Active ingredient and use thereof for rebuilding intestinal permeability and / or preventing or combating multi-factor diseases

Abstract

The present invention relates to an active ingredient consisting of the following molecules: acetic acid, butyric acid, lactic acid and propionic acid, and / or salts and / or esters and / or anhydrides of one or more of these molecules, and optionally at least one pharmaceutically acceptable excipient, to a composition comprising said active ingredient, and to a pharmaceutical composition comprising said active ingredient. And to the use thereof, in particular as a medicament.

Description

Technical Field

[0001] The present invention relates to the prevention and / or treatment of multifactorial diseases. In particular, the present invention relates to an active ingredient composed of a plurality of selected specific molecules, a composition comprising such an active ingredient, and its use in reducing intestinal permeability and / or reconstructing normal intestinal permeability, and / or preventing or combating various multifactorial diseases involving intestinal permeability. Background Art

[0002] Most diseases, especially chronic diseases, are multifactorial. They always involve a genetic component related to the "environment" as well as immune and toxic components, namely bacteria, viruses, chemical agents, etc.

[0003] Among the known multifactorial chronic diseases, mention may be made in particular of degenerative diseases such as Parkinson's disease, Alzheimer's disease, post-stroke inflammation, amyotrophic lateral sclerosis, Huntington's disease, etc.

[0004] Degenerative diseases are diseases that cause the gradual deterioration of one or more organs. They are usually of genetic origin and can be triggered by high and long-term exposure to biological and / or toxic products. Specifically, any bacterial component and / or other toxin that crosses the mucosa causes the activation of the immune system, which always triggers the stimulation (degeneration) of autoreactive clones that attack the target tissue in patients with chronic conditions. Therefore, degenerative diseases are closely related to excessive intestinal permeability, like many infectious diseases, especially viral diseases.

[0005] In a healthy human intestine, small particles (radius <4 Å) can migrate through the pores in claudins, which are the most important components of tight junctions, but particles up to 10 Å - 15 Å (3.5 kDa) can pass through the paracellular absorption pathway. The intestine usually has a certain degree of permeability, which allows nutrients to cross the intestine while maintaining a barrier function to prevent potential harmful substances from leaving the intestine and further migrating into the body.

[0006] The intestinal microbiota constantly interacts with the intestinal immune system it comes into contact with. The interaction between the large number of antigens constituted by the intestinal microbiota and the intestinal immune system is extremely complex, but in a balanced organism, this maintains the "immune background noise", that is, the basic balance between the bacteria of the microbiota and the immune system that regulates them.

[0007] An unbalanced microbiota (referred to as dysbiosis) leads to an exacerbated response of the gut immune system, increasing inflammation and causing changes in tight junctions. In response to fragments of bacterial walls (referred to as endotoxins) that are disrupted by the gut entering the systemic circulation, the body releases large amounts of inflammatory cytokines, and if there is a large influx of endotoxins, this can trigger the onset of septic shock, respiratory failure, renal ischemia, or cytokine storm. Blood endotoxin measurement is also a reliable marker of increased gut permeability.

[0008] There are many reasons for increased gut permeability. Any disruption of the gut habitat, any dysbiosis, will cause an immune system response, releasing inflammatory cytokines, which leads to an inflammatory state of the mucosa of the small intestine and colon and epithelial changes. The reasons for this dysbiosis may especially be:

[0009] - Stress, which greatly reduces the volume and quality of all digestive secretions,

[0010] - Emotional and psychological shocks,

[0011] - Severe overwork or physical shocks

[0012] - Antibiotic treatment,

[0013] - Viral, bacterial, or parasitic infections,

[0014] - Radiation

[0015] - Toxic chemical agents: air pollution or water or food contamination; pesticides and heavy metals; drugs (statins, anti-inflammatory agents, immunosuppressants, etc.).

[0016] Increased gut permeability, in addition to playing a role in triggering degenerative diseases in genetically susceptible patients, also leads to inflammatory, infectious, and autoimmune diseases as well as allergies and severe food intolerances.

[0017] Currently, the proposed solutions for preventing or combating dysbiosis basically consist of administering probiotics and / or prebiotics, but their efficacy is highly variable and depends on the patient's underlying gut microbiota.

[0018] In addition, especially regarding degenerative diseases, these diseases are usually very difficult for patients. Some symptoms can be alleviated, but such diseases are never completely cured, and there is currently no satisfactory treatment. Many chemical agents have therapeutic properties, but their toxicity, their expiration date, or their rapid elimination makes them unsuitable for treating degenerative diseases.

[0019] Specifically, although these diseases are multifactorial, current treatments target only one of the causative factors of these diseases and do not seek to act on excessive intestinal permeability. For example, amyotrophic lateral sclerosis is associated with many factors, particularly oxidative stress response, mitochondrial dysfunction, neuroinflammation, excitotoxicity, oligodendrocyte dysfunction and degeneration, altered proteostasis, altered DNA repair system, changes in nuclear and cytoplasmic RNA and RNA related to transport proteins, axonal transport defects, and vesicle transport defects. Currently, the treatment recommended for amyotrophic lateral sclerosis is which only acts on the inhibition of glutamate release to counteract excitotoxicity and does not consider the effect on intestinal permeability. The same observation can be made for other degenerative diseases.

[0020] Therefore, there is a need for an effective and non-toxic solution that is easy to administer and can act on various factors to prevent and / or counteract excessive intestinal permeability and the effects of related multifactorial diseases, particularly degenerative, autoimmune, inflammatory, or infectious diseases. Summary of the Invention

[0021] To meet this need, the present invention proposes an active ingredient P1 that simultaneously - reduces the inflammatory process

[0022] - reduces intestinal permeability

[0023] - is administered in a single dose, preferably as a single injection

[0024] - and preferably rebalances the neuro-metabolism that causes neuronal and motor neuron degeneration.

[0025] The active ingredient P1 according to the present invention may also be referred to as composition P1 or even reagent P1. In fact, the present invention is based on a combination of 4 specific acids.

[0026] To this end, the present invention relates to an active ingredient P1 consisting of the following: the following molecules:

[0027] - acetic acid,

[0028] - butyric acid,

[0029] - lactic acid,

[0030] - propionic acid,

[0031] and / or salts and / or esters and / or acid anhydrides of one or more of these molecules, and

[0032] - optionally at least one pharmaceutically acceptable excipient.

[0033] Advantageously, the molecules constituting the active ingredient P1 act together to reconstitute the intestinal permeability function that has been disrupted by the imbalanced microbiota.

[0034] To enhance the efficacy and bioavailability of these molecules, they are preferably conjugated to specific polymers.

[0035] The present invention also relates to a composition C1 comprising the active ingredient P1 according to the present invention.

[0036] The present invention also relates to a method for preparing the composition C1 according to the present invention.

[0037] The active ingredient P1 and / or the composition C1 according to the present invention can be used alone as a medicine or in combination with at least one other active ingredient and / or another composition.

[0038] The present invention also relates to an active ingredient P2 consisting of the following: the following molecules:

[0039] - Taurine,

[0040] - Spermine

[0041] - Biotin,

[0042] - Coenzyme Q10,

[0043] - Glutathione,

[0044] - α-Tocopherol,

[0045] and / or salts and / or esters and / or acid anhydrides of one or more of these molecules, and

[0046] - Optionally at least one pharmaceutically acceptable excipient.

