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EP-4739357-A1 - POLYMERIC RADIOTHERAPEUTIC PARTICLES, SUSPENSIONS AND METHODS FOR PRODUCING SAME

EP4739357A1EP 4739357 A1EP4739357 A1EP 4739357A1EP-4739357-A1

Abstract

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 locoregional radiotherapy, brachytherapy and transarterial radioembolization.

Inventors

  • CABRI, WALTER
  • STORY, Colin John
  • BELLO, Pietro Bubba

Assignees

  • BetaGlue Therapeutics SpA

Dates

Publication Date
20260513
Application Date
20240927

Claims (20)

  1. 1 . 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, wherein the particle has a size in the range of 5-400 pm, and wherein said particle has a smooth surface with little or no protrusions.
  2. 2. The alpha- and/or beta-emitting radionuclide labelled particle according to claim 1 , 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.
  3. 3. The alpha- and/or beta-emitting radionuclide labelled particle according to claims 1-2, wherein the smooth surface with little or no protrusions is defined by a particle with a surface that has less than 10 protrusions each with a minimum height of 1 m.
  4. 4. The alpha- and/or beta-emitting radionuclide labelled particle according to any of the preceding claims, wherein said particle is essentially phosphate free.
  5. 5. The alpha- and/or beta-emitting radionuclide labelled particle according to any of the preceding claims, wherein the amount of phosphate in the particle is less than 1 ppm.
  6. 6. The alpha- and/or beta-emitting radionuclide labelled particle according to any of the preceding claims, wherein the polymeric resin is a styrene divinylbenzene copolymer.
  7. 7. The alpha- and/or beta-emitting radionuclide labelled particle according to any of the preceding claims, wherein the polymeric resin a polystyrene-divinylbenzene sulfonic acid resin.
  8. 8. The alpha- and/or beta-emitting radionuclide labelled particle according to any of the preceding claims, wherein 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, 2 01 Ti, 111 ln, 161 Tb, 212 Pb and 177 Lu.
  9. 9. The alpha- and/or beta-emitting radionuclide labelled particle according to any of the preceding claims, wherein the beta-emitting radionuclide is 90 Y.
  10. 10. The alpha- and/or beta-emitting radionuclide labelled particle according to any of the preceding claims, wherein the decay of said alpha, and/or beta-emitting radionuclide emits no more than 10 % gamma radiation of the total decay radiation.
  11. 11. The alpha- and/or beta-emitting radionuclide labelled particle according to any of the preceding claims, wherein the alpha- and/or beta-emitting 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.
  12. 12. The alpha- and/or beta-emitting radionuclide labelled particle according to any of the preceding claims, wherein the decay of said alpha, and/or beta-emitting radionuclide is primarily alpha and/or beta decay.
  13. 13. A pharmaceutical composition comprising a particle according claim 1-12.
  14. 14. The pharmaceutical composition according to claim 13, comprising a diluent, carrier, surfactant, deflocculant and/or excipient.
  15. 15. The pharmaceutical composition according to claim 13 or 14, further comprising a biocompatible adhesive or a component thereof.
  16. 16. The pharmaceutical composition according to any of claims 13-15, further comprising an albumin, such as e.g., bovine serum albumin.
  17. 17. The pharmaceutical composition according to any of claims 13-16, prepared 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.
  18. 18. The pharmaceutical composition according to any of claims 13-17, which is suitable for intratumor, intracavitary, and/or intra-arterial injection.
  19. 19. An alpha- and/or beta-emitting radionuclide labelled particle according to any of claims 1-12, or a pharmaceutical composition according to any of claims 13-18, for use as a medicament.
  20. 20. An alpha- and/or beta-emitting radionuclide labelled particle according to any of claims 1-12, or a pharmaceutical composition according to any of claims 13-18, for use in the treatment or amelioration of cancer.

Description

POLYMERIC RADIOTHERAPEUTIC PARTICLES, SUSPENSIONS AND METHODS FOR PRODUCING SAME FIELD 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. BACKGROUND Many previous attempts have been made to locally administer radioactive materials to patients with cancer as a form of therapy. In some of these the radioactive materials have been incorporated into particles and alike, which can be administered directly into e.g., cancerous tumours, where radioactive particles provided as a form of transarterial radioembolization (TARE) (also known as selective internal radiation therapy (SIRT)). In TARE radioactive particles are administered via a catheter directly into the arterial blood supply of the target organ, such as the liver, to enable the delivery of the radioactive dosage directly at the tumour site, without systemic exposure of the radionuclide to the patient. This has the benefit that a higher amount of the desired radioactive dose is provided to the target lesion, without exposing ‘healthy’ tissue to otherwise harmful radiation. Such stable radiotherapeutic particles e.g., non-degradable glass spheres (TheraSphere™) or resin based spheres (SIR-SpheresTM) have been used for radioembolization for treating primary tumors and metastases to the liver. For such radioactive exposure to be efficacious and restricted to the target tissue 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. To overcome the leaching problem phosphate precipitation has been utilized in e.g., WO2015168726, which immobilizes the radionuclide on polymeric particles, by the precipitation of 90Y 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 90Y raw materials. Alternatives which enable a more efficient absorption of 90Y on particles, which does not form such protrusions is highly favourable, since it enables a more stable and robust radioactive particle to be formed that in turn may reduce potential off-target unwanted radiation for the patient. SUMMARY 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, 89Sr, 153Sm, 159Gd, 18F, 68CU, 69CU, 67Ga, "mTc, 201Ti, 111 In, 161Tb and 177Lu, preferably selected from the groups consisting of 90Y, 68Cu, 69Cu, 225Ac, 212Pb, 177Lu, more preferably the radionuclide is "Y. Accordingly, 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. In addition, 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. In embodiments, 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. Preferably, 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 componen