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EP-3829555-B1 - COMPOSITIONS COMPRISING RESVERATROLOSIDES AND CURCUMIN

EP3829555B1EP 3829555 B1EP3829555 B1EP 3829555B1EP-3829555-B1

Inventors

  • RAVAGNAN, GIAMPIETRO
  • BONUCCI, Massimo

Dates

Publication Date
20260513
Application Date
20190801

Claims (16)

  1. Composition comprising a combination of polydatin and curcumin for use in a method for treating tumors of the glia chosen among gliomas and glioblastomas characterized in that the composition is administered sublingually.
  2. Composition for use according to the preceding claim, wherein curcumin consists of a mixture of Curcumin I, Curcumin II and Curcumin III.
  3. Composition for use according to any one of claims 1-2 which is a pharmaceutical or nutraceutical composition.
  4. Composition for use according to any one of claims 1-3 for use in the treatment of one of the following pathologies: astrocytomas, oligodendrogliomas, ependymomas, more particularly anaplastic astrocytomas and glioblastomas.
  5. Composition for use according to any one of claims 1-4 wherein polydatin is combined with one or more resveratrolosides of general formula (I): and curcumin is combined with one or more curcumins having a linear diarylheptanoid structure, with 2 phenolic groups linked by a chain with 7 carbon atoms; or having a cyclized structure for inner cyclization or having a hydrogenated structure without unsaturated bonds; and corresponding mixtures.
  6. Composition for use according to claim 5 in which resveratrolosides are selected from: Resveratroloside with CAS number 27208-80-6, Astringin with CAS number 29884-49-9, (2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-(4-((E)-3-hydroxystyrylphenoxy)-tetrahydro-2H-piran-3,4,5-triol, and corresponding mixtures; and curcumins are selected from: curcumin I, curcumin II, curcumin III, hydrocurcumin, cyclocurcumin, and corresponding mixtures.
  7. Composition for use according to any one of claims 1-6 formulated in solid, liquid, gel, aerosol form; as liposomial formulation with mono- and plurilamellar liposomes, as phytosome; or formulated with bioadhesive polymers, with arrays of glucans or based on graphene, or combined with carbon nano-particles.
  8. Composition for use according to any one of claims 1-7, which comprises: from about 4.5% to about 7.5%, preferably from about 5.5% to about 6.5%, by weight of polydatin; from about 5.5% to about 8.5% by weight of curcumin, preferably from about 6% to about 8%, and a pharmaceutically acceptable carrier.
  9. Composition for use according to any one of claims 1-8 administered in combination with: - active ingredients selected from: anti-edema compounds in amounts ranging from about 0.0% to about 1.5%, and more preferably from about 1.2% to about 1.4% by weight; anticancer drugs; antineoplastic drugs, such as Temozolomide, Dacarbazine, Lomustine, Cisplatin; antiangiogenic agents, such as Trastuzumab; radioprotective agents; drugs administered before or after surgery to reduce or remove the tumor; and related combinations; - "whole brain" radiotherapy technologies; gamma-knife radiosurgery; tomotherapy; hadrotherapy; stereotactic radiosurgery (Cyberknife).
  10. Composition for use according to any one of claims 1-9 administered in a daily dose of at least about 400 mg total of active compounds; preferably in a dose from about 2 mg to about 4 mg of polydatin and from about 2 mg to about 5 mg of curcumin per kilogram of body weight of the patient per day.
  11. Composition for use according to claim 10 administered in a single unit or several dosage units per day.
  12. Composition for use according to any one of claims 1-10 administered daily for at least 6 weeks during treatment with radiotherapy and chemotherapy, for at least 1 year (6-12 cycles of Temozolomide), preferably for the rest of the patient's life.
  13. Composition for use according to any one of claims 1-10 administered with two periods of administration, a periodicity relative to the acute phase and a periodicity relative to the maintenance phase.
  14. Composition for use according to claim 13 wherein the administration during the acute phase, which can last from 6 months to 1 year, is in amounts of at least 500 mg per day in a single or fractionated dose.
  15. Composition for use according to claim 13 wherein the administration during the maintenance phase, which can last for the rest of the patient's life, is in amounts of at least 300 mg in a single or fractionated daily dose.
  16. Composition for use according to any one of claims 1-15 which is a pediatric composition.

Description

TECHNICAL FIELD The present invention is defined in the appended claims. The references to methods of treatment in the summary and detailed description of the invention in this description are to be interpreted as references to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for treatment of the human (or animal) body by therapy. The present invention relates to novel methods to treat tumors of the Central Nervous System in humans (also referred to hereinafter as CNS), more particularly tumors of grade 3° and 4°, even more particularly glioblastoma (also referred to hereinafter to as GBL), and relates to the administration of compositions comprising therapeutically effective amounts of resveratrolosides (hereinafter also referred to as piceids) and curcumins, in particular natural extracts comprising said two components simultaneously. The invention also relates to the realization of pharmaceutical and nutraceutical compositions comprising resveratrolosides and curcumins. More specifically, the invention relates to compositions formulated for the release of the active components for sublingual administration. The object of the present invention is to provide pharmaceutical and nutraceutical compositions with improved efficacy in the context of the protocols of integrated anticancer therapies. More particularly, the invention relates to tumors of the Central Nervous System in humans, even more particularly to tumors of grade 3° and 4°, with particular reference to glioblastoma. The improvement associated with the compositions according to the invention consists in controlling factors that lead to the progression of tumor pathologies with poor prognosis, such as glioblastoma. The resveratrolosides to which the invention relates in particular are the glucosidic stilbenoids known with the names of piceid (CAS number 38963-95-0) and polydatin (CAS number 27208-80-6). STATE OF ART Tumors of the Central Nervous System (CNS) comprise a diverse set of pathological entities. Due to the fact that glia tumors alone account for almost 40% of all CNS tumors, in the literature it is customary to make a distinction between glia tumors (or gliomas) and non glia tumors. Glia tumors include: astrocytomas (which originate from the astrocytic cells of the glia), oligodendrogliomas (from oligodendroglial cells) and ependymomas (from ependymal cells). Different systems have been suggested for the gradation (of malignancy) of CNS tumors over time. Since 1993 the 4-level grading system proposed by the World Health Organization (WHO) has proved to be the most widely accepted and widespread. It is based on four histological features: nuclear atypia, presence of mitosis, endothelial proliferation, necrosis. Obviously tumors with the worst outcome are 3rd and 4th grade tumors. Among the 3rd grade tumors are anaplastic astrocytomas, among the 4th grade tumors are glioblastomas. Glioblastoma is the most aggressive of the primitive brain tumors. It is among those defined as "orphan drugs" for which no cure exists https://www.osservatoriomalattierare.it/glioblastoma. Despite the progress in neurosurgery and neuro-oncology, the survival of glioblastoma patients is short, on average only 15 months after diagnosis. This tumor affects about 1,500 Italians every year, with an incidence peak between 50 and 65 years. Glioblastoma is produced by aberrant stem cells that, instead of generating a normal tissue, give rise to a highly malignant brain tumor. Unlike other tumors, an early diagnosis that leads to healing is not possible in glioblastoma. Glioblastoma stem cells in fact, in addition to being resistant to drug therapies, have the ability to migrate from the tumor and spread to different brain areas. This is why surgical therapy only manages to prolong survival, but it never brings healing to those suffering from this disease. GBL-tumorigenesis is characterized by a high production of lipids derived from arachidonic acid. These molecules stimulate the development of the peritumoral cerebral edema and tumor progression. Glucocorticoids are the most effective drugs currently used for the treatment of cerebral edema, but they are associated with numerous side effects. Since the available therapies are not very effective, over 50% of GBL-patients use complementary and alternative approaches, among which herbal therapies are the most commonly used, but with little success. Glucosidic stilbenoids, also called piceids, and curcumins are compounds that can be natural or synthetic. The natural sources are mainly grapes, polygonacee (for example, Fallopia japonica) and turmeric, from which they can be extracted by known methods (EP1292319, "Botanicals, a Phytocosmetic Desk Reference" Frank S. D'Amelio, CRC Press, pgs. 39-48). Both piceids and curcumins are widely used alone or in combination with each other in the pharmaceutical field, such as drugs, and in the nutraceutical field, as food supple