[0047] The active ingredient P2 can advantageously act in a combined manner:

[0048] - As a neuroprotective agent;

[0049] - As an anti-inflammatory agent;

[0050] - As a cytoprotective agent;

[0051] - As a protector of cell membranes;

[0052] - As an antioxidant;

[0053] - Stabilization of cell membranes; and

[0054] - As a scavenger of free radicals and metals.

[0055] To enhance the efficacy and bioavailability of these molecules, they are preferably conjugated to specific polymers.

[0056] The present invention also relates to a composition C2 comprising the active ingredient P2 according to the present invention.

[0057] The present invention also relates to a method for preparing the composition C2 according to the present invention.

[0058] The active ingredient P2 and / or the composition C2 according to the present invention can be used alone as a medicament or in combination with at least one other active ingredient and / or another composition.

[0059] Preferably, the active ingredient P1 can be combined with the active ingredient P2 for use in the composition C3.

[0060] Advantageously, the composition C3 can be administered in a single dose, preferably as a single injection.

[0061] Other features and advantages will become apparent from the specific embodiments, examples and the following drawings of the present invention. Description of the Drawings

[0062] Figure 1 Figure 1 Shows a diagrammatic representation of micelle formation according to an embodiment of the present invention: 10 = micelle; 12 = polymer (such as polylysine); 14 = covalently conjugated molecule (such as in particular a fatty acid); 16 = highly hydrophobic molecule that cannot be conjugated to polylysine (such as coenzyme Q10).

[0063] Figure 2 Figure 2 Is a graphical representation of a comparative study of the cytotoxicity of the molecules present in the active ingredient P1 according to the present invention. Detailed Description

[0064] Definition :

[0065] For the purposes of the present invention, the term "animal" means any animal other than a human being.

[0066] For the purposes of the present invention, the term "amphiphilic conjugate" means a conjugate formed from a hydrophobic molecule X and a hydrophilic polymer Y, and thus the conjugate has amphiphilic characteristics.

[0067] For the purposes of the present invention, "consisting of" or "made of" means that the composition or active ingredient consists only of the elements listed thereafter.

[0068] ​​​​For the purposes of the present invention, the term "molecule X conjugated to polymer Y" means a molecule X covalently bonded to polymer Y, the bond preferably being an amide, urea or urethane bond, depending on the chemical nature of molecule X and polymer Y. Preferably, the covalent bond is formed directly between molecule X and polymer Y without the mediation of another molecule such as a binder.

[0069] For the purposes of the present invention, a "pharmaceutically acceptable excipient" is a component that does not confer therapeutic or prophylactic properties but can play a significant role in absorption, stability, its formulation, its taste or its appearance. Pharmaceutically acceptable excipients can include gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like, sweeteners, preservatives, flavorings, colorants, dispersants, wetting agents, suspending agents or diluents, buffers.

[0070] For the purposes of the present invention, a "single dose" or "single injection" means injecting the active ingredient or composition according to the present invention in a single administration. Preferably, a single administration of the active ingredient or composition according to the present invention is carried out once a day. Preferably, the time between two administrations of the active ingredient or composition according to the present invention is greater than or equal to 24 hours.

[0071] Active ingredient P1

[0072] Thus, the present invention relates to an active ingredient P1 consisting of: the following molecules:

[0073] - acetic acid,

[0074] - butyric acid,

[0075] - lactic acid,

[0076] - propionic acid,

[0077] and / or salts and / or esters and / or acid anhydrides of one or more of these molecules, and

[0078] - optionally at least one pharmaceutically acceptable excipient. Surprisingly, the inventors have found that a specific combination of the molecules constituting active ingredient P1, namely several specifically selected short-chain fatty acids, helps to prevent and / or counteract the effects of intestinal hyperpermeability and related multifactorial diseases.

[0079] For all the molecules present in active ingredient P1, when they are mentioned in the present application, they can be the molecule itself (e.g., butyric acid) and / or salts of these molecules (e.g., butyrate) and / or esters and / or acid anhydrides (e.g., butyrate).

[0080] According to a variant, active ingredient P1 according to the present invention consists only of the following molecules:

[0081] - Acetic acid,

[0082] - Butyric acid,

[0083] - Lactic acid,

[0084] - Propionic acid,

[0085] and / or salts and / or esters and / or anhydrides of one or more of these molecules.

[0086] According to another variant, the active ingredient P1 according to the invention consists only of one or more pharmaceutically acceptable excipients and the following molecules:

[0087] - Acetic acid,

[0088] - Butyric acid,

[0089] - Lactic acid,

[0090] - Propionic acid,

[0091] and / or salts and / or esters and / or anhydrides of one or more of these molecules.

[0092] Preferably, the amount of butyric acid in the active ingredient P1 is greater than the amount of each of the other molecules taken alone.

[0093] According to one embodiment, the amount of butyric acid in the active ingredient P1 is at least twice the amount of each of the other molecules taken alone.

[0094] Preferably, each active molecule in the active ingredient P1 is in the range of 0.5E - 05M to 10E - 05M.

[0095] According to one embodiment, in order to improve the solubility, efficacy and bioavailability of the molecules of the active ingredient P1, at least one molecule selected from the group consisting of acetic acid, butyric acid, lactic acid, propionic acid, salts of these acids, esters of these acids and anhydrides of these acids of the active ingredient P1 is covalently conjugated to at least one molecule of a polymer selected from polylysine, polyethylene glycol, polyornithine, polyarginine and polyhistidine.

[0096] In fact, molecules selected from acetic acid, butyric acid, lactic acid, propionic acid, salts of these acids, esters of these acids and anhydrides of these acids can all be specifically covalently conjugated to a polymer selected from polylysine, polyethylene glycol, polyornithine, polyarginine and polyhistidine via amide, urea or carbamate bonds.

[0097] According to a particularly suitable variant, all the molecules constituting the active ingredient P1 according to the invention are covalently conjugated to at least one molecule of a polymer selected from polylysine, polyethylene glycol, polyornithine, polyarginine and polyhistidine.

[0098] Preferably, one or more polymers conjugated to these molecules are selected from poly-L-lysine, polyethylene glycol, poly-L-ornithine, poly-L-arginine, and poly-L-histidine.

[0099] According to one embodiment, the polymer is polylysine, preferably poly-L-lysine. Preferably, the polylysine used is ε-poly-L-lysine having a molecular weight of 12,000 Da to 20,000 Da.

[0100] Thus, according to one variant, the active ingredient P1 consists of:

[0101] - one or more acetate-poly-L-lysine conjugates

[0102] - one or more butyrate-poly-L-lysine conjugates

[0103] - one or more lactate-poly-L-lysine conjugates

[0104] - one or more propionate-poly-L-lysine conjugates, and

[0105] - optionally at least one pharmaceutically acceptable excipient.

[0106] In this variant, poly-L-lysine can be replaced with another polylysine or with polyethylene glycol, poly-L-ornithine, poly-L-arginine, or poly-L-histidine.

[0107] According to another variant, the active ingredient P1 consists only of:

[0108] - one or more acetate-poly-L-lysine conjugates

[0109] - one or more butyrate-poly-L-lysine conjugates

[0110] - one or more lactate-poly-L-lysine conjugates

[0111] - one or more propionate-poly-L-lysine conjugates.

[0112] According to one embodiment, the active ingredient P1 consists of the following molecules:

[0113] - at least 0.72 mg / mL of acetate-poly-L-lysine;

[0114] - at least 1.5 mg / mL of butyrate-poly-L-lysine;

[0115] - at least 0.73 mg / mL of lactate-poly-L-lysine;

[0116] - Propionate - poly-L-lysine at least 0.72 mg / mL.

[0117] The active ingredient P1 optionally contains at least one pharmaceutically acceptable excipient, which is specifically selected to match the pH and osmolarity of an injectable solution in humans or animals. For example, they can be acids or bases for adjusting pH or NaCl for adjusting osmolarity.

[0118] The active ingredient P1 can be in liquid form or in solid form. The solid form is preferably obtained from the liquid form, preferably by lyophilization.

[0119] When the active ingredient P1 is in liquid form, it can contain at least one pharmaceutically acceptable excipient, preferably a buffer, especially water for injection and / or phosphate buffered saline (PBS).

[0120] When the active ingredient P1 is in solid form, it may not contain excipients, or it may contain at least one pharmaceutically acceptable excipient derived from the lyophilized liquid form, such as dehydrated PBS buffer.

[0121] The present invention also relates to a composition C1 comprising the active ingredient P1.

[0122] The composition C1 can be in liquid form or in solid form. When in liquid form, the composition C1 contains at least water and the active ingredient P1. The solid form is preferably obtained from the liquid form, preferably by lyophilization.

[0123] The composition C1 preferably contains at least one pharmaceutically acceptable excipient, which is specifically selected to meet the pH and osmolarity requirements of a solution for injection into humans or animals. For example, they can be acids or bases for adjusting pH or NaCl for adjusting osmolarity.

[0124] The composition C1 can be in liquid form or in solid form. The solid form is preferably obtained from the liquid form, preferably by lyophilization.

[0125] When the composition C1 is in liquid form, it can contain at least one pharmaceutically acceptable excipient, preferably a buffer, especially water for injection and / or phosphate buffered saline (PBS).

[0126] When the composition is in solid form, it can contain at least one pharmaceutically acceptable excipient derived from the lyophilized liquid form, preferably dehydrated PBS buffer.

[0127] The composition C1 according to the invention is intended for administration to humans or animals and is thus in a form suitable for such administration. When the composition is in liquid form, it is preferably suitable for subcutaneous or intravenous administration, in particular intravenous infusion, and the composition is packaged in a suitable container known to those skilled in the art for packaging such products. The composition C1 according to the invention can also be administered in liquid form via a pump such as an insulin pump.

[0128] When the composition is in solid form, it is preferably suitable for the following administration routes:

[0129] - Transdermal administration, and the composition is preferably formulated and packaged in the form of a patch, or

[0130] - Nasal administration in the form of a powder, or

[0131] - Sublingual administration in the form of a powder or tablet, or

[0132] - Mucosal administration, and the composition is preferably formulated and packaged in the form of a mucoadhesive tablet.

[0133] Advantageously, the composition C1 can be administered in a single dose, preferably by a single injection.

[0134] According to a variant, the composition C1 consists of the active ingredient P1.

[0135] Method for preparing active ingredient P1

[0136] The active ingredient P1 according to the invention can be prepared by any suitable method.

[0137] If the molecules constituting the active ingredient P1 are used as such in a solvent, they can all be mixed together in the said solvent.

[0138] If the molecules in the active ingredient P1 are conjugated to a polymer, the preparation method can include mixing the following compounds in an aqueous solution:

[0139] - One or more acetate - poly-L-lysine conjugates

[0140] - One or more butyrate - poly-L-lysine conjugates

[0141] - One or more lactate - poly-L-lysine conjugates

[0142] - One or more propionate - poly-L-lysine conjugates.

[0143] Advantageously, the amphiphilic nature of the components of the active ingredient makes the method for preparing the active ingredient P1 easy to implement.

[0144] Preferably, the active ingredient P1 can be freeze-dried into a solid form.

[0145] Active ingredient P2

[0146] The present invention also relates to an active ingredient P2 consisting of the following: the following molecules:

[0147] - Taurine,

[0148] - Spermine

[0149] - Biotin,

[0150] - Coenzyme Q10,

[0151] - Glutathione.

[0152] - α-Tocopherol,

[0153] and / or salts and / or esters and / or anhydrides of one or more of these molecules, and

[0154] - Optionally at least one pharmaceutically acceptable excipient.

[0155] For all the active molecules present in the active ingredient P2, when they are mentioned in the present application, they can be the molecules themselves and / or salts and / or esters and / or anhydrides of these molecules.

[0156] According to a variant, the active ingredient P2 according to the present invention consists only of the following molecules:

[0157] - Acetic acid,

[0158] - Butyric acid,

[0159] - Lactic acid,

[0160] - Propionic acid,

[0161] and / or salts and / or esters and / or anhydrides of one or more of these molecules.

[0162] According to another variant, the active ingredient P2 according to the present invention consists only of one or more pharmaceutically acceptable excipients and the following molecules:

[0163] - Acetic acid,

[0164] - Butyric acid,

[0165] - Lactic acid,

[0166] - Propionic acid,

[0167] and / or salts and / or esters and / or anhydrides of one or more of these molecules.

[0168] Preferably, the amount of butyric acid in the active ingredient P1 is greater than the amount of each of the other molecules taken alone.

[0169] According to one embodiment, the mass ratio of all the molecules constituting the active ingredient P2 to each other is 1. In other words, the amount of each molecule constituting P2 is the same.

[0170] The active ingredient P2 has the same concentration of each of the following molecules: taurine, spermine, biotin, coenzyme Q10, glutathione, and α-tocopherol and / or salts and / or esters and / or anhydrides of one or more of these molecules in the active ingredient P2.

[0171] Preferably, each of the active molecules in the active ingredient P2 accounts for 6E-05M to 18E-05M.

[0172] According to one embodiment, in order to improve the solubility, efficacy, and bioavailability of the molecules of the active ingredient P2, at least one molecule selected from the group consisting of taurine, spermine, biotin, glutathione, and α-tocopherol, salts of these molecules, esters of these molecules, and anhydrides of these molecules of the composition is covalently conjugated to at least one molecule of a polymer selected from the group consisting of polylysine, polyethylene glycol, polyornithine, polyarginine, and polyhistidine.

[0173] In fact, the molecules selected from the group consisting of taurine, spermine, biotin, glutathione, and α-tocopherol, salts of these molecules, esters of these molecules, and anhydrides of these molecules can all be specifically covalently conjugated to a polymer selected from the group consisting of polylysine, polyethylene glycol, polyornithine, polyarginine, and polyhistidine via an amide, urea, or carbamate bond.

[0174] According to a particularly suitable variant, all the molecules selected from the group consisting of taurine, spermine, biotin, glutathione, and α-tocopherol, salts of these molecules, esters of these molecules, and anhydrides of these molecules present in the active ingredient P2 according to the invention are covalently conjugated to at least one molecule of a polymer selected from the group consisting of polylysine, polyethylene glycol, polyornithine, polyarginine, and polyhistidine.

[0175] Among all the molecules to be conjugated, one of the molecules is highly hydrophobic (logP value greater than 1, preferably greater than 2 and preferably greater than 3), and is chemically unsuitable for covalent conjugation due to the absence of reactive functional groups and due to chemical incompatibility. This is coenzyme Q10. However, considering the hydrophilic properties of certain polymers such as polylysine, polyethylene glycol, polyornithine, polyarginine or polyhistidine and the hydrophobic properties of α-tocopherol suitable for covalent conjugation, according to the present invention, these specific conjugates act as surfactants in aqueous solutions. Thus, some of these (amphiphilic) conjugates act as polymeric micelles in an aqueous medium, creating a hydrophobic pocket capable of encapsulating the hydrophobic coenzyme Q10, thereby significantly improving its solubility and stability in aqueous solutions.

