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US-12622924-B2 - Composition for the protection and repair of the blood brain barrier

US12622924B2US 12622924 B2US12622924 B2US 12622924B2US-12622924-B2

Abstract

The present invention relates to a pharmaceutical composition for its application as a drug, in particular for use in the protection of the blood-brain barrier and/or the repair and/or the restoration of the blood brain barrier. The present invention finds an application in particular in the therapeutic, pharmaceutical and veterinary fields.

Inventors

  • Denis Barritault
  • Myriam BERNAUDIN
  • Omar TOUZANI
  • Jérôme TOUTAIN
  • Yacine KHELIF

Assignees

  • CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE
  • Organes Tissus Regeneration, Reparation, Remplacement
  • Denis Barritault
  • UNIVERSITÉ DE CAEN NORMANDIE

Dates

Publication Date
20260512
Application Date
20200430
Priority Date
20190527

Claims (11)

  1. 1 . A method for the protection of the blood-brain barrier from external attacks selected from an isotopic compound, a toxin and/or a pathogen, comprising administering a pharmaceutical composition comprising: a biocompatible polymer of the following general formula (I) A a X x Y y Z z (I) in which: A is glucose, X represents an R 1 COOR 2 group, in which R1 is a methyl group —CH 2 — and R2 is a group R21 R22 in which R21 is an anion and R22 is a cation which is an alkali metal or X is —CH2COO—, Y represents —R 7 SO 3 R 8 in which R7 is a bond and R8 is an alkali metal selected from the group consisting of lithium, sodium, potassium, rubidium and cesium or Y is a —SO3- group, Z is phenylalanine or acetate; a represents the number of monomers, x represents the degree of substitution of monomers A by X groups, y represents the degree of substitution of monomers A by Y groups, wherein x is between 10 and 150%, wherein the degree of substitution “y” is between 10 and 170%, and wherein the degree of substitution of all the monomers A by Z groups represented by “z” is between 1 and 50%, to an individual at risk from external attacks selected from an isotopic compound, a toxin and/or a pathogen; wherein the pharmaceutical composition is administered orally, nasally, subcutaneously, intramuscularly, intravenously, intraarterially, intracranially, or intrathecally.
  2. 2 . The method of claim 1 , wherein the pharmaceutical composition further comprises hyaluronic acid.
  3. 3 . The method of claim 1 , wherein the number of monomer “a” is such that the mass of said polymers of formula (I) is greater than or equal to 2,000 daltons.
  4. 4 . The method of claim 1 , wherein said pharmaceutical composition is administered orally at a dose of 0.1 to 5 mg/kg of body weight, and/or intracranially at a dose of 0.1 to 100 μg·ml −1 .
  5. 5 . The method of claim 2 , wherein the concentration of hyaluronic acid is from 1 to 10 mg/ml.
  6. 6 . The method of claim 1 , wherein Z is phenylalanine.
  7. 7 . The method of claim 1 , wherein Z is acetate.
  8. 8 . The method of claim 1 , wherein X is —CH2-COO—, Y is a —SO3- group, and Z is phenylalanine.
  9. 9 . The method of claim 1 , wherein X is —CH2-COO—, Y is a —SO3- group, and Z is acetate.
  10. 10 . A method for the protection and/or repair/restoration of the blood-brain barrier, comprising identifying or selecting an individual who has an altered blood-brain barrier, and administering a pharmaceutical composition comprising: a biocompatible polymer of the following general formula (I) A a X x Y y Z z (I) in which: A is glucose, X represents an R 1 COOR 2 group, in which R1 is a methyl group —CH 2 — and R2 is a group R21 R22 in which R21 is an anion and R22 is a cation is an alkali metal or X is —CH2-COO—, Y represents —R 7 SO 3 R 8 in which R7 is a bond and R8 is an alkali metal selected from the group consisting of lithium, sodium, potassium, rubidium and cesium or Y is a —SO3- group, Z is phenylalanine, a represents the number of monomers, x represents the degree of substitution of monomers A by X groups, y represents the degree of substitution of monomers A by Y groups, wherein x is between 10 and 150%, wherein the degree of substitution “y” is between 10 and 170%, and wherein the degree of substitution of all the monomers A by Z groups represented by “z” is between 1 and 50%, to the individual.
