EA046226B1 - APPLICATION OF PHARMACEUTICAL COMPOSITION AS A MEDICINE FOR PROTECTION AND/OR REPAIR/RESTORATION OF THE BLOOD-BRAIN BARRIER - Google Patents

Abstract

The present invention relates to the use of a pharmaceutical composition as a medicament for protecting the blood-brain barrier and/or repairing and/or restoring the blood-brain barrier, wherein said composition comprises a biocompatible polymer of the following general formula (I): AaXxYy (I) wherein A is a monomer which is glucose, X is a group R]COOR2 or -R9(C=O)Ri0, Y is an O- or N-sulfonate group which corresponds to one of the following formulas: -R3OSO3R4, -R5NSO3R6, -R7SO3R8, where Ri, R3, R5 and R9 independently represent an aliphatic hydrocarbon chain, optionally branched and/or unsaturated, which optionally contains one or more aromatic rings, with the exception of benzylamine and benzylamine sulfonate, R2, R4, Re and R8 independently represent a hydrogen atom or a cation M\ and R7 and R]0 independently represent a bond, an aliphatic hydrocarbon chain, optionally branched and/or unsaturated, and represents the number of monomers, wherein the number "a" is such that the mass of said polymer of formula (I) is greater than or equal to 2000 daltons; x represents the degree of substitution of monomers A by groups X, wherein the degree of substitution x is from 10 to 150%; y represents the degree of substitution of monomers A by groups Y, wherein the degree of substitution "y" is from 10 to 170%. The present invention finds application, in particular, in the therapeutic, pharmaceutical and veterinary fields.

Description

Technical field

The present invention relates to the use of a pharmaceutical composition as a medicament for protecting the blood-brain barrier.

The present invention also relates to the use of a pharmaceutical composition as a medicament for the restoration and/or repair of the blood-brain barrier.

The present invention relates to the use of a pharmaceutical composition as a medicament for the protection and/or restoration and/or repair of the blood-brain barrier.

The present invention finds 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 blood-brain or blood-meningeal barrier, consists of a monolayer of endothelial cells in the microvasculature of the brain. These endothelial cells have tight junctions with each other, which limits para- and transcellular exchange between the blood compartment and the parenchymal compartment. Endothelial cells are surrounded by a basement membrane, astrocytic stalks and pericytes, thus strengthening the BBB (Sharif et al., 2018 [16]). The basal lamina, which underlies 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 laminins -1 and -2 and is synthesized by astrocytes. The third, characterized by the presence of collagen IV, is located between the first two and is formed by two types of cells. These three layers are also composed of different types of collagen, glycoproteins and proteoglycans, particularly heparan sulfate proteoglycans (HSPG) (Cardoso et al., 2010[4]).

The basal lamina also contains numerous proteins, metalloproteinases (MMPs) and their inhibitors, which are involved in the dynamic regulation of the BBB under both physiological and pathological conditions.

The BBB protects neurons from factors present in the systemic circulation and maintains the internal environment of the central nervous system necessary for the good functioning of synapses and neurons (Sharif et al., 2018 [16]).

Alteration of the BBB has been reported in many brain diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, acute cerebrovascular accident (ACVA), chronic traumatic encephalopathy, and brain infections (Abdullahi et al., 2018 [1] ]; Sweeney et al., 2018 [19]; Erickson and Banks 2018 [5]). The BBB is also disrupted in the presence of brain tumors, as well as after irradiation of the brain during radiation therapy (Katherine Elizabeth Warren., 2018 [22]). BBB disruption promotes the influx of neurotoxic agents derived from blood, cells, and microbial pathogens into the brain and is associated with inflammatory and immune responses that can initiate and exacerbate multiple pathways of neuronal death (Sharif et al., 2018 [16]).

The prior art includes therapeutic protocols and/or strategies aimed at protecting components of the BBB structure: tight junctions and cellular receptors; or in the fight 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 significant therapeutic effect, particularly for BBB protection.

Other strategies to protect the BBB were also considered. For example, current patent documents describe methods targeting cellular signaling pathway (delta-PKC) molecules (patent application US 20090062208 A1); transcription factors (HMGB1) (application WO 2018207792A1), S100B protein (patent document CN 101632728B) or even intercellular junctions (claudin-5) (patent document CN 105148276B) in association with the BBB. However, none of these methods and/or strategies have led to therapy or clinical application to date. In addition, at the current level of technology there are no drugs that are known to act directly as a protector or promote the restoration of the BBB. In other words, there is currently no compound and/or pharmaceutical composition capable of protecting and/or restoring and/or repairing the blood-brain barrier.

Therefore, there is a real need in the prior art to find a compound and/or composition capable of protecting the BBB, for example, from damage and/or changes caused, for example, by pathologies and/or treatments, for example, chemotherapy and/or radiation therapy, for example, brain.

There is also a real need in the prior art to find a compound and/or composition that makes it possible to restore changes and/or damage to the BBB, for example, due to pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis resulting from acute cerebrovascular accident (stroke), traumatic encephalopathy, for example, chronic infections, brain infections, such as meningitis, for example, viral or bacterial,

- 1 046226 changes and/or lesions caused, for example, by brain tumors, and/or treatment, for example chemotherapy and/or radiation therapy, for example, of the brain.

There is also a real need in the prior art to find a compound and/or composition that provides functional restoration of the BBB, for example, after damage and/or destruction of the said BBB.

Description of the invention

It is the object of the present invention to meet these needs by providing a pharmaceutical composition for use or use as a medicament for the protection and/or restoration and/or repair, preferably functional, of the blood-brain barrier, said composition containing a biocompatible polymer of the following general formula (I )

AaXxYy (I) where:

A is a monomer representing glucose,

X represents the group R ₁ COOR ₂ or -R ₉ (C=O)R ₁₀ ,

Y represents an O- or N-sulfonate group, which corresponds to one of the following formulas: -R3OSO3R4, -R5NSO3R6, -R7SO3R8, where:

R1, R3, R5 and R9 independently represent an aliphatic hydrocarbon chain, optionally branched and/or unsaturated, which optionally contains one or more aromatic rings, except benzylamine and benzylamine sulfonate, R2, R4, R6 and R8 independently represent a hydrogen atom or cation M+, and R7 and _R10 independently represent a bond, an aliphatic hydrocarbon chain, optionally branched and/or unsaturated, a represents the number of monomers, wherein the number a is such that the weight of said polymer of formula (I) is greater than or equal to 2000 daltons;

x represents the degree of substitution of monomers A by groups X, the degree of substitution of x being from 10 to 150%;

y represents the degree of substitution of monomers A by groups Y, with the degree of substitution of y ranging from 10 to 170%.

The inventor of the present invention has unexpectedly demonstrated the advantage that the use of a biocompatible polymer according to the invention makes it possible to strengthen, strengthen and/or restore the blood-brain barrier (BBB).

In particular, the inventors have unexpectedly demonstrated that the use of a biocompatible polymer in accordance with the invention advantageously allows when the blood-brain barrier (BBB) has been altered, for example by inflammation and/or lesion and/or any other change known to one skilled in the art , regardless of the cause or origin, ensure repair and/or strengthening and/or restoration of the blood-brain barrier (BBB).

The inventors have also surprisingly and unexpectedly demonstrated that the use of the polymer according to the invention advantageously accelerates and improves the functional restoration of the blood-brain barrier (BBB). In addition, the inventors have surprisingly and unexpectedly demonstrated that when changes in the BBB affect motor and/or cognitive functions, the use of the polymer according to the invention also allows for faster and/or improved recovery of motor and cognitive functions.

As used herein, protection of the blood-brain barrier is understood to mean, for example, improving the structure of the basement membrane of the blood-brain barrier and/or stimulating the endothelial cells of the blood-brain barrier and/or strengthening the tight junctions of the blood-brain barrier. Advantageously, protecting the blood-brain barrier allows, for example, to protect the latter from external negative influences, for example, from ionizing radiation, for example, from X-rays, gamma rays, from isotope compounds, for example, from xenobiotic substances, various toxins and pathogens. Protecting the blood-brain barrier may also make it possible to maintain central nervous system homeostasis, such as regulating ion flow and/or regulating molecular and cellular flow, particularly between the blood compartment and the central nervous system. These currents can be harmful to the central nervous system if this barrier is damaged and permeable.

As used herein, the term blood-brain barrier repair means, for example, restoring and/or improving the structure of the blood-brain barrier, for example, when the structure of the blood-brain barrier has been altered, for example, due to injury, external influence, such as a pathogen, disease, inflammation and/or any other phenomenon known to one skilled in the art, as well as the ability to alter and/or modify the structure and/or function of the blood-brain barrier. This may be, for example, accelerating the healing of a blood-brain barrier lesion, reducing blood-brain barrier inflammation, healing and/or improving

- 2 046226 tion of the basement membrane of the blood-brain barrier and/or endothelial cells of the blood-brain barrier and/or tight junctions of the blood-brain barrier.

As used herein, the term "blood-brain barrier restoration" means repair of structures and/or improvement of the blood-brain barrier and restoration/improvement of blood-brain barrier function, e.g., blood-brain barrier permeability, and/or any physiological function of the blood-brain barrier.

As used herein, a monomer is understood to mean, for example, a monomer selected from the group consisting of sugars, esters, alcohols, amino acids or nucleotides.

In the present invention, monomers A, which constitute the building blocks of the polymers of formula I, are glucose.

The number of monomers A, defined in formula (I) as a, is such that the mass of said polymer of formula (I) is greater than or equal to 2000 daltons.

In the present invention, in the group -R1COOR ₂ representing X, R1 represents an aliphatic hydrocarbon chain, optionally branched and/or unsaturated, which optionally contains one or more aromatic rings other than benzylamine and benzylamine sulfonate, and R2 independently represents a hydrogen atom or a cation M+. R1 may be a C1Cg alkyl, e.g. methyl, ethyl, butyl, propyl, pentyl, preferably a methyl group, and R2 may be a _C1 - _C6 alkyl bond, e.g. methyl, ethyl, butyl, propyl, pentyl , group R ₂₁ R ₂₂ , where R ₂₁ represents an anion and R ₂₂ represents a cation selected from the group of alkali metals.

Preferably, the group X is a group of the formula -R1COOR2, in which R1 is a methyl group -CH2-, and R2 is a group _R21R22 , wherein _R21 is an _anion and R22 is a cation selected from the group of alkali metals, preferably the group X is a group of the formula -CH2- ^COO- or carboxymethyl.

In the present invention, in the group -R ₉ (C=O)Ri ₀ representing X, R ₉ may represent a Q^-alkyl, for example, methyl, ethyl, butyl, propyl, pentyl, preferably a methyl group, and R ₁₀ may represent is a bond, C ₁ -C ₆ -alkyl, for example, methyl, ethyl, butyl, propyl, pentyl, hexyl.

The degree of substitution of all monomers A by groups X, defined as x in general formula (I), may be from 10 to 150%, from 40 to 80%, and preferably of the order of 50% or 60%.

In the present invention, in a group corresponding to one of the following formulas -R3OSO3R ₄ , R ₅ NSO3R ₆ , -R7SO3R8 and representing a Y group, R3 may represent a bond, ^-^-alkyl, for example, methyl, ethyl, butyl, propyl, pentyl , preferably a methyl group, R5 may be a bond, ^-^-alkyl, e.g. methyl, ethyl, butyl, propyl, pentyl, preferably a methyl group, R7 may be a bond, ^-^-alkyl, e.g. methyl, ethyl , butyl, propyl, pentyl, preferably a methyl group, R4, _R6 and R8 may independently be a hydrogen atom or an M+ cation, for example M+ may be an alkali metal.

Preferably, the group Y is a group of the formula -R7SO3R8, in which R7 is a bond and R8 is an alkali metal selected from the group consisting of lithium, sodium, potassium, rubidium and cesium. Y represents the group -SO ₃ ^- , -SO ₃ ^- Na ⁺ .

The degree of substitution of all monomers A by groups Y, defined in the general formula (I) as y, may be from 10 to 170%, from 30 to 150%, from 55 to 160%, from 55 to 85%. from 120 to 160% and preferably of the order of 70, 140 or 150%.

In the present invention, the definition of the above degrees of substitution is that a degree of substitution x equal to 100% means that each monomer A of the polymer of the present invention statistically contains group X. Likewise, a degree of substitution y equal to 100% means that each the polymer monomer of the present invention randomly contains a Y group. A degree of substitution greater than 100% reflects the fact that each monomer statistically contains more than one group of the type in question; conversely, degrees of substitution less than 100% reflect the fact that each monomer statistically contains less than one group of the type in question.

Polymers may also contain functional chemical groups, designated Z, other than X and Y.

In the present invention, the Z groups may be the same or different and may be independently selected from fatty acids.

Advantageously, Z groups can impart additional biological or physicochemical properties to polymers. For example, Z groups can increase the solubility or lipophilicity of the polymer, for example, providing better diffusion or tissue penetration.

Advantageously, Z groups can impart additional biological or physicochemical properties to polymers. Thus, the polymers of the invention, for example, when group Z is selected from an antioxidant compound, an anti-aging compound, the polymers of the invention can advantageously carry these compounds and thus provide an additional and/or complementary biological effect.

Polymers in which Z is present may correspond to the following formula II: Aa Xx Yy Zz (II) where A, X, Y, a, x, y have the meanings given above and z represents the degree of substitution

- 3 046226 groups Z.

In the present invention, the degree of substitution with Z groups, designated by z, may be from 1 to 50%, 10 and 25%, and is preferably 15, 20 or 25%.

The X, Y and Z groups may be independently attached to monomer A and/or independently attached to each other. When at least one of the X, Y and Z groups is independently attached to a group of X, Y and Z other than the first, one of said X, Y or Z groups is attached to the monomer A.

Thus, the Z groups can be covalently attached directly to the A monomers or covalently attached to the X and/or Y groups.

In the present invention, Z groups can also be conjugated to polymers of formula AaXxYy through bonds other than covalent bonds, for example through ionic bonds, for example through ionic interactions, hydrophilic bonds or hydrophobic bonds. The polymers of the invention can then constitute a Z-vectorization system.

In the present invention, the polymer may be, for example, a polymer selected from the group consisting of compounds OTR4120, OTR41201, OTR41202, OTR41203, OTR41205, OTR41210 OTR41301, OTR41302, OTR41303, OTR41305, OTR41310, OTR3131.

As used herein, the polymer may be, for example, a polymer selected from the group consisting of OTR41201, OTR41202, OTR41203, OTR41205, OTR41210, OTR4120, OTR4122, OTR4125, OTR41301, OTR41302, OTR41303, OTR41305, OTR41310, OTR 3131, OTR4132, OTR4135, OTR415 with the characteristics shown in the table below.

Table: polymers of the families Aa Xx Yy (1) and Aa Xx Yy Zz (II), where A is glucose (molecular weight 180 daltons), X is carboxymethyl (molecular weight 58 daltons) Y: SO ₃ ^- (MW 80 daltons ) and Z is acetate (molecular weight 43 daltons) or phenylalanine (molecular weight 165 daltons).

- 4 046226

polymer A: glucose X -CH ₂ COO -so ₃ - Z -OSSNz Z phenylalanine Name RGTA Average molecular weight +/-15% Dextran starting polymer (PM in Daltons) CM/% glucose replacement SO ₄ / glucose) % replacement OSSNz /% Substitutions glucose CMDS OTR4120 1 3000 1500 60+/-20 150+/-20 0 CMDS OTR4120 2 6000 3000 60+/-20 150+/-20 0 CMDS OTR41203 10000 5000 60+/-20 150+/-20 0 CMDS OTR41205 20000 10000 60+/-20 150+/-20 0 CMDS OTR41210 40000 20000 60+/-20 150+/-20 0 CMDS OTR4120 80000 40000 60+/-20 150+/-20 0 CMDS OTR4122 220000 110000 60+/-20 150+/-20 0 CMDS OTR4125 500000 250000 60+/-20 150+/-20 0 CMDSA OTR41301 3000 1500 60+/-20 140+/-20 20+/-5 CMDSA OTR41302 6000 3000 60+/-20 140+/-20 20+/-5 CMDSA OTR41303 10000 5000 60+/-20 140+/-20 20+/-5 CMDSA OTR41305 20000 10000 60+/-20 140+/-20 20+/-5 CMDSA OTR41310 40000 20000 60+/-20 140+/-20 20+/-5 CMDSA OTR4131 80000 40000 60+/-20 140+/-20 20+/-5 CMDSA OTR4132 220000 110000 60+/-20 140+/-20 20+/-5 CMDSA OTR4135 500000 250000 60+/-20 140+/-20 20+/-5 CMDSP OTR415 5000 60+/-20 70+/-15 - 15+/-5

In the present invention, the composition may have a concentration of biocompatible polymer from 0.1 to 100 μg/ml by weight relative to the volume of the composition. For example, the composition may contain a concentration of biocompatible polymer from 1 to 10 μg/ml by weight relative to the total volume of the composition.

In the present invention, the composition can be formulated and/or adapted in accordance with its administration. For example, for parenteral administration, the composition can be administered to deliver a dose of biocompatible polymer from 0.01 to 5 mg per kilogram of body weight, preferably from 0.1 to 1.5 mg per kilogram of body weight, at a frequency of one administration per week.

For example, for oral administration, the composition can be administered to deliver a dose of biocompatible polymer from 0.1 to 5 mg per kilogram of body weight, preferably from 0.01 to 1.5 mg/kg, at a frequency of administration daily or biweekly.

When administered sublingually, the dose may be daily or twice weekly and range from 0.5 to 100 mcg/kg.

For example, for intra-arterial administration, the biocompatible polymer may have a concentration of from 0.1 to 100 μg/ml by weight of the biocompatible polymer relative to the total volume of the composition, preferably from 1 to 20 ml.

Advantageously, when the composition and/or polymer is administered by the intra-arterial route, the administration may be first in the brain, for example, in the internal carotid artery.

- 5 046226

For example, for intracranial injection, the biocompatible polymer may have a concentration of from 0.1 to 100 μg/ml by weight of the biocompatible polymer relative to the total volume of the composition, preferably from 5 to 20 μl.

Advantageously, when the composition and/or polymer is administered by the intracranial route, administration can be carried out simultaneously or sequentially in different intracranial areas.

For example, for intraventricular or intrathecal injection, the injected volume may be from 5 μl to 2 ml, for example 500 μl, for example 2 ml. For example, for intraventricular or intrathecal injection, the injected volume may be isovolumetric, for example up to 2 ml. For example, the volume administered may be as described in Marks et al., 2008 [10], Raffi et al., 2014 [13] and/or Blaney et al., 2004 [3].

For oral administration, for example in the form of a pill or capsule, the dose of the biocompatible polymer may be from 0.0001 to 5 mg per kilogram of body weight.

For oral administration, for example in the form of a pill or capsule, dosage may be daily.

According to the invention, the molecular weight of the biocompatible polymer can be from 3000 to 2500000 daltons.

For example, the molecular weight of the biocompatible polymer may be from 3000 to 6000 daltons, from 6000 to 2500000 daltons, preferably from 20000 to 250000 daltons and, for example, from 75000 to 150000 daltons.

Advantageously, the molecular weight of the biocompatible polymers present in the composition can be selected in accordance with the route of administration of the composition and the frequency of administration. For example, for injection by the intravascular route, such as intra-arterial, the molecular weight of the biocompatible polymer may be from 3000 to 200,000 daltons depending on the level of damage to the blood-brain barrier, preferably from 3000 to 150,000 daltons.

Advantageously, the molecular weight of the biocompatible polymers present in the composition can be selected in accordance with the deterioration and/or condition of the blood-brain barrier.

For example, when the blood-brain barrier undergoes significant structural changes, such as a lesion causing high permeability of the blood-brain barrier, the molecular weight of the biocompatible polymer may be from 3,000 to 200,000 daltons, preferably from 70,000 to 150,000 daltons.

Advantageously, the molecular weight of the biocompatible polymer can be adapted following and/or in accordance with the gradual restoration of the blood-brain barrier. For example, when the blood-brain barrier exhibits significant structural changes, the molecular weight of the biocompatible polymer may be from 3,000 to 200,000 daltons, preferably from 70,000 to 150,000 daltons. Subsequently, the molecular weight used can be reduced, for example it can be from 3000 to 100,000 daltons, preferably from 10,000 to 70,000 daltons.

According to the invention, the composition may also contain a hydrogel.

As used herein, hydrogel refers to any suitable hydrogel known to one skilled in the art. This may be, for example, a hydrogel selected from the group consisting of hyaluronic acid or its derivative, biocompatible hydrogels used to fill the space of the brain after injury. This could be, for example, a hydrogel described in the document Vladimir A. Kornev et al.: Hydrogel-assisted neuroregeneration approaches towards brain injury therapy: A state-of-the-art review. Computational and Structural Biotechnology Journal 16 j.csbj.2018.10.011 [24] and/or described in Gopalakrishnan A, Shankarappa SA, Rajanikant GK. Hydrogel Scaffolds: Towards Restitution of Ischemic Stroke-Injured Brain 2019 Feb; 10(1):1-18 [25].

As used herein, the composition may contain a hydrogel at a concentration of 0.1 to 5%, preferably 0.5 to 2.5%, by weight of the hydrogel.

According to the invention, the composition may contain hyaluronic acid and/or at least one hydrogel, and/or a mixture thereof.

As used herein, hyaluronic acid means any hyaluronic acid known to one skilled in the art, for example, a non-sulfated linear glycosaminoglycan consisting of repeating units of D-glucuronic acid and N-acetyl-D-glucosamine. This may be, for example, hyaluronic acid (HA) in its acid form or in the form of a salt (hyaluronate) of cross-linked hyaluronic acid. HA is a non-sulfated linear glycosaminoglycan consisting of repeating units of D-glucuronic acid and N-acetyl-E-glucosamine (Tammi R., Agren UM., Tuhkanen AL, Tammi M. Hyaluronan metabolism in skin. Progress in Histochemistry & Cytochemistry. 29( 2):1-81, 1994 [26]). This may be, for example, hyaluronic acid having average molecular weight fractions from 5000 to 3,000,000 daltons, preferably from 50,000 to 2,000,000 daltons. In this case, hyaluronic acid can be obtained by any method known to a person skilled in the art. These may be, for example, the methods described in the journal Hyaluronan fragments: an information-rich system (R. Stern et al., European Journal of Cell Biology 58 (2006) 699715[27]). It may also be natural or modified commercially available hyaluronic acid, regardless of their name and/or molecular weight, e.g. commercial hyaluronic acid

- 6 046226 acid selected from Hyactive CPN; Crystalhyal; NutraHA; OLIGO-HA; D-Factor; Hyaluderm; juvelift; Restylane; Revitacare, if this list is not exhaustive. It may also be hyaluronic acid sold by Contipro (https://www.contipro.com/portfolio/manufacturer-of-anti-ageing-cosmeticraw-materials/HyActive) and/or Givaudan (https://www.givaudan.com /fragrances/activebeauty/products/cristalhyal%C2%AE-range).