[0176] Specifically, coenzyme Q10 and its esters, salts and anhydrides cannot be covalently bonded to, i.e., conjugated with, polymers selected from polylysine, polyethylene glycol, polyornithine, polyarginine and polyhistidine. Similarly, preferably, coenzyme Q10 and / or esters and salts of coenzyme Q10 are encapsulated in micelles. Thus, the active ingredient P2 preferably comprises micelles in which at least coenzyme Q10 and / or esters and / or salts and / or anhydrides of coenzyme Q10 are encapsulated.

[0177] According to a particularly suitable embodiment, at least one of the micelles of the active ingredient P2 is formed by amphiphilic conjugates, each of which is composed of at least one molecule covalently conjugated to a molecule of a polymer selected from polylysine, polyethylene glycol, polyornithine, polyarginine and polyhistidine. Even more preferably, as Figure 1 shown, at least one of the micelles 10 of the active ingredient P2 is formed by amphiphilic conjugates, each of which is composed of at least one molecule 14 selected from taurine, biotin, glutathione and α-tocopherol, salts of these molecules, esters of these molecules and anhydrides of these molecules covalently conjugated to a molecule of a polymer 12 selected from polylysine, polyethylene glycol, polyornithine, polyarginine and polyhistidine, thereby encapsulating coenzyme Q10 and / or esters and / or salts and / or anhydrides 16 of coenzyme Q10. In fact, taurine, spermine, biotin, glutathione and α-tocopherol, salts of these molecules, esters of these molecules and anhydrides of these molecules are hydrophobic, and poly-L-lysine, polyethylene glycol, polyornithine, polyarginine or polyhistidine are hydrophilic polymers.

[0178] Therefore, the active ingredient P2 preferably consists of:

[0179] - conjugates of taurine, spermine, biotin, glutathione and α-tocopherol, salts of these molecules, esters and / or anhydrides of these molecules with polylysine, polyethylene glycol, polyornithine, polyarginine or polyhistidine, and

[0180] - Micelles formed from at least one of these conjugates, the micelles encapsulating coenzyme Q10.

[0181] Specifically, this configuration enables the following:

[0182] - Prolonging the half-life of the molecules of active ingredient P2 in the body,

[0183] - Targeting the tissues or cells to which the molecules of active ingredient P2 are to act,

[0184] - Enabling the active molecules of active ingredient P2 to cross the blood-brain barrier and enter the cells

[0185] - Improving the stability and bioavailability of the active ingredient.

[0186] Therefore, the efficacy of active ingredient P2 is enhanced, and a lower dose can be administered and the acute or chronic toxicity of the active molecules contained in the composition can be reduced.

[0187] Preferably, one or more polymers conjugated to these molecules are selected from poly-L-lysine, polyethylene glycol, poly-L-ornithine, poly-L-arginine, and poly-L-histidine.

[0188] According to one embodiment, the polymer is polylysine, preferably poly-L-lysine. Preferably, the polylysine used is poly-L-lysine having a molecular weight of 12,000 Da to 20,000 Da.

[0189] Thus, according to one variant, active ingredient P2 consists of: - A. The following conjugates, each conjugate consisting of a molecule covalently bonded to polylysine:

[0190] - One or more taurine-poly-L-lysine conjugates

[0191] - One or more spermine-poly-L-lysine conjugates

[0192] - One or more α-tocopherol-poly-L-lysine conjugates

[0193] One or more biotinyl-poly-L-lysine conjugates

[0194] - One or more glutathione-poly-L-lysine conjugates, and

[0195] B. Coenzyme Q10 and / or esters and / or salts of coenzyme Q10, which are encapsulated in micelles, preferably encapsulated in micelles formed from one or more of the conjugates listed in point A; and

[0196] C. Optionally at least one pharmaceutically acceptable excipient.

[0197] According to another variant, the active ingredient P2 consists only of the following:

[0198] - A. The following conjugates, each conjugate consisting of a molecule covalently bonded to polylysine:

[0199] - one or more taurine-poly-L-lysine conjugates

[0200] - one or more spermine-poly-L-lysine conjugates

[0201] - one or more α-tocopherol-poly-L-lysine conjugates

[0202] - one or more biotinyl-poly-L-lysine conjugates

[0203] - one or more glutathione-poly-L-lysine conjugates, and

[0204] B. Coenzyme Q10 and / or an ester and / or a salt of coenzyme Q10, which is encapsulated in micelles, preferably encapsulated in micelles formed by one or more of the conjugates listed in point A.

[0205] In this composition, poly-L-lysine can be replaced by another polylysine or by polyethylene glycol, poly-L-ornithine, poly-L-arginine or poly-L-histidine.

[0206] According to one embodiment, the active ingredient P2 consists of the following molecules:

[0207] - at least 0.86 mg / mL of taurine-poly-L-lysine;

[0208] - at least 0.86 mg / mL of spermine-poly-L-lysine;

[0209] - at least 0.86 mg / mL of α-tocopherol-poly-L-lysine;

[0210] - at least 0.86 mg / mL of biotinyl-poly-L-lysine;

[0211] - at least 0.86 mg / mL of glutathione-poly-L-lysine; and

[0212] - at least 0.86 mg / mL of coenzyme Q10.

[0213] The active ingredient P2 optionally contains pharmaceutically acceptable excipients, which are specifically selected to meet the pH and isotonicity requirements of a solution for injection into humans or animals. For example, they can be an acid or a base for adjusting the pH or NaCl for adjusting the isotonicity.

[0214] The active ingredient P2 can be in liquid form or in solid form. The solid form is preferably obtained from the liquid form, preferably by lyophilization.

[0215] When the active ingredient P2 is in liquid form, it can contain at least one pharmaceutically acceptable excipient, preferably a buffer, especially water for injection and / or phosphate buffered saline (PBS).

[0216] When the active ingredient P2 is in solid form, it can be free of excipients or it can contain at least one pharmaceutically acceptable excipient derived from the lyophilized liquid form, such as dehydrated PBS buffer.

[0217] The present invention also relates to a composition C2 comprising the active ingredient P2.

[0218] The composition C2 according to the present invention can be in solid form or in liquid form. When in liquid form, the composition C2 contains at least water and the active ingredient P2. The solid form is preferably obtained from the liquid form, preferably by lyophilization. Thus, when the composition C2 in liquid form contains micelles and it is lyophilized into solid form, the micelles reform when the composition C2 in solid form is put back into an aqueous solution.

[0219] The composition C2 can also contain at least one pharmaceutically acceptable excipient. These excipients can be specifically selected to meet the pH and osmolarity requirements of a solution for injection into humans or animals. For example, they can be an acid or a base for adjusting the pH or NaCl for adjusting the osmolarity.

[0220] The composition C2 can be in liquid form or in solid form. The solid form is preferably obtained from the liquid form, preferably by lyophilization.

[0221] When the composition C2 is in liquid form, it can contain at least one pharmaceutically acceptable excipient, preferably a buffer, especially water for injection and / or phosphate buffered saline (PBS).

[0222] When the composition is in solid form, it can contain at least one pharmaceutically acceptable excipient derived from the lyophilized liquid form, preferably dehydrated PBS buffer.

[0223] The composition C2 according to the present invention is intended for administration to humans or animals and is thus in a form suitable for such administration. When the composition is in liquid form, it is preferably suitable for subcutaneous or intravenous administration, especially intravenous infusion, and the composition is packaged in a suitable container known to those skilled in the art for packaging such products. The composition C2 according to the present invention can also be administered in liquid form via a pump such as an insulin pump.

[0224] When the composition is in solid form, it is preferably suitable for the following routes of administration:

[0225] - Transdermal administration, and the composition is preferably formulated and packaged in the form of a patch, or

[0226] - Nasal administration in the form of a powder, or

[0227] - Sublingual administration in the form of a powder or tablet, or

[0228] - Mucosal administration, and the composition is preferably formulated and packaged in the form of a mucoadhesive tablet.

[0229] Advantageously, composition C2 can be administered in a single dose, preferably by a single injection.

[0230] According to one variant, composition C2 consists of the active ingredient P2.

[0231] According to another variant, the present invention relates to a composition C3 comprising the active ingredient P1 and the active ingredient P2 and optionally one or more excipients.

[0232] Method for preparing active ingredient P2

[0233] The active ingredient P2 according to the present invention can be prepared by any suitable method.

[0234] If the molecules constituting the active ingredient P2 are used as such in a solvent, they can all be mixed together in the said solvent.

[0235] If some of the molecules in the active ingredient P2 are conjugated to a polymer while other molecules are in micelles, the preparation method may include the following steps:

[0236] - a. Generating an amphiphilic premix: Mixing in an aqueous solution one or more conjugates selected from the following:

[0237] - One or more taurine-poly-L-lysine conjugates

[0238] - One or more spermine-poly-L-lysine conjugates

[0239] - One or more α-tocopherol-poly-L-lysine conjugates

[0240] - One or more biotin-based poly-L-lysine conjugates

[0241] - One or more glutathione-poly-L-lysine conjugates

[0242] -b. Add at least coenzyme Q10 to the amphiphilic premix and stir to form micelles formed by one or more conjugates in a conjugate of the amphiphilic premix encapsulating coenzyme Q10.

[0243] Specifically, a variant of the present invention lies in utilizing the amphiphilic nature of most of the individual components to produce an amphiphilic premix that allows for the controlled solubilization of hydrophobic coenzyme Q10. The solubilization method according to a preferred embodiment lies in the controlled addition of the hydrophobic molecules to the amphiphilic premix and allowing the time required for them to dissolve under stirring.

[0244] Poly-L-lysine can be replaced by another polylysine or by polyethylene glycol, poly-L-ornithine, poly-L-arginine, or poly-L-histidine.

[0245] Preferably, the stirring is carried out for at least 5 minutes, even more preferably 5 minutes to 20 minutes, and preferably at a stirring speed of less than or equal to 900 revolutions per minute, especially at a stirring speed of 50 revolutions per minute to 800 revolutions per minute.

[0246] According to a preferred embodiment, the production method according to the present invention further includes step c: separating the soluble phase and the insoluble phase in order to recover the soluble phase. In this case, the insoluble phase is removed, and the soluble phase constitutes the active ingredient P2 according to the present invention. In fact, a physical separation process (filtration, ultrafiltration) is preferably carried out to ensure the separation of the soluble fraction containing the amphiphilic premix, copolymer, and solubilizing molecules.

[0247] Then the active ingredient P2 in liquid form can be lyophilized or preferably dehydrated into solid form by slow freeze-drying for example for 12 hours to 36 hours.

[0248] Furthermore, if the molecule-polymer conjugates of the active ingredient P2 are not incorporated into the premix in step a, they can be added to the mixture after step b, that is, after micelle formation and encapsulation of coenzyme Q10.

[0249] The active molecule-polymer conjugates can be produced by any means known to those skilled in the art for covalently conjugating molecules to polymers, depending on their chemical nature. Thus:

[0250] - Spermine and taurine are conjugated to the polymer via urea bonds.

[0251] - Glutathione, biotin, and α-tocopherol are conjugated to the polymer via amide bonds.

[0252] Exemplary embodiments of urea and carbamate bonds are described for example in the following:

[0253] -Zhuxian Z, Jianbin T, Qihang S, William J. "A multifunctional PEG-PLL drug conjugate forming redox-responsive nanoparticles for intracellular drug delivery", Issue 38, 2015. Journal of Materials Chemistry B (amide bond),

[0254] -Scheper V, Wolf M, Scholl M, Kadlecova Z, Perrier T, Klok HA, Saulnier P, Lenarz T, Stover T. "Potential novel drug carriers for inner ear treatment: hyperbranched poly-lysine and lipid nanocapsules." Nanomedicine (Lond). August 2009; 4(6): 623-35 (urea bond),

[0255] -Stéphanie Gac-Breton, Jean Coudane, Mahfoud Boustta and Michel Vert (2004) "Norfloxacin-Poly(1-Lysine Citramide Imide) Conjugates and Structure-dependence of the Drug Release", Journal of Drug Targeting, 12:5, 297-307 (carbamate bond),

[0256] -Elmore, W.M. (2013). "Nanoparticles Stabilized with MPEG-Polylysine Carbamate: Synthesis and Characterization" (carbamate bond),

[0257] -Ning-Ping Huang, Janos Susan M. De Paul, Marcus Textor, and Nicholas D. Spencer. “Biotin-Derivatized Poly(l-lysine)-g-poly(ethylene glycol): A Novel Polymeric Interface for Bioaffinity Sensing.” Langmuir 2002 18(1), 220 - 230 (urethane bond).

[0258] Use of active ingredient P1

[0259] The present invention also relates to the active ingredient P1 used as a medicament, in particular for the prevention and / or treatment of multifactorial diseases, especially chronic multifactorial diseases, particularly diseases related to intestinal permeability.

[0260] The active ingredient P1 is capable of acting in a combinatorial manner:

[0261] - As a synergistic cellular substrate, especially through the presence of butyrate,

[0262] - Regulating the mucosa and intestinal microbiota, especially through the presence of acetate, lactate, propionate, and butyrate

[0263] The various molecules present act synergistically and can, in particular, restore the function of intestinal permeability.

[0264] Advantageously, the presence of these 4 short-chain fatty acids is sufficient to reconstruct the intestinal permeability function.

[0265] Therefore, the active ingredient P1 can be used to reconstruct the function of the intestinal membrane and / or maintain intestinal permeability and / or prevent or counteract hyperpermeability of the intestinal mucosa.

[0266] According to a variant, the present invention relates to the use of the active ingredient P1 as a food supplement for healthy humans or animals, especially for reducing the intestinal permeability of humans or animals to which the active ingredient is administered.

[0267] Therefore, the intestine plays a key role in the initiation and regulation of the chronicization of diseases. Thus, the active ingredient P1 can be particularly administered to humans or animals to prevent or counteract diseases in which the intestine plays an important role, especially chronic diseases, particularly degenerative chronic diseases such as neurodegenerative diseases, for example, amyotrophic lateral sclerosis. The active ingredient P1 can also be used as an immune system activator to prevent or counteract autoimmune and infectious diseases.

[0268] The active ingredient P1 can be particularly used to reduce the chronicization of chronic diseases.

[0269] Preferably, once the first symptoms of high intestinal permeability or chronic diseases appear, the active ingredient P1 is used for prevention or treatment to prevent the chronic development of the diseases, thereby preventing cytokine storms caused by long-term high intestinal permeability.

[0270] Specifically, the active ingredient P1 is at least particularly used for:

[0271] - reducing the inflammatory process, and / or

[0272] - reducing the autoimmune process, and / or

[0273] - reducing intestinal permeability.

[0274] In particular, the present invention relates to the active ingredient P1 for use in the prevention and / or treatment of multi-factorial diseases, especially chronic multi-factorial diseases, especially diseases selected from inflammatory diseases, neurodegenerative diseases, bacterial diseases, viral diseases, autoimmune diseases, allergies and food intolerances.

[0275] According to a specific embodiment, the present invention relates to the active ingredient P1 for use in the prevention and / or treatment of diseases selected from eczema, psoriasis, chronic inflammatory bowel diseases (especially Crohn's disease and celiac disease), Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis.

[0276] According to an embodiment, the active ingredient P1 is administered in a single dose, preferably as a single injection.

[0277] Therefore, the present invention also relates to a composition C1 comprising or consisting of the active ingredient P1 according to the present invention, which composition is used as a medicament, especially in humans or animals, i.e., for human or animal subjects.

[0278] In particular, the present invention relates to the composition C1 for use in the prevention and / or treatment of multi-factorial diseases, especially chronic multi-factorial diseases, especially diseases selected from inflammatory diseases, neurodegenerative diseases, bacterial diseases, viral diseases, autoimmune diseases, allergies and food intolerances.

[0279] According to a specific embodiment, the present invention relates to the composition C1 for use in the prevention and / or treatment of diseases selected from eczema, psoriasis, chronic inflammatory bowel diseases (especially Crohn's disease and celiac disease), Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis.

[0280] According to an embodiment, the composition C1 is administered in a single dose, preferably as a single injection.

[0281] The composition C1 can be used alone or in combination with one or more other compositions.

[0282] According to another embodiment, composition C1 is preferably used together with composition C2. Composition C2 contains or consists of the active ingredient P2.

[0283] Compositions C1 and C2 can also be used alone or in combination to treat or prevent diseases associated with the pathological dysbiosis of the gut microbiota. Notably, compositions C1 and C2 can be used alone or in combination to prevent or treat:

[0284] - neurodegenerative diseases associated with the pathological dysbiosis of the gut microbiota, such as diseases selected from amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, and Alzheimer's disease;

[0285] - intestinal diseases associated with the pathological dysbiosis of the gut microbiota, such as diseases selected from Crohn's disease, chronic inflammatory bowel disease, hemorrhagic proctocolitis, irritable bowel syndrome, ulcerative colitis, rheumatoid arthritis, and food intolerance (especially gluten intolerance).

[0286] According to another embodiment, the active ingredient P1 is combined with the active ingredient P2 for use in composition C3. Composition C3 according to the invention contains or consists of the active ingredient P1 and the active ingredient P2.

[0287] Advantageously, composition C3 can be administered in a single dose, preferably as a single injection.

[0288] Use of active ingredient P2

[0289] The present invention also relates to the active ingredient P2 for use as a medicament, in particular for the prevention and / or treatment of multifactorial diseases, especially chronic multifactorial diseases, particularly for the treatment of neurodegenerative diseases, autoimmune diseases, infectious diseases, or cancer. In particular, it has great efficacy in the prevention and treatment of amyotrophic lateral sclerosis. The active ingredient P2 intervenes in conventional and known processes to reduce the chronicity of the disease. Its action is particularly suitable for neurodegenerative diseases, autoimmune diseases, cancer, and infectious diseases.

[0290] In particular, it is capable of acting in a combined manner:

[0291] - as a neuroprotective agent, especially through the presence of taurine and coenzyme Q10

[0292] - as an anti-inflammatory agent, especially through the presence of spermine,

[0293] - as a cytoprotective agent, especially through the presence of coenzyme Q10 (especially protection at the mitochondrial chain level)

[0294] - as a cell membrane protective agent, especially through the presence of α-tocopherol,

[0295] - As an antioxidant, especially through the presence of taurine, spermine, α-tocopherol, coenzyme Q10, and glutathione

[0296] - Stabilization of cell membranes,

[0297] - As a scavenger of free radicals and metals, especially through the presence of taurine, spermine, coenzyme Q10, and glutathione.

[0298] The various molecules present act synergistically, especially making it possible to prevent or counteract the factors that are the root cause of chronic diseases, especially amyotrophic lateral sclerosis.

[0299] Therefore, the active ingredient P2 can be used for the prevention and / or counteraction of chronic diseases, especially acting on disease-specific metabolism. The active ingredient P2 can be especially used to reduce the chronicity of chronic diseases.

[0300] Preferably, once the first symptoms of a chronic disease, especially a neurodegenerative disease, specifically amyotrophic lateral sclerosis, appear, the active ingredient P2 is used for prevention or treatment.

[0301] According to one embodiment, the active ingredient P1 is administered in a single dose, preferably as a single injection.

[0302] Therefore, the present invention also relates to a composition C2 comprising or consisting of the active ingredient P2 according to the present invention, which composition is used as a medicament, especially in humans or animals, i.e., for human or animal subjects.

[0303] In particular, the present invention relates to the use of the composition C2 in the prevention and / or treatment of multifactorial diseases, especially chronic multifactorial diseases, especially diseases selected from inflammatory diseases, neurodegenerative diseases, bacterial diseases, viral diseases, autoimmune diseases, allergies, and food intolerances, especially amyotrophic lateral sclerosis.

[0304] According to a specific embodiment, the present invention relates to the use of the composition C2 in the prevention and / or treatment of diseases selected from eczema, psoriasis, chronic inflammatory bowel diseases (especially Crohn's disease and celiac disease), Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis.

[0305] According to one embodiment, the composition C2 is administered in a single dose, preferably as a single injection. The composition C2 is very preferably used in combination with the composition C1.

[0306] Accordingly, a specific object of the present invention is that composition C1 and composition C2 are used together as a medicament, particularly for preventing and / or treating multi-factorial diseases, particularly chronic multi-factorial diseases, especially diseases selected from inflammatory diseases, neurodegenerative diseases, bacterial diseases, viral diseases, autoimmune diseases, allergies and food intolerances, and especially for preventing and / or treating diseases selected from eczema, psoriasis, Crohn's disease, celiac disease, chronic inflammatory bowel disease, Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis.

[0307] Composition C1 and composition C2 are used together as a medicament in a single administration, preferably a single injection.

[0308] Composition C3

[0309] The present invention also relates to composition C3 comprising or consisting of active ingredient P1 and active ingredient P2.

[0310] Composition C3 according to the present invention can be in liquid form or in solid form. When in liquid form, composition C3 comprises at least water and active ingredients P1 and P2. The solid form is preferably obtained from the liquid form, preferably by lyophilization. Thus, when composition C3 in liquid form comprises micelles and it is lyophilized into solid form, the micelles reform when the solid form of composition C3 is put back into an aqueous solution.

[0311] Composition C3 can be obtained by mixing active ingredient P1 and active ingredient P2.

[0312] Composition C3 can also comprise at least one pharmaceutically acceptable excipient. These excipients can be particularly selected to meet the pH and isotonicity requirements of a solution for injection into humans or animals. For example, they can be an acid or a base for adjusting the pH or NaCl for adjusting the isotonicity.

[0313] Composition C3 can be in liquid form or in solid form. The solid form is preferably obtained from the liquid form, preferably by lyophilization.

[0314] When composition C3 is in liquid form, it can comprise at least one pharmaceutically acceptable excipient, preferably a buffer, especially water for injection and / or phosphate buffered saline (PBS).

[0315] When the composition is in solid form, it can comprise at least one pharmaceutically acceptable excipient derived from the lyophilized liquid form, preferably dehydrated PBS buffer.

[0316] Composition C3 according to the invention is intended for administration to humans or animals and is thus in a form suitable for such administration. When the composition is in liquid form, it is preferably suitable for subcutaneous or intravenous administration, in particular intravenous infusion, and the composition is packaged in a suitable container known to those skilled in the art for packaging such products. Composition C3 can also be administered in liquid form via a pump such as an insulin pump.

[0317] When the composition is in solid form, it is preferably suitable for the following routes of administration:

[0318] - Transdermal administration, and the composition is preferably formulated and packaged in the form of a patch, or

[0319] - Nasal administration in the form of a powder, or

[0320] - Sublingual administration in the form of a powder or tablet, or

[0321] - Transmucosal administration, and the composition is preferably formulated and packaged in the form of a mucoadhesive tablet.

[0322] Advantageously, composition C3 can be administered in a single dose, preferably by a single injection.

[0323] According to a particularly preferred variant, the invention relates to a composition C3 comprising active ingredient P1 and active ingredient P2 and optionally one or more excipients. The invention also relates to a composition C3 comprising active ingredient P1 and active ingredient P2 according to the invention, which composition is used as a medicament, in particular in humans or animals, i.e. for human or animal subjects.

[0324] In particular, the invention relates to the use of composition C3 in the prevention and / or treatment of multifactorial diseases, in particular chronic multifactorial diseases, especially diseases selected from inflammatory diseases, neurodegenerative diseases, bacterial diseases, viral diseases, autoimmune diseases, allergies and food intolerances, especially amyotrophic lateral sclerosis.

[0325] According to a specific embodiment, the invention relates to the use of composition C3 in the prevention and / or treatment of diseases selected from eczema, psoriasis, chronic inflammatory bowel diseases (especially Crohn's disease and celiac disease), Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis.

[0326] According to one embodiment, composition C3 is administered in a single dose, preferably by a single injection.

[0327] Composition C3 can also be used to treat or prevent diseases associated with a pathological dysbiosis of the gut microbiota. In particular, composition C3 can be used to prevent or treat:

[0328] - Neurodegenerative diseases associated with pathological dysbiosis of the gut microbiota, such as diseases selected from amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, and Alzheimer's disease;

[0329] - Intestinal diseases associated with pathological dysbiosis of the gut microbiota, such as diseases selected from Crohn's disease, chronic inflammatory bowel disease, hemorrhagic proctocolitis, irritable bowel syndrome, ulcerative colitis, rheumatoid arthritis, and food intolerances (especially gluten intolerance).

[0330] Composition C4:

[0331] According to one variant, the invention also relates to composition C4 consisting of the following: the following molecules:

[0332] - Acetic acid,

[0333] - Butyric acid,

[0334] - Lactic acid,

[0335] - Propionic acid,

[0336] and / or salts and / or esters and / or anhydrides of one or more of these molecules, and

[0337] - Optionally at least one pharmaceutically acceptable excipient.

[0338] Advantageously, the embodiments described for active ingredient P1 can be transferred to composition C4.

[0339] Example :

[0340] Example 1: Analysis of the cytotoxicity of the active ingredient according to the present invention against colon cells.

[0341] This example represents the analysis of the cytotoxicity of the active ingredient according to the invention on human colonic mucosal epithelial cells (i.e., Caco-2 cells).

[0342] These cells are one of the therapeutic targets for combating dysbiosis and restoring intestinal permeability.

[0343] The cytotoxicity tests were performed in triplicate per plate and on 3 different plates to limit cell bias for each sample.

[0344] The concentrations tested started at 1000 μg / mL and were serially diluted down to 2 μg / mL.

[0345] The LD50 was analyzed and determined as the % survival of OD obtained using the tetrazolium salt MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) after incubation with the molecules at 37 °C and 5% CO2 for 48 hours.

[0346] a) Analysis of the cytotoxicity of each molecule present in the active ingredient according to the present invention

[0347] Cytotoxicity tests were carried out to evaluate the cytotoxicity of each molecule present in the active ingredient according to the invention, as well as the association of each molecule with poly-L-lysine. The results are shown in Table 1 below.

[0348] [Table 1]

[0349]

[0350] When combined with poly-L-lysine, the compounds showed lower cytotoxicity.

[0351] b) Analysis of the cytotoxicity of different combinations of molecules present in the active ingredient according to the invention.

[0352] The results for the various combinations of molecules present in the active ingredient according to the invention are presented in Table 2 below.

[0353] [Table 2]

[0354]

[0355] Compared with the various combinations of the molecules considered, the active ingredient according to the invention showed the lowest toxicity.

[0356] A complete analysis of all the results showed that the IC50 of the active ingredient according to the invention was in the range of 7.5 μg / mL to 12.8 μg / mL, which was close to the literature value of polylysine.

[0357] In Figure 1 The results compiled in

[0358] showed that the addition of the conjugate did not alter the inherent cytotoxicity of polylysine, nor did it alter the combination between each molecule present in the active ingredient according to the invention.

[0359] Example 2: Evaluation of the efficacy of composition C1 according to the invention.

[0360] A - Materials and methods

[0361] 1 - Establish a chronic inflammation model

[0362] After the animals arrived, these animals (Wistar rats, 280 g - 300 g) were housed in 900 cm 2In cages (3 animals / cage). During this adaptation period, the animals will have free access to water and food. After this period, the animals (n = 9) will randomly receive food and a solution of 2%, 3% or 4% (w / v) dextran sulfate sodium (DSS) in drinking water.

[0363] Oral ingestion of DSS induces inflammation, leading to intestinal permeability defects in rats.

[0364] The induction of intestinal inflammation will be monitored at 3 days, 5 days and 7 days after the start of adding DSS. The control group (n = 3) will randomly receive food and water.

[0365] These results indicate that a 2% concentration is optimal for inducing enteritis without causing animal death. Concentrations of 3% or 4% are not suitable for measuring intestinal permeability.

[0366] 2 - Permeability study

[0367] Permeability studies will be performed on isolated organs (jejunum or colon) to determine the efficacy of the composition C1 of the present invention in reconstructing intestinal permeability.

[0368] a) Composition C1 according to the present invention

[0369] The composition C1 used in this example comprises the following elements:

[0370] - Acetate-PLL at 1.17 g / L;

[0371] - Butyrate-PLL at 1.88 g / L;

[0372] - Lactate-PLL at 1.17 g / L;

[0373] - Propionate-PLL at 1.18 g / L.

[0374] b) Sampling of digestive tract segments

[0375] This ex vivo method uses segments of the jejunum or colon from the digestive tract of rats.

[0376] The serosal and mucosal compartments of the organ were rapidly rinsed with saline solution (37 °C), and the organ was everted. Ligation was performed at one end. The second end was allowed to introduce 1 mL of Krebs-Henseleit medium. Then this end was ligated, the organ was weighed, and then it was placed in a container containing 10 mL of Krebs-Henseleit survival medium plus 250 mg of FITC-dextran, 4 kDa (mucosal compartment). Throughout the experiment, the everted organ was maintained at 37 °C and oxygenated with an O2 / CO2 mixture (95% / 5%). Every 30 minutes, the mucosal compartment medium was stirred by performing 3 aspiration-discharge cycles using a 1 mL micropipette. After incubation for 2 hours, 1 mL of sample was taken from the mucosal side.

[0377] The organ was removed from the glass container, and one end was cut off. The serosal medium was sampled and placed in a pre-weighed test tube. After sampling, the test tube was weighed again to evaluate the transfer of the survival medium during the experiment. After weighing, FITC-dextran was measured in duplicate by fluorometry (excitation, 490 nm; emission, 530 nm).

[0378] After weighing the organ, a longitudinal cut was made in the organ, and it was rapidly frozen in liquid nitrogen. Then the frozen organ was placed in a zip bag and frozen in liquid nitrogen, and then stored at -80 °C.

[0379] B - Results

[0380] a) In vivo method

[0381] For the implementation of this method, the experiment included 3 groups, namely:

[0382] - Control group force-fed FITC

[0383] - Two groups of rats force-fed FITC + 2% DSS and subcutaneously treated with composition C1 for 3 days. Plasma samples were collected 10 days after DSS injection. The results of FITC measurement are shown below:

[0384] [Table 3]

[0385]

[0386] These results indicate that treating rats with composition C1 according to the present invention restored intestinal permeability.

[0387] b) Ex vivo method

[0388] For the implementation of this method, the experiment also included 3 groups, namely:

[0389] - Control group force-fed FITC

[0390] - Two groups of rats force-fed with FITC + 2% DSS and treated subcutaneously with composition C1 for 3 days

[0391] As described in the experimental section, the ex vivo method was based on using ileum and jejunum segments taken from rats belonging to the above 3 groups 10 days after injection of DSS in the treatment groups. Thus, samples were taken every 30 minutes from the mucosal side to measure FITC. The results are shown in the table below:

[0392] Ileum (5 cm) + Jejunum (5 cm) 30 minutes 60 minutes 90 minutes 120 minutes 150 minutes Control group (FITC) 34.4 103.4 254.6 526.9 861.5 Group 1 (2% DSS + FITC + Composition C1) 30.7 137.9 457.2 841.4 1101 Group 2 (2% DSS + FITC + Composition C1) 27.4 85.3 293 659.6 1030

[0393] These results indicate that treating rats with composition C1 according to the present invention restored intestinal permeability.

Claims

1. An active ingredient, which consists of the following: The following molecules: - Acetic acid - Butyric acid - Lactic acid - Propionic acid and / or salts and / or esters and / or acid anhydrides of one or more of these molecules, and - Optionally at least one pharmaceutically acceptable excipient, characterized in that at least one molecule of the molecules of the composition selected from acetic acid, butyric acid, lactic acid, propionic acid, salts of these acids, esters of these acids and acid anhydrides of these acids is covalently conjugated to at least one molecule of a polymer selected from polylysine, polyethylene glycol, polyornithine, polyarginine and polyhistidine.

2. The active ingredient according to the preceding claim, characterized in that The polylysine is poly-L-lysine having a molecular weight of 12,000 Da to 20,000 Da.

3. A composition, the composition comprising an active ingredient according to one of claims 1 to 2.

4. The composition according to the preceding claim, characterized in that The composition is in liquid form or in solid form.

5. The composition according to one of claims 3 or 4, characterized in that The composition further comprises at least one pharmaceutically acceptable excipient.

6. A method for preparing an active ingredient according to one of claims 1 to 2, characterized in that The method comprises mixing the following compounds in an aqueous solution: - One or more acetate-poly-L-lysine conjugates - One or more butyrate-poly-L-lysine conjugates - One or more lactate-poly-L-lysine conjugates - One or more propionate-poly-L-lysine conjugates.

7. The active ingredient according to one of claims 1 to 2 or the composition according to one of claims 3 or 5, for use as a medicament.

8. The active ingredient according to one of claims 1 to 2 or the composition according to one of claims 3 to 5, for use in the prevention and / or treatment of diseases selected from inflammatory diseases, neurodegenerative diseases, bacterial diseases, viral diseases, autoimmune diseases, allergies and food intolerances.

9. The active ingredient according to one of claims 1 to 2 or the composition according to one of claims 3 to 5, for use in the prevention and / or treatment of diseases selected from eczema, psoriasis, chronic inflammatory bowel disease, Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis.

10. The active ingredient according to one of claims 1 to 2 or the composition according to one of claims 3 to 5, used as claimed in one of claims 7 to 9, characterized in that The composition is administered in a single dose.

11. The active ingredient according to one of claims 1 to 2 for use according to one of claims 7 to 10 or the composition according to one of claims 4 to 6, for use in combination with a second active ingredient consisting of: The following molecules: - Taurine, - Spermine - Biotin, - Coenzyme Q10, - Glutathione, - α-Tocopherol and / or salts and / or esters and / or acid anhydrides of one or more of these molecules; and - Optionally at least one pharmaceutically acceptable excipient.

12. The active ingredient according to one of claims 1 to 2 or the composition according to one of claims 3 to 5, as used according to claim 11, characterized in that In the second active ingredient, at least one molecule of the molecules of the composition selected from taurine, spermine, biotin and glutathione, salts of these molecules, esters of these molecules and acid anhydrides of these molecules is covalently conjugated to a molecule of a polymer selected from polylysine, polyethylene glycol, polyornithine, polyarginine and polyhistidine.

13. The active ingredient according to one of claims 1 to 2 or the composition according to one of claims 3 to 5, as used according to one of claims 11 or 12, characterized in that In the second active ingredient, the coenzyme Q10 is encapsulated in micelles.

14. The active ingredient according to one of claims 1 to 2 or the composition according to one of claims 3 or 4, as used according to claim 13, characterized in that At least one micelle of the second active ingredient is formed from an amphiphilic conjugate, each amphiphilic conjugate being composed of at least one molecule covalently conjugated to a molecule of a polymer selected from polylysine, polyethylene glycol, polyornithine, polyarginine, and polyhistidine.

15. The active ingredient according to one of claims 1 to 2 or the composition according to one of claims 3 to 5, as used according to claim 13 or 14, characterized in that At least one micelle of the second active ingredient is formed from an amphiphilic conjugate, each amphiphilic conjugate being composed of at least one molecule selected from taurine, spermine, biotin, glutathione, and α-tocopherol, salts of these molecules, esters of these molecules, and acid anhydrides of these molecules covalently conjugated to a molecule of a polymer selected from polylysine, polyethylene glycol, polyornithine, polyarginine, and polyhistidine.

16. The active ingredient according to one of claims 1 to 2 or the composition according to one of claims 3 or 4, as used according to one of claims 6 to 15, for the prevention and / or treatment of a pathological dysbiosis of the gut microbiota.

17. The active ingredient according to one of claims 1 to 2 or the composition according to one of claims 3 to 5, as used according to one of claims 7 to 17, for the prevention and / or treatment of a bowel disease associated with a pathological dysbiosis of the gut microbiota.

18. The active ingredient according to one of claims 1 to 2 or the composition according to one of claims 3 to 4, as used according to one of claims 6 to 17, for the prevention and / or treatment of a bowel disease selected from Crohn's disease, chronic inflammatory bowel disease, hemorrhagic proctocolitis, irritable bowel syndrome, ulcerative colitis, rheumatoid arthritis, and gluten intolerance.

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