Active ingredients and their use in restoring intestinal permeability and / or preventing or combating multifactorial 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 a salt and / or an ester and / or an anhydride of one or more of these molecules and optionally at least one pharmaceutically acceptable excipient, a composition comprising said active ingredient and their use in particular as a medicinal product.

Description

Description Title of the invention: Active ingredients and their use for restoring intestinal permeability and / or prevent or combat multifactorial diseases Technical field

[0001] = The invention relates to the prevention and / or treatment of multifactorial diseases. In particular, the invention relates to an active ingredient consisting of several selected specific molecules, a composition comprising such an active ingredient and their use to reduce intestinal permeability and / or restore intestinal function. normal intestinal permeability and / or to prevent or combat various multifactorial diseases involving intestinal permeability.

[0002] = State of the art

[0003] = Most diseases and especially chronic diseases are multi-factorial. toricles. They always involve a genetic component and components immunological and toxic linked to the “environment”, that is to say to bacteria, viruses, chemical agents, etc.

[0004] … Among the known multifactorial chronic diseases, we can cite in particular degenerative diseases such as Parkinson's disease, Alzheimer's disease, post-stroke inflammatory effects, Charcot's disease (or amyo- trophic), Huntington's disease, etc.

[0005] — Degenerative diseases are pathologies which lead to a pro- progressive of one or more organs. Often of genetic origin, they can be de- triggered after strong and long exposure to biological products and / or toxic. Indeed, any excessive passage of bacterial constituents and / or other toxins through the mucous membranes, causes immune activation, which, in patients suffering from chronic illnesses, always takes the path of stimulating self-clones reagents attacking target tissues (degeneration). