclide labelled particle suspension with a biocompatible adhesive.
  • the adhesive may e.g., be a single component adhesive or two- or more component adhesive, wherein said adhesive is curable once administered to the intended site, such as e.g., a tumour. Curing of a single component adhesive may occur by addition of heat, oxygen, UV-light, or similar methods. Curing of a two-component adhesive generally involves mixing of a first component and a second component, whereafter the mixture of the two initiates the curing of the adhesive.
  • curable two-component adhesives examples include BIOGLUE®, comprising the two components bovine serum albumin and glutaraldehyde, VISTAS EALTM comprising the components fibrinogen and thrombin, hyaluronic acid-based adhesives and gelatine-based adhesives.
  • the method provided herein may be used to prepare a composition, pharmaceutical composition and/or injectable composition comprising an alpha- and/or betaemitting radionuclide labelled particle.
  • the radionuclide labelled particle suspensions prepared as described herein have a low leaching rate leading of as low as 0,005% of the radionuclide following heat treatment up to 150*C for 30 minutes.
  • this low leaching rate further enables the use of autoclave and/or treatment by other heat intensive sterilisation methods after preparation of the radionuclide particle suspensions as disclosed herein.
  • the low leaching rate under high temperatures enables the radionuclide particle suspensions and bioglues comprising radionuclide particle suspensions produced according to the method disclosed herein to be used with procedures that have a heat intensive element, e.g. laser surgery, without experiencing any substantially increased leaching of the radionuclide from the site of insertion.
  • the present invention relates to a method of preparing a cured 90 Y radiotherapeutic composition comprising, a) Providing, i. a "Y labelled particle suspension,
  • an uncured biocompatible adhesive and/or non-polymerized hydrogel in an aqueous solution ill. a curing and/or polymerizing agent which upon mixture with ii), or i) and ii) induces curing of said biocompatible adhesive and/or polymerization of said hydrogel, and b) Mixing i., ii. and ill. to obtain a cured "Y radiotherapeutic composition, comprising biocompatible adhesive and/or hydrogel embedded "Y radiotherapeutic particles.
  • "cured” denotes the state where the adhesive has completed its transformation from a liquid or malleable form into a solid or semi-solid state. This transformation occurs through chemical reactions, exposure to specific catalysts, ultraviolet (UV) light, or elevated temperatures, depending on the type of adhesive. Once cured, the adhesive forms a strong, permanent bond between surfaces, exhibiting properties like strength, stability, and resistance to external factors.
  • the uncured biocompatible adhesive is an albumin.
  • the non-polymerized hydrogel comprises one or more components selected from the list consisting of chitosan, hyaluronic acid, collagen, gelatin, elastin, alginate, cellulose, and glycosaminoglycan.
  • the curing agent may e.g., be glutaraldehyde or similar amide crosslinking agents, such as e.g., NHS-based or imidoester-based cross linkers, or hydroxy targeting crosslinkers such as diglycidyl ether (DDE) based crosslinkers.
  • DDE diglycidyl ether
  • the present invention also relates to kits for producing the particles and/or compositions as disclosed herein.
  • the present invention also relates to a kit comprising; unlabelled particles comprising, or consisting of a polymeric resin conjugated with sulfonic acid; optionally reagents for preparing an alpha- and/or beta-emitting radionuclide labelled particle, or a pharmaceutical composition as disclosed herein; and optionally instructions for preparing said particle or pharmaceutical composition.
  • Said kit may further comprise, aqueous solution comprising an uncured curable biocompatible adhesive and/or non-polymerized hydrogel in an aqueous solution.
  • the kit may further comprise an aqueous solution comprising a curing and/or polymerizing agent.
  • said curable biocompatible adhesive is preferably an albumin, preferable bovine serum albumin in additional embodiments, said curing and/or polymerizing agent is an amide cross linking agent, preferably glutaraldehyde.
  • the kit enables the production of said particles and/or compositions as disclosed herein, directly at the practitioner, thus greatly simplifying the process of providing the proper treatment dose, without the need for extensive and laborious preparation of the radioactive particle.
  • the invention also relates to a method of preparing a cured 90 Y radiotherapeutic composition
  • a method of preparing a cured 90 Y radiotherapeutic composition comprising, providing a 90 Y labelled particle suspension and an uncured biocompatible adhesive and/or non-polymerized hydrogel in an aqueous solution.
  • Said method may further comprise providing a curing and/or polymerizing agent which upon mixture with said biocompatible adhesive and/or non-polymerized hydrogel induces curing of said biocompatible adhesive and/or polymerization of said hydrogel.
  • Curing or polymerization of said biocompatible adhesive and/or non-polymerized hydrogel may also be initiated by other external factors such as but not limited to exposure to UV-radiation, heat and/or air.
  • Said method may thus comprise curing and/or polymerizing said "Y radiotherapeutic composition using a curing and/or polymerizing agent which upon mixture with said uncured biocompatible adhesive and/or non-polymerized hydrogel induces curing of said biocompatible adhesive and/or polymerization of said hydrogel, or initiating curing via exposure to UV-radiation, heat and/or air, thus obtaining a cured/polymerized "Y radiotherapeutic composition.
  • a cured or polymerized composition may for instance be exceptionally suitable for cancer therapy where it is essential that the radioactive component of the treatment is kept in place in the indented surroundings, in order to reduce potential risks of particle mitigation, where the particles may migrate to unintended tissues and result in unwanted and harmful irradiation.
  • a medical device A medical device
  • the particle according to the present invention is the particle according to the present invention a medical device or is comprised in a medical device.
  • a medical device is any instrument, apparatus, appliance, software, material or other article, whether used alone or in combination, including the software intended by its manufacturer to be used specifically for diagnostic and/or therapeutic purposes and necessary for its proper application, intended by the manufacturer to be used for human beings for the purpose of: Diagnosis, prevention, monitoring, treatment or alleviation of disease; Diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap; Investigation, replacement or modification of the anatomy or of a physiological process; Control of conception; and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means.
  • Medical devices vary according to their intended use and indications. Examples range from simple devices such as tongue depressors, medical thermometers, and disposable gloves to advanced devices such as computers which assist in the conduct of medical testing, implants, and prostheses.
  • a medical device is “an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is: recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them, intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes.”
  • the particles are carriers of radioactivity that are designed to have a limited, if any, chemical action within the body, and this allows for radiotherapy with very limited unwanted sideeffects, such as toxicity.
  • the particles or compositions as disclosed herein are for use as a medicament.
  • the particles or pharmaceutical composition disclosed herein are for use in loco-regional radiotherapy, such as brachytherapy and transarterial radioembolization (TARE).
  • TARE Transarterial radioembolization
  • SIRT selective internal radiation therapy
  • one embodiment of the present invention relates to the particles or pharmaceutical composition disclosed herein are for use in transarterial radioembolization (TARE).
  • One embodiment of the present invention relates to the particles or pharmaceutical composition disclosed herein are for use in brachytherapy.
  • Loco-regional radiotherapy is a procedure where ionizing radiation is precisely directed to eliminate or damage cancer cells in specific local and regional areas, avoiding off-target and/or systemic exposure to the radioactive source.
  • This modality primarily targets the tumor and its adjacent tissues, reducing the probability of local and regional recurrence. It can be administered externally or internally and is often used in conjunction with other cancer therapies like surgery, chemotherapy, target therapies (such as but not limited to immunotherapy), aiming to provide optimal therapeutic benefits with minimized adverse effects to the surrounding healthy tissues and organs.
  • the particle as disclosed herein is for use in loco-regional radiotherapy.
  • Brachytherapy is a specialized and precise form of loco-regional radiotherapy.
  • Brachytherapy involves placing a fixed radioactive source directly inside or very close to the tumor, enabling the delivery of high doses of radiation to more localized areas. This helps to minimize damage to surrounding healthy tissues. Brachytherapy is particularly effective for cancers of the prostate, cervix, liver, and breast, allowing targeted treatment with fewer side effects. The precise nature of brachytherapy makes it a viable option for tumors located in critical body structures where accuracy is paramount.
  • composition as disclosed herein which comprises the radioactive particles, and a biocompatible adhesive is especially suited for brachytherapy as it enables the administration of high radioactivity doses, to specific areas, such as a tumour, which are fixed in place due to the curing of the adhesive once administered. As mentioned the curing reduces the side effects otherwise associated with classical radiation therapy.
  • the particle as disclosed herein is for use in brachytherapy.
  • TARE is a medical procedure used to treat liver tumours, such as primary hepatocellular carcinoma or secondary liver cancers.
  • radioactive microspheres are injected directly into the blood vessels that supply the tumour. These microspheres emit radiation that targets and destroys cancer cells while sparing healthy tissue.
  • TARE can help shrink tumours, alleviate symptoms, and improve the quality of life for patients who are not suitable candidates for surgery including liver resection and orthotopic liver transplantation or other treatments, offering a targeted and well-tolerated option for managing certain liver malignancies and other types of malignancies.
  • the particles of the present invention or compositions comprising same are also suitable for use in transarterial radioembolization.
  • the particles of the present invention or compositions comprising same are for use in the treatment or amelioration of cancer.
  • uses of the particles or compositions as disclosed herein may also include use in the treatment or amelioration of cancer, such as e.g., in the treatment of head and neck squamous cell carcinoma, metastatic melanoma, sarcoma, non-small cell lung cancer, colorectal cancer, primary and secondary hepatocellular carcinoma, pancreatic ductal adenocarcinoma, renal cell carcinoma, ovarian cancer, muscle invasive bladder cancer, prostate cancer, and/or osteosarcoma, preferably, unresectable hepatocellular carcinoma and/or locally-advanced borderline-resectable pancreatic ductal adenocarcinoma.
  • the particles or compositions as disclosed herein are used in the treatment of unresectable hepatocellular carcinoma.
  • Transarterial radioembolization may include treatment of primary or metastatic cancer in an organ e.g., the liver by administering the particles of the present invention to a blood vessel leading to a tumor in the liver or another solid organ infiltrated by tumor tissue.
  • different dosages of 90 Y to be delivered may be preferable for different types of metastatic cancer, depending on the tumour size, density, position and surrounding tissue.
  • Gray stands as a fundamental unit for quantifying radiation dose. This measurement signifies the amount of ionizing radiation energy deposited within biological tissues.
  • Gray is essential for determining the optimal radiation dose delivered to the targeted tissue or tumor while minimizing harm to healthy surrounding tissues.
  • the choice of the appropriate radiation dose in Grays hinges on factors such as the disease type, its stage, the specific radionuclide used, the affected tissue or organ, and individual patient characteristics. Before treatment, the practitioner often calculates the required dosage to be administered tailored to each patient's unique medical situation.
  • Radionuclide therapy is a specialized field within nuclear medicine, where the Gray (Gy) plays a vital role in ensuring safe and effective radiation treatment. By maintaining this balance, medical professionals can optimize therapeutic outcomes while minimizing potential side effects. For example, for HCC, 120 Gy is typically considered a reasonable minimum target dose, and the more precise the targeting of the treatment is, the higher doses may be administered. For other indications, lower of higher doses may be favored.
  • the target-absorbed dose is in the range of 1 Gy to 500 Gy, such as between 50 Gy and 400 Gy, such as about 50Gy, 60Gy, 70Gy, 80Gy, 90Gy, 100Gy, 110Gy, 120Gy, 130Gy, 140Gy, 150Gy, 160Gy, 170Gy, 180Gy, 190Gy, 200Gy, 210Gy, 220Gy, 230Gy, 240Gy, 250Gy, 260Gy, 270Gy, 280Gy, 290Gy, 300Gy, 310Gy, 320Gy, 330Gy, 340Gy, 350Gy, 360Gy, 370Gy, 380Gy, 390Gy, or such as about 400Gy.
  • the target-absorbed dose is in the range of 40-300 Gy, such as about 40, 50, 60, 70, 80, 100, 150, 200, 250, or about 300 Gy.
  • MBq (megabecquerel) is often also used to measure the actual dose delivered to a patient, where the dose in the syringe can be readily measured and compared to the amount of radioactivity present in the syringe after injection, the active dose delivered to the patient may be readily calculated.
  • the active dose delivered to the patients is in the range of 1 kBq to 10 GBq, such as in the range of 10-50 MBq, such us in the range of 50-500 MBq, such as in the range of 500 MBq to 1 GBq, or such as in the range of 1 GBq to 3 GBq, or such as in the range of 3-10 GBq.
  • the particles are administered directly into a tumor.
  • Another aspect of the present invention relates to a method of treatment or amelioration comprising administration of the particles or the pharmaceutical composition as disclosed herein to an individual in need thereof.
  • the particles and/or compositions described herein are administered by through the hepatic artery.
  • the particles and/or compositions are used to treat hepatocellular carcinoma, including but not limited to injection or administration into a lesion, or to a treatment site following resection of a lesion.
  • treatment may include intra-tumoral administration or distal metastasis site.
  • composition as disclosed herein is for single treatment or repeated dosing.
  • Radionuclide imaging leverages beta-emitting radionuclides to visualize internal structures and assess physiological functions within the human body.
  • Beta-emitters such as " m Tc and 131 l, are commonly employed in this imaging modality due to their ability to emit beta particles, which are high-energy electrons or positrons.
  • the particles of the present invention are preferably administered via intratumor administration, allowing for direct targeting to target specific tissues and/or organs of interest. Once administered, the beta-emitting radionuclides undergo radioactive decay, emitting beta particles that can be detected by a gamma camera or positron emission tomography (PET) scanner.
  • PET positron emission tomography
  • radionuclide imaging may also be used to evaluate the site of injection of particles and/or compositions described herein.
  • particles and compositions as described herein may be for use in radionuclide imaging.
  • the present example aims to show that it is possible to incorporate the Yttrium onto microspheres by absorption at a neutral pH, without precipitating it as an insoluble phosphate salt.
  • Yttrium (90Y) chloride in dilute HCI 0.04 M contains 0.1-300 GBq Yttrium (90Y) pr. 1 ml, on the reference date and time corresponding to 0.005-15 micrograms of Yttrium [90Y] (as Yttrium [90Y] chloride).
  • 89Y was used instead of 90Y, and to mimic the intended amount of radiation required in the final vials, the amount of yttrium was calculated from the intended dose/mL.
  • the procedure has been tested through 4 main steps: titration of the resin; conditioning of the resin as sodium salt; preparation of YCI3 solution; absorption of Yttrium onto the resin.
  • the step is designed to generate 530 mg of phosphate free resin with 1 .5 GBq of 90-Y solution.
  • 1 .5 and 1 .7 g of AG 50W-X4 cation exchange resin was added to a 5 ml syringe fitted with a polypropylene disc.
  • the resin was washed; firstly with 3.5 ml of NaOH 1 .0 M to perform the cation exchange and then four times with 2 ml of water for injection (WFI) to complete the conditioning of the resin as sodium salt.
  • WFI water for injection
  • the neutralized YCI3 solution was added to the syringe containing the resin and 1 ml of water was used to wash the Yttrium vial and the syringe. The mixture was then gently shaken for 15 min, to allow absorption of yttrium into the activated resin microspheres.
  • EDS Energy-dispersive X-ray spectroscopy
  • Yttrium labelled particles were imaged by scanning electron microscopy and compared to particles prepared by phosphate precipitation of Yttrium to the particles.
  • EDS Energy-dispersive X-ray spectroscopy
  • the Scanning Electron Microscopy (SEM) of the product presented in figure 2 shows a homogeneous and thin surface of the microspheres compare to the particles prepared according to the methods of the prior art, utilizing phosphate precipitation, (See figure 3 and figure 4), which shows a denser structure with rough surfaces due to the precipitate.
  • Such rough structure may be more susceptible of leaching in case of alterations in the environmental conditions, such as e.g., changes in pH.
  • the Yttrium-90 bound on biodegradable microspheres produced according to the described process provides an improved and simplified labelling process.
  • the aim of the present example is to test the feasibility of incorporation of high amounts of Yttrium on the particles.
  • the experiments have been carried out using the novel method and the phosphate-salt precipitation method.
  • the particles were washed multiple times with 2.0 mL of phosphate buffer solution 0.1 M pH 7.5 until the pH is stabilized. Microspheres washed with 2.0 mL of water for injection.
  • Scanning Electron Microscopy (SEM) of the product shows an homogeneous and thin surface of the microspheres analysis of the product (figure 5) shows that this procedure allows Yttrium to be absorbed on the resin, concluding that the incorporation of Yttrium onto the resin at neutral pH without the use of phosphate salts and without precipitation of the metal, is possible even using over 100-times more Yttrium.
  • EDS Energy-dispersive X-ray spectroscopy
  • the particles prepared according to the phosphate precipitation method using the high Yttrium amounts was not able to assure a stable structure when high amount of Yttrium is used, due to deposition of multiple layers of the phosphate salts, which will lead to a leaching and flaking of free Yttrium from the particles.
  • the pH is kept at 12.5, there is a risk of formation of water-soluble anionic hydroxides [Y(OH)4]- that could lead to the removal of yttrium-90 from the surface of the microspheres.
  • the pH is greater than 9, this may result in irritation of the blood vessels when the suspension is injected into the artery.
  • the pH is preferably less than 8.5 and more preferably less than 7.5, but more preferably about 7.4.
  • the present example thus demonstrates that stressing the process using over 100 times more Yttrium compared to conventional process still allows the absorption of high quantity of Yttrium onto microspheres and that the absorbed Yttrium does not substantially leach from the particulate material under physiological conditions.
  • the present example aims to show that it is possible to measure and produce radioactive particles using the new process described in example 1 incorporating radioactive Yttrium (90Yttrium) onto microspheres by absorption at a neutral pH, without precipitating it as an insoluble phosphate salt.
  • the procedure has been tested through 6 main steps: titration of the resin; conditioning of the resin as sodium salt; preparation of 90YCI3 solution; absorption of 90Yttrium onto the resin; extraction and elution phase by washing the Y-90 resin; process yield calculation.
  • AG 50W-X4 cation exchange resin AG 50W-X4 resin 200-400 from BioRad Laboratories, Inc
  • Resin was collected from vacuum filtration unit and transferred to 50 mL polypropylene tube.
  • the activity 0.1 mL of 90YCI3 (from Eckert & Ziegler) original sample was measured in the dose calibrator.
  • the 0.1 mL 90YCI3 sample was diluted by adding 0.90 mL of 0.04 N HCI to obtain a homogenous solution.
  • 0.4 ml NaOH 0.1 M was added to the Yttrium Chloride solution to reach neutral pH (Acceptance Criteria: 6.00-8.00).
  • the activity of the diluted 90Y sample was measured in the dose calibrator.
  • the neutralized 90YCI3 solution was transferred, using a syringe, and was added to the 50 mL propylene tube containing the resin. Using the same syringe 1 ml of water was used to wash all the 90Yttrium solution from the syringe and was pushed onto the resin tube. The mixture was then gently shaken for 15 min, to allow absorption of 90Yttrium into the activated resin microspheres.
  • the leftover activity in the 90Yttrium vial was measured using a dose calibrator.
  • a funnel with polyethylene frit was put on ring stand and a new 50 mL polypropylene tube was placed underneath (elution fraction tube).
  • the 90Y-resin was transferred from 50 mL polypropylene tube to funnel.
  • the leftover activity in the 50 mL polypropylene tube was measured using a dose calibrator.
  • the product wash pushed through the funnel and the fraction was collected in the 50 mL polypropylene tube.
  • the resin fraction was washed 4 times with 1.6 mL of water: using the plunger of a 10 mL syringe, the water was pushed through the funnel until resin was dry.
  • the activity of the resin in the funnel was measured using a dose calibrator as well as the activity of the elution fraction.
  • Losses elution fraction + unwashed 50 mL tube + empty polyethylene funnel/frit.
  • Yttrium labelled particles were imaged by scanning electron microscopy.
  • Scanning Electron Microscopy (SEM) of the product shows an homogeneous and thin surface of the microspheres analysis of the product (figure 8) shows that this procedure allows Yttrium to be absorbed on the resin, concluding that the incorporation of Yttrium onto the resin at neutral pH without the use of phosphate salts and without precipitation of the metal, is possible.
  • Yttrium-90 decays with a half-life of 64 hours, while emitting a high energy pure beta radiation.
  • the process is also applicable to all the others metals/radionuclides which may also be used in place of Yttrium-90 (i.e. but not limited to holmium, lutetium, actinium, rhenium) applying same stoichiometry described above.
  • Example 4 In vitro stability of radiolabelled microparticles
  • the present example aims to show that 90-Yttrium microspheres produced with the novel method are stable at high temperature so they can be terminal sterilized using autoclave.
  • a control group at ambient temperature (25 °C) was used as well.
  • the starting activity of 90Yttrium was different but the production and measurements steps of radioactive microspheres are the same as described in example 3: titration of the resin; conditioning of the resin as sodium salt; preparation of 90YCI3 solution; absorption of 90Yttrium onto the resin; extraction and elution phase by washing the Y-90 resin; process yield calculation.
  • the resulting suspension was spitted into 4 equal parts (2 mL each sample) into 10 mL glass vials with crimped septum.
  • Table 2 Stress Temperature conditions The activity of each vial was checked using a dose calibrator after equilibration at room temperature according to what is reported in Table 3.
  • the measured % of loss of 90Y after Temperature stress test was very low (0.005%-0.7%). Moreover, for the 2 approved autoclave cycle (121 °C for 30 minutes and 132 for 7 minutes) the measured % of loss of 90Y after Temperature stress test was 0.005% and 0.04% respectively.
  • the goal was to mimic a terminal sterilization process, heating the final product and determining the amount of activity remaining attached to the microspheres and the % of 90 Yttrium loss after the heating process.
  • microspheres were overstressed by subjecting the composition to a temperature of 150 °C for 30 minutes, which is above the normal conditions of autoclavation.
  • the simulation of the terminal sterilization of the 90Y-resin using high temperature showed that the 90Y remained attached to the resin when exposed to various temperatures for different time durations.
  • the % of loss Y90 measured was very low (0.005% and 0.04% i.e., less than 1 % (0.7%) even under over-stressing condition.
  • Example 5 Measurement and production of radioactive particles using a resin conditioned with NaOH
  • the present example aims to show that it is possible to measure and produce radioactive particles using the new process described in the present disclosure, incorporating radioactive Yttrium (90Yttrium) onto microspheres by absorption at a neutral pH, without precipitating it as an insoluble phosphate salt, using microspheres Aminex 50W-X4 resin, 25-37 pm. Despite the resin comes already in sodium form, it has been decided to evaluate the conditioning step with NaOH anyway and seek for results.
  • the procedure has been tested through 6 main steps: titration of the resin; conditioning of the resin as sodium salt; preparation of 90YCI3 solution; absorption of 90Yttrium onto the resin; extraction and elution phase by washing the Y-90 resin; process yield calculation.
  • Resin was collected from vacuum filtration unit and transferred to 50 mL polypropylene tube.
  • the activity 0.1 mL of 90YCI3 (from Eckert & Ziegler) original sample was measured in the dose calibrator.
  • the 0.1 mL 90YCI3 sample was diluted by adding 0.90 mL of 0.04 N HCI to obtain a homogenous solution.
  • 0.4 ml NaOH 0.1 M was added to the Yttrium Chloride solution to reach neutral pH (Acceptance Criteria: 6.00-8.00).
  • the activity of the diluted 90Y sample was measured in the dose calibrator.
  • the neutralized 90YCI3 solution was transferred, using a syringe, and was added to the 50 mL propylene tube containing the resin. Using the same syringe 1 ml of water was used to wash all the 90Yttrium solution from the syringe and was pushed onto the resin tube. The mixture was then gently shaken for 15 min, to allow absorption of 90Yttrium into the activated resin microspheres.
  • the leftover activity in the 90Yttrium vial was measured using a dose calibrator.
  • a funnel with polyethylene frit was put on ring stand and a new 50 mL polypropylene tube was placed underneath (elution fraction tube).
  • the 90Y-resin was transferred from 50 mL polypropylene tube to funnel.
  • the leftover activity in the 50 mL polypropylene tube was measured using a dose calibrator.
  • the product wash pushed through the funnel and the fraction was collected in the 50 mL polypropylene tube.
  • the resin fraction was washed 4 times with 1.6 mL of water: using the plunger of a 10 mL syringe, the water was pushed through the funnel until resin was dry.
  • the activity of the resin in the funnel was measured using a dose calibrator as well as the activity of the elution fraction.
  • Losses elution fraction + unwashed 50 mL tube + empty polyethylene funnel/frit.
  • Yttrium-90 decays with a half-life of 64 hours, while emitting a high energy pure beta radiation.
  • the process is also applicable to all the others metals/radionuclides which may also be used in place of Yttrium-90 (i.e. but not limited to holmium, lutetium, actinium, rhenium) applying same stoichiometry described above.
  • the present example aims to show that it is possible to measure and produce radioactive particles using the new process as described in the present disclosure, incorporating radioactive Yttrium (90Yttrium) onto microspheres by absorption at a neutral pH, without precipitating it as an insoluble phosphate salt, using microspheres Aminex 50W-X4 resin, 25-37 pm.
  • the procedure has been tested through 5 main steps: washing with water for injection; preparation of 90YCI3 solution; absorption of 90Yttrium onto the resin; extraction and elution phase by washing the Y-90 resin; process yield calculation.
  • Resin was collected from vacuum filtration unit and transferred to 50 mL polypropylene tube.
  • the activity 0.1 mL of 90YCI3 (from Eckert & Ziegler) original sample was measured in the dose calibrator.
  • the 0.1 mL 90YCI3 sample was diluted by adding 0.90 mL of 0.04 N HCI to obtain a homogenous solution.
  • 0.4 ml NaOH 0.1 M was added to the Yttrium Chloride solution to reach neutral pH (Acceptance Criteria: 6.00-8.00).
  • the activity of the diluted 90Y sample was measured in the dose calibrator.
  • the neutralized 90YCI3 solution was transferred, using a syringe, and was added to the 50 mL propylene tube containing the resin. Using the same syringe 1 ml of water was used to wash all the 90Yttrium solution from the syringe and was pushed onto the resin tube. The mixture was then gently shaken for 15 min, to allow absorption of 90Yttrium into the activated resin microspheres.
  • the leftover activity in the 90Yttrium vial was measured using a dose calibrator.
  • a funnel with polyethylene frit was put on ring stand and a new 50 mL polypropylene tube was placed underneath (elution fraction tube).
  • the 90Y-resin was transferred from 50 mL polypropylene tube to funnel.
  • the leftover activity in the 50 mL polypropylene tube was measured using a dose calibrator.
  • the product wash pushed through the funnel and the fraction was collected in the 50 mL polypropylene tube.
  • the resin fraction was washed 4 times with 1.6 mL of water: using the plunger of a 10 mL syringe, the water was pushed through the funnel until resin was dry.
  • the activity of the resin in the funnel was measured using a dose calibrator as well as the activity of the elution fraction.
  • Losses elution fraction + unwashed 50 mL tube + empty polyethylene funnel/frit.
  • Yttrium-90 decays with a half-life of 64 hours, while emitting a high energy pure beta radiation.
  • the process is also applicable to all the other metals/radionuclides which may also be used in place of Yttrium-90 (i.e. but not limited to holmium, lutetium, actinium, rhenium) applying same stoichiometry described above.
  • Example 7 Measurement and production of radioactive particles no conditioning with NaOH - scale up activity
  • the present example aims to show that it is possible to measure and produce radioactive particles using the new process as described in the present disclosure, incorporating radioactive Yttrium (90Yttrium) onto microspheres by absorption at a neutral pH, without precipitating it as an insoluble phosphate salt, using microspheres Aminex 50W-X4 resin, 25-37 pm.
  • the procedure has been tested through 5 main steps: washing of the resin with water for injection; preparation of 90YCI3 solution; absorption of 90Yttrium onto the resin; extraction and elution phase by washing the Y-90 resin; process yield calculation.
  • Resin was collected from vacuum filtration unit and transferred to 50 mL polypropylene tube.
  • the activity 0.1 mL of 90YCI3 (from Eckert & Ziegler) original sample was measured in the dose calibrator.
  • the 0.1 mL 90YCI3 sample was diluted by adding 0.90 mL of 0.04 N HCI to obtain a homogenous solution.
  • 0.4 ml NaOH 0.1 M was added to the Yttrium Chloride solution to reach neutral pH (Acceptance Criteria: 6.00-8.00).
  • the activity of the diluted 90Y sample was measured in the dose calibrator.
  • the neutralized 90YCI3 solution was transferred, using a syringe, and was added to the 50 mL propylene tube containing the resin. Using the same syringe 1 ml of water was used to wash all the 90Yttrium solution from the syringe and was pushed onto the resin tube. The mixture was then gently shaken for 15 min, to allow absorption of 90Yttrium into the activated resin microspheres.