As used herein, the composition may contain hyaluronic acid at a concentration of 0.1 to 5% by weight, based on the total weight of the composition. For example, the composition may contain hyaluronic acid at a concentration of from 0.5% to 2.5% by weight, based on the total weight of the composition.

Herein, the hydrogel composition may be formulated for administration by direct intracranial route, for local intracranial injection, particularly by intra-arterial route, the composition may have a hyaluronic acid concentration of 1 to 10 mg/ml by weight relative to the total volume of the composition.

As used herein, the term pharmaceutical composition means any form of pharmaceutical composition known to one skilled in the art. As used herein, the pharmaceutical composition may be, for example, an injection solution. This may be, for example, an injection solution, for example, for local or systemic injection, for example, in physiological serum, in a glucose solution for injection, in the presence of excipients, for example, dextrans, for example, in concentrations known to a person skilled in the art, for example, from one microgram to more than milligrams per ml. The pharmaceutical composition may be, for example, an oral drug selected from the group consisting of a liquid formulation, an effervescent oral dosage form, an oral powder, a multiparticulate system, or an orally dispersible dosage form.

For example, when the pharmaceutical composition is for oral administration, it may be in the form of a liquid preparation selected from the group consisting of solution, syrup, suspension or emulsion. When the pharmaceutical composition is in the form of an effervescent oral dosage form, it may be in a form selected from the group consisting of tablets, granules, powders. When the pharmaceutical composition is in the form of an oral powder or multiparticulate system, it may be in a form selected from the group consisting of beads, granules, minitablets and microbeads. When the pharmaceutical composition is in an orodispersible dosage form, it may be in a form selected from the group consisting of orodispersible tablets, lyophilized capsules, thin films, chewable tablet, tablet, capsule, or medicinal chewing gum.

According to the present invention, the pharmaceutical composition may be a pharmaceutical composition for oral administration, for example buccal and/or sublingual, for example selected from the group consisting of buccal or sublingual tablets, lozenges, drops, spray solution.

According to the present invention, the pharmaceutical composition may be a pharmaceutical composition for topical or transdermal administration, for example, selected from the group consisting of ointments, creams, gels, lotions, patches and foams.

According to the present invention, the pharmaceutical composition may be a pharmaceutical composition for nasal administration, for example, selected from the group consisting of nasal drops, nasal spray, nasal powder.

According to the present invention, the pharmaceutical composition may be a pharmaceutical composition for parenteral administration, for example, subcutaneous, intramuscular, intravenous, intra-arterial, intracranial, intrathecal. Preferably, the pharmaceutical composition may be a pharmaceutical composition for intra-arterial and/or intracranial administration. The composition of the present invention may also contain at least one other active ingredient, in particular another therapeutically active ingredient, for example for simultaneous, separate or staggered administration over time depending on the herbal composition used. This other ingredient may be, for example, an active ingredient used, for example, in the treatment of suitable diseases that may develop in a patient having alteration and/or damage to the blood-brain barrier. They may also be pharmaceutical products known to one skilled in the art, for example, antibiotics, anti-inflammatory agents, anticoagulants, neuroprotectors, acetylcholinesterase inhibitors, antidepressants, antivirals.

According to the invention, the composition can be administered, for example, daily, twice daily and weekly. This may be, for example, administration once a day, twice a day or more.

According to the invention, the composition can be administered, for example, over a period of 1 day to 3 months, for example within 2 months. For example, the composition can be administered over a period of 3 months with daily administration.

The subject of the present invention is also the use of a pharmaceutical composition containing a biocompatible polymer of the formula AaXxYy (I) or AaXxYyZz (II) for the production of drugs

- 7 046226 venous agent for the protection and/or reparation/restoration of the blood-brain barrier.

The biocompatible polymer is defined above.

In this embodiment, the term drug should be understood to mean a pharmaceutical composition as defined above.

Advantageously, the inventors have demonstrated that the biocompatible polymer unexpectedly allows both to accelerate the repair/restoration of the blood-brain barrier when the latter is altered, both at the structural and/or functional level. In addition, the inventors have demonstrated that the biocompatible polymer advantageously and unexpectedly provides functional restoration of the blood-brain barrier, in particular restoration of its permeability, regardless of the cause and/or origin of its modification and/or alteration.

Brief description of graphic materials

In fig. Figure 1 shows the change in the permeability of the blood-brain barrier (BBB) after an ischemic acute vascular insult depending on time; the ordinate corresponds to permeability, and the abscissa corresponds to time in hours.

In fig. 2 shows an example of the structure of a biocompatible polymer, for example, the structure of the compound OTR4132.

In fig. Figure 3 is a histogram showing changes in BBB permeability in regions of interest studied using MRI. In this figure, the abscissa corresponds to the time in hours or days after cerebral ischemia: 1 hour, 3 hours, 24 hours, 48 hours and 7 days after ischemia. The obtained values correspond to the mean +/- standard deviation. In this figure, the ordinate corresponds to the volume of change in the integrity of the BBB in mm ³ . The values obtained for rats administered the composition containing the biocompatible polymer (OTR4132) are represented by white bars; the values obtained for rats administered the control composition are represented by black bars.

In fig. Figure 4 is a histogram showing BBB permeability after cerebral ischemia by Evans blue staining. In this figure, the ordinate represents the amount of Evans blue in μg/g of brain tissue according to the region of central nervous system ischemia, ipsilateral or contralateral. The values obtained for rats administered the composition containing the biocompatible polymer (OTR4132) are represented by gray bars, the values obtained for rats administered the control composition are represented by black bars.

Other advantages may also be apparent to one skilled in the art upon reading the following examples, illustrated by the accompanying figures, provided by way of illustration.

Examples

Example 1. Use of a biocompatible polymer for the treatment of blood-brain barrier disruption and functional restoration of the blood-brain barrier.

A. Preparation of biocompatible polymers.

The synthesis of biocompatible polymers, RGTA, is widely described in the prior art, for example, in US patent No. 7396923, entitled Process for the sulfonation of compounds containing free hydroxyl (OH) groups or primary or secondary amines, as well as in the bibliographic reference Yasunori I. et. al., Biomaterials 2011, 32: 769e776) and Petit E. et al., Biomacromolecules. 2004 Mar-Apr; 5(2):44552 [28].

Several RGTAs are known and described, including OTR4120, for which there are numerous publications on preclinical and clinical studies (RGTA®-based matrix therapy - A new branch of regenerative medicine in locomotion. Barritault D, Desgranges P, Meddahi-Pelle A, Denoix JM, Saffar JL. Joint Bone Spine. 2017 May;84(3):283-292. DOI: 10.1016/j.jbspia2O16.06.012 [29], RGTA® or ReGeneraTing Agents mimic heparan sulfate in regenerative medicine: from concept to curing patients Barritault D, Gilbert-Sirieix M, Rice KL, Sineriz F, Papy-Garcia D, Baudouin C, Desgranges P, Zakine G, Saffar JL, van Neck J. Glycoconj J. 2017 Jun;34(3):325-338 DOI: 10.1007/s10719-016-9744-5 [2] Compound OTR4131 is a compound containing a Z radical, which is a fatty acid, namely acetic acid, as described in Frescaline G. et al., Tissue Eng Part A 2013 Jul; 19 (13-14): 1641-53. DOI: 10.1089/ten.TEA.2012.0377 [30]), Randomized controlled trial demonstrates the benefit of RGTA® based matrix therapy to treat tendinopathies in racing horses. Jacquet-Guibon S, Dupays AG, Caudry V, Crevier-Denoix N, Leroy S, Snerizi F, Chiappini F, Barritault D, Denoix JM. PLoS One. 2018 Mar 9; 13(3):e0191796. DOI: 10.1371/journal.pone.0191796 [31]. Other compounds are also described in patent documents US06689741, US2014301972A1, in which Z represents an amino acid such as phenylalanine (Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Holmes BB, DeVos SL, Kfoury N, Li M, Jacks R, Yanamandra K, Ouidja MO, Brodsky FM, Marasa J, Bagchi DP, Kotzbauer PT, Miller TM, Papy-Garcia D, Diamond Ml. Proc Natl Acad Sci USA 2013 Aug 13;110(33):E3138-47.DOI:10.1073/ pnas.1301440110 [32]) or other hydrophobic compound (Structure-activity studies of heparan mimetic polyanions for anti-prion therapies. Ouidja MO, Petit E, Kerros ME, Ikeda Y, Morin C, Carpentier G, Barritault D, Brugere-Picoux J, Deslys JP, Adjou K, Papy-Garcia D. Biochem Biophys Res

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Commun. 2007 Nov 9; 363 (1): 95-100 [33]).

B. Functional restoration of the blood-brain barrier using a biocompatible polymer.

The present example evaluates the effect of a biocompatible polymer according to the invention, RGTA, on the permeability of the BBB after a change, for example, after an acute cerebrovascular accident (ACVA).

In this example, a rat model of stroke was used. This was cerebral ischemia lasting 1 hour, achieved by intraluminal cerebral artery occlusion followed by reperfusion. The rats used were male Sprague-Dawley rats with an average weight of 300-350 g. The number of rats used was four to six rats per group at a time. In this model, it is well known that BBB permeability gradually increases, reaching a peak 24–48 h after induction of cerebral ischemia (Garrigue et al. 2016 [6]; Sharif et al., 2018 [16]). In fig. Figure 1 shows the change in permeability as a function of time in the model used as described in Abdullahi et al., 2018.

BBB permeability was assessed using MRI after injection of the Dotarem® contrast agent at different times: 1 hour, 3 hours, 24 hours, 48 hours and 7 days after cerebral ischemia. This contrast agent does not cross the BBB under physiological conditions. The contrast agent was administered intravenously through the femoral vein. The amount of contrast agent administered by injection was 200 µmol/kg (Dotarem (registered trademark), Guerbet S.A).

Rats, namely four to five animals per group and at a time, were treated with a biocompatible polymer, namely RGTA OTR4132 with a molecular weight of 100,000 to 150,000 Da. In fig. Figure 2 shows the structure of this polymer. The biocompatible polymer OTR4132 was administered 1 hour after cerebral ischemia, the volume of the administered composition containing a concentration of 0.5 mg/kg OTR4132 was 300 μl per tail vein.

The rats, namely four to five animals per group and each time, were injected with a control solution, that is, physiological serum (0.9% NaCl saline solution). The control solution was administered in the same manner as the composition containing compound OTR4132, namely, 1 hour after cerebral ischemia, the volume of the administered composition was 250 μl, which was administered through the femoral vein.

Monitoring the permeability and diffusion of the contrast agent was performed by evaluating the images obtained using MRI. The regions of the central nervous system observed were located in the ischemic cerebral hemisphere as well as in the healthy contralateral hemisphere. Determination of contrast agent diffusion in acquired images was performed using MRI-based analysis using appropriate software (Image J (trade mark) (Wayne Rasband, NIMH, MD, USA)). Contrast agent distribution and/or blood-brain barrier permeability is shown in FIG. 3.

As shown in the diagram of Fig. 3 rats injected with contrast agent and control solution show increased blood-brain barrier permeability at 24 hours, 48 hours and 7 days after stroke (black bars); these results were consistent with those found in current studies (Garrigue et al. 2016 [6]). This graph also clearly and unexpectedly demonstrates that treatment of rats with the biocompatible polymer OTR4132 significantly reduces BBB permeability at 24 and 48 h post-ischemia in the RGTA-treated rat group compared with the ischemic control group. In particular, the results demonstrated a statistically significant difference between rats receiving the control solution compared to rats receiving the composition containing the biocompatible polymer of the invention (ANOVA followed by post hoc test with Tukey's HSD test, p<0.05).

The results obtained and illustrated in Fig. 3 clearly demonstrate that the use of biocompatible polymers according to the invention allows maintaining the integrity of the BBB after stroke. In particular, these results clearly demonstrate that the use of a biocompatible polymer in accordance with the invention allows both to protect the BBB and promote its restoration, and, in the case where the physiological properties of the BBB are changed/modified, to restore the physiological properties and/or reduce their changes.

In addition to the results obtained by MRI, BBB permeability was measured by Evans blue staining after induction of cerebral ischemia according to the method described in Hone et al., 2018 [7]. Male Sprague-Dawley rats with an average weight of 300-350 g were used as rats; the experiment was carried out on 11 rats, including five rats that, 72 hours after the induction of cerebral ischemia, were intravenously injected with a concentration of 2% Evans blue, which does not cross the BBB under physiological conditions, while the injected volume was 4 ml/kg, that is, from 1.2 to 1.4 ml for a rat weighing from 300 to 350 g, respectively.

Six rats were treated with a biocompatible polymer, namely RGTA OTR4132 with a molecular weight of 100,000 to 150,000 Da, administered 1 hour after induction of cerebral ischemia, with a volume of the composition comprising a dose of 2.22 μg of OTR4132, which was injected into the internal carotid artery,

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Five rats were administered a control solution, namely saline serum (0.9% saline NaCl), administered in the same manner as the composition containing the compound OTR4132, namely 1 hour after the induction of cerebral ischemia, the volume of the composition that was administered at internal carotid artery, was 50 µl.

Thirty minutes after the administration of Evans blue, the animal was given an intracardiac infusion of saline, the brain was removed, and the hemispheres were separated. The samples were then ground in phosphate-buffered saline and then placed at 4°C in the presence of 60% trichloroacetic acid. The samples were then centrifuged (1000 g for 30 min) and the supernatant was collected for spectrophotometer reading at 610 nm. In parallel, a range of increasing concentrations of Evans blue was prepared.

Evans blue-stained tissue present in the collected supernatant was then quantified by spectrophotometry, measuring at 610 nm.

In fig. Figure 4 presents the results obtained for individual subjects. The results obtained in the control group demonstrate a significant change in BBB permeability in the ipsilateral hemisphere compared to the contralateral hemisphere (2-way ANOVA (p group = 0.1582; p hemisphere = 0.0933; p group * hemisphere = 0.0175) followed by post hoc test with Tukey's HSD test with p = 0.0374). Surprisingly, no difference was observed between the ipsilateral and contralateral hemispheres in the group of animals treated with the biocompatible polymer OTR4132 (2-way ANOVA (p group = 0.1582; p hemisphere = 0.0933; p group * hemisphere = 0.0175) with post hoc test with Tukey's HSD test with p = 0.9965). In addition, the analyzes also demonstrate a statistically significant reduction in BBB change in the ipsilateral hemisphere in animals treated with the biocompatible polymer OTR4132 compared to control animals (2-way ANOVA (p group = 0.1582; p hemisphere = 0.0933; p group * hemisphere = 0.0175) followed by post hoc test with Tukey's HSD test with p = 0.0439).

This example clearly demonstrates that examples of the composition according to the invention containing a polymer of the formula AaXxYy or AaXxYyZz advantageously protect the BBB and/or restore the physiological properties of the BBB. In particular, this example clearly demonstrates that examples of the composition according to the invention containing a polymer of the formula AaXxYy or AaXxYyZz allow maintaining the integrity of the BBB after stroke. In particular, these results clearly demonstrate that the use of a biocompatible polymer in accordance with the invention allows both to protect the BBB and promote its restoration, and, in the case where the physiological properties of the BBB are changed/modified, to restore the physiological properties and/or reduce their changes.

Example 2. Use of a biocompatible polymer for the treatment of an altered blood-brain barrier and functional restoration of the blood-brain barrier.

A man, a 75 year old man (75 kg) suffering from neurological disorders, in particular cognitive disorders associated with several cardiovascular diseases, as noted by neurologists, which led to changes in the blood-brain barrier, was treated with a biocompatible polymer, namely the compound OTR4120 in as a daily dose of 30 ml of a 100 mcg/ml aqueous solution of OTR4120 for 45 days. The dose administered was 3 mg/day per 75 kg or 40 mcg/kg/day. After administration, neurologists, as well as the treating or referring physician and the patient's family members, observed improvements in cognitive function.

Another person, an 85-year-old woman, with severe memory problems, in particular difficulty reading and recognizing people, especially close relatives (family members), inability to write, etc. A person (weighing approximately 60 kg) diagnosed with Alzheimer's disease with a social disability quotient, indicating an alteration of the blood-brain barrier, was treated with a sublingual dose of OTR4120 of 300 to 100 mcg/ml or 0.5 mcg twice weekly (0. 5 mcg/kg twice a week). After treatment for 6 months, the patient had improved cognitive functions, social relationships, for example, with others, especially relatives and medical staff, he was able to make calls, go out, see friends, play Scrabble, etc. These improvements were, in part, associated with improved and restored blood-brain barrier function.

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Links.