  11. 11 . The method of claim 10 , wherein X is —CH2-COO—, Y is a —SO3- group.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a National Phase of PCT/EP2020/062081, filed on Apr. 30, 2020, which claims priority to French Patent Application No. 1905566, filed on May 27, 2019, the disclosures of which are hereby incorporated by reference in their entireties. TECHNICAL FIELD The present invention relates to a pharmaceutical composition for its application as a drug, in particular for its use for the protection of the blood-brain barrier. The present invention also relates to a pharmaceutical composition for its application as a drug, in particular for its use for the repair and/or restoration of the blood-brain barrier. The present invention relates to a pharmaceutical composition for its application as a drug, in particular for its use for the protection and/or repair and/or restoration of the blood-brain barrier. The present invention finds an application in particular in the therapeutic, pharmaceutical and veterinary fields. In the description below, references in parentheses ( ) refer to the list of references presented at the end of the text. STATE OF THE ART The blood-brain barrier (BBB), also called the hematoencephalic or hematomeningeal barrier, is made up of a monolayer of endothelial cells in the micro-vessels of the brain. These endothelial cells have tight junctions between them thus limiting the para- and transcellular exchanges between the blood compartment and the parenchymal compartment. The endothelial cells are surrounded by a basement membrane, astrocytic feet and pericytes thus reinforcing the BBB (Sharif et al., 2018 [16]). The basal lamina underlying the cerebral endothelium actively participates in the dynamics of the BBB, consists of 3 layers. The first, synthesized by endothelial cells, is characterized by the presence of laminin 4 and 5. The second is characterized by the presence of laminin-1 and -2, and is synthesized by astrocytes. The third, characterized by the presence of collagen IV, is found between the first two and is formed by the two cell types. These three layers are also made up of different types of collagen, glycoproteins and proteoglycans, in particular heparan sulphates proteoglycans (HSPGs) (Cardoso et al., 2010 [4]). The basal lamina also contains numerous proteins, metalloproteases (MMPs) and their inhibitors which are involved in the dynamic regulation of BBB under physiological as well as pathological conditions. BBB protects neurons against factors present in the systemic circulation and maintains the internal environment of the central nervous system, necessary for good synaptic and neuronal functioning (Sharif et al., 2018 [16]). The alteration of BBB has been reported in many brain diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, cerebrovascular accident (CVA), chronic traumatic encephalopathy, but also brain infections (Abdullahi et al., 2018 [1]; Sweeney et al., 2018 [19]; Erickson and Banks 2018 [5]). The BBB is also impaired in the presence of brain tumors as well as following brain irradiation as part of radiotherapy (Katherine Elizabeth Warren, 2018 [22]). The disruption of BBB allows the influx into the brain of neurotoxic agents derived from blood, cells and microbial pathogens and is associated with inflammatory and immune responses, which can initiate and exacerbate several pathways of neuronal death (Sharif et al. 2018 [16]). In the state of the art, there are therapeutic protocols and/or strategies aimed at protecting the components of the BBB structure: tight junctions and cell receptors; or at fighting against the causes of its permeability: inflammation; oxidation; activation of MMPs (Sifat et al., 2017 [17]). However, these therapeutic protocols and/or strategies have not demonstrated any real efficacy and/or a significant therapeutic effect, in particular for the protection of the BBB. Other strategies for the protection of BBB have also been considered. For example, there are in the state of the art patent documents describing methods targeting molecules of cellular signaling pathways (delta-PKC) (patent application US20090062208A1); transcription factors (HMGB1) (application WO2018207792A1), the S100B protein (patent document CN101632728B), or even cell junctions (Claudin-5) (patent document CN105148276B) in association with the BBB. However, none of these methods and/or strategies has resulted in treatment or clinical application to date. In addition, in the state of the art, there are no products known to act directly as a protector or to promote the restoration of the BBB. In other words, there is currently no compound and/or pharmaceutical composition capable of protecting and/or repairing and/or restoring the blood-brain barrier. Therefore, there is a real need in the state of the art to find a compound and/or a composition making it possible to protect the BBB, for example from lesions and/or alterations due, for example, to pathologies and/or tr