  • the leftover activity in the 90Yttrium vial was measured using a dose calibrator.
  • a funnel with polyethylene frit was put on ring stand and a new 50 mL polypropylene tube was placed underneath (elution fraction tube).
  • the 90Y-resin was transferred from 50 mL polypropylene tube to funnel.
  • the leftover activity in the 50 mL polypropylene tube was measured using a dose calibrator.
  • the product wash pushed through the funnel and the fraction was collected in the 50 mL polypropylene tube.
  • the resin fraction was washed 4 times with 1.6 mL of water: using the plunger of a 10 mL syringe, the water was pushed through the funnel until resin was dry.
  • the activity of the resin in the funnel was measured using a dose calibrator as well as the activity of the elution fraction.
  • Losses elution fraction + unwashed 50 mL tube + empty polyethylene funnel/frit.
  • Yttrium labelled particles were imaged by scanning electron microscopy.
  • Scanning Electron Microscopy (SEM) of the product shows an homogeneous and thin surface of the microspheres analysis of the product.
  • the SEM shows that this procedure allows Yttrium to be absorbed on the resin, concluding that the incorporation of Yttrium onto the resin at neutral pH without the use of phosphate salts and without precipitation of the metal, is possible.
  • Yttrium-90 decays with a half-life of 64 hours, while emitting a high energy pure beta radiation.
  • the process is also applicable to all the other metals/radionuclides which may also be used in place of Yttrium-90 (i.e. but not limited to holmium, lutetium, actinium, rhenium) applying same stoichiometry described above.
  • the present example aims to show that 90-Yttrium microspheres produced with the novel method are stable at high temperature so they can be terminal sterilized using autoclave.
  • the starting activity of 90Yttrium was different but the production and measurements steps of radioactive microspheres are the same as described in example 7: washing of the resin with water for injection; preparation of 90YCI3 solution; absorption of 90Yttrium onto the resin; extraction and elution phase by washing the Y-90 resin; process yield calculation.
  • the resulting suspension was spitted into 4 equal parts (2 mL each sample) into 10 mL glass vials with crimped septum.
  • the measured % of loss of 90Y after Temperature stress test was very low (0.003%-0.005%). Moreover, for the 2 approved autoclave cycle (121 °C for 30 minutes and 132 for 7 minutes) the measured % of loss of 90Y after Temperature stress test was 0.004% and 0.003% respectively.
  • the simulation of the terminal sterilization of the 90Y-resin using high temperature showed that the 90Y remained attached to the resin when exposed to various temperatures for different time durations.
  • the % of loss Y90 measured was very low (0.003% and 0.005% i.e., much less than 1% (0.005%) even under over-stressing condition.

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Abstract

La présente invention concerne des particules radiothérapeutiques polymères, des compositions et des procédés de production de celles-ci, le radionucléide étant un radionucléide émetteur alpha et/ou bêta. L'invention concerne également l'utilisation de ladite particule et desdites compositions, dans le traitement du cancer et leur utilisation dans la radiothérapie locorégionale, la curiethérapie et la radioembolisation transartérielle.
PCT/EP2024/077336 2023-09-29 2024-09-27 Particules radiothérapeutiques polymères, suspensions et leurs procédés de production Pending WO2025068543A1 (fr)

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CN116549679A (zh) * 2023-07-06 2023-08-08 北京普尔伟业生物科技有限公司 含有放射性微球的混悬液及其制备方法和应用
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WO2015168726A1 (fr) 2014-05-08 2015-11-12 Sirtex Medical Limited Méthode de traitement du carcinome des cellules rénales
US20230181774A1 (en) * 2015-05-13 2023-06-15 Sirtex Medical Inc. Method, Apparatus, and System for Radiation Therapy
CN116271115A (zh) * 2022-12-13 2023-06-23 北京普尔伟业生物科技有限公司 一种医用微球及其制备方法和应用
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MARK A. WESTCOTT ET AL: "The development, commercialization, and clinical context of yttrium-90 radiolabeled resin and glass microspheres", ADVANCES IN RADIATION ONCOLOGY, vol. 1, no. 4, 1 October 2016 (2016-10-01), pages 351 - 364, XP055493405, ISSN: 2452-1094, DOI: 10.1016/j.adro.2016.08.003 *
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