1. Abdullahi W, Tripathi D _; Ronaldson P.T. Blood-Brain Barrier Dysfunction in Ischemic Stroke: Targeting Tight Junctions and Transporters for Vascular Protection. Am J Physiol Cell Physiol. 2018 Jun 27. doi: 10.1152/ajpcell. 00095 2018 [Epub ahead of print] PubMed PM ID: 29949404

Barritault D, Gilbert-Sirieix M, Rice KL, Sineriz F, Papy-Garcia D, Baudouin C, Desgranges P, Zakine G, Saffar JL, van Neck J RGTA(®) or ReGeneraTing Agents mimic heparan sulfate in regenerative medicine: from concept to treating patients. Glycoconj J. 2017 Jun:34(3):325-338. doi: 10.1007/sl 0719-016-9744-5. Epub 2016 Dec 7 Review. PubMed PM ID: 27924424; PubMed Central PMCID: PMC5487810

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Hone EA, Hu H, Sprawls SA, Farooqi I, Grasmick K, Lockman PR, et al Biphasic Blood-Brain Barrier Openings after Strake. Neurol Disord Stroke Int. 2018; 1(2): 1011.

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Khelif, Y„ Toutain, J., Quittet, M S., Chantepie, S., Laffray, X., Valable, S., & Barritault, D. (2018). A heparan sulfate-based matrix therapy reduces brain damage and enhances functional recovery following stroke. Theranostics, 8(21), 5814.

Marks Jr, W. J., Ostrem, J. L., Verhagen, L., Starr, P. A., Larson, P. S., Bakay, R. A & Bartus, R. T. (2009). Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus serotype 2neurturin) to patients with idiopathic Parkinson's disease: an open-label, phase I trial. The Lancet Neurology.. 7(5), 400-408.

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14. Rajendran P, Rengarajan T, Thangavel J, Nishigaki Y, Sakthisekaran D, Sethi G, Nishigaki I. The vascular endothelium and human diseases. Int J Biol Sci 2013 Nov 9:9(10):1057-69. doi: 10.7150/ijbs.7502. eCollection 2013. Review. PubMed PMID: 24250251; PubMed Central PMCID: PMC3831119.

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1. 2018 I https://doi.org/10.3389/fonc.20. Review

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   24. Vladimir A Kornev et al : Hydrogel-assisted neuro regen erat ion approaches towards brain injury therapy: A state-of-the-art review. Computational and Structural Biotechnology Journal 16 j.csbj.2018.10.011 25. Gopalakrishnan A, Shankarappa SA, Rajanikant GK Hydrogel Scaffolds: Towards Restitution of Ischemic Stroke-Injured Brain 2019 Feb;10(1 ):1-18.

   26. Tammi R.. Agren UM.. TuhkanenAL., Tammi M. Hyaluronan metabolism in skin. Progress in Histochemistry & Cytochemistry. 29(2):1-81, 1994

   27. R. Stern et al., European Journal of Cell Biology 58 (2006) 699-715.

   28. Yasunori I et al , Biomaterials 2011, 32 :769e776) et Petit E. et al,. Biomacromolecules. 2004 Mar-Apr; 5(2):445-52

   29. RGTA®-based matrix therapy - A new branch of regenerative medicine in locomotion. Barritault D, Desgranges P, Meddahi-Pelle A, Denoix JM, Saffar JL Joint Bone Spine 2017 May;84(3):283-292. doi: 10.1016/j.jbspin.2016.06.012

   30. Frescaline G. et al., Tissue Eng Part A. 2013 Jul; 19(13-14):1641-53. doi: 10.1089/ten TEA 2012 0377

   31. Randomized controlled trial demonstrates the benefit of RGTA® based matrix therapy to treat tendinopathies in racing horses Jacquet-Gui bon S, Dupays AG, Coudry V, Crevier-Denoix N, Leroy S, Sifieriz F_; Chiappini F, Barritault D, Denoix JM. PLoS One 2018 Mar 9;13(3):e0191796. doi: 10.1371/journal.pone.0191796

   32. Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Holmes BB, DeVos SL, Kfoury N, Li M, Jacks R, Yanamandra K. Ouidja MO, Brodsky FM, Marasa J, Bagchi DP, Kotzbauer PT, Miller TM, Papy-Garcia D, Diamond Ml. Proc Natl Acad Sci USA 2013 Aug 13;110(33):E3138-47. doi: 10.1073/pnas. 1301440110 33. Structure-activity studies of heparan mimetic polyanions for anti-prion therapies. Ouidja MO, Petit E, Kerros ME, Ikeda Y, Morin C, Carpentier G, Barritault D, Brugere-Picoux J, Deslys JP, Adjou K, Papy-Garcia D. Biocshem Biophys Res Commun. 2007 Nov 9; 363(1 ):95-100

   ФОРМУЛА ИЗОБРЕТЕНИЯ

   1. Применение фармацевтической композиции в качестве лекарственного средства для защиты и/или репарации/восстановления гематоэнцефалического барьера, причем указанная композиция содержит:

   биосовместимый полимер следующей общей формулы (I):

   AaXxYy (I) где

   A представляет собой мономер, представляющий собой глюкозу,

   X представляет собой группу R₁COOR2 или -R₉(C=O)R₁₀,

   Y представляет собой O- или N-сульфонатную группу, которая соответствует одной из следующих формул: -R3OSO3R4, -R5NSO3R6, -R7SO3R8, где

   R1, R₃, R5 и R₉ независимо представляют собой алифатическую углеводородную цепь, необязательно разветвленную и/или ненасыщенную, которая необязательно содержит одно или более ароматических колец, за исключением бензиламина и бензиламинсульфоната, R2, R4, R₆ и R8 независимо представляют собой атом водорода или катион M+, и R7 и R₁₀ независимо представляют собой связь, алифатическую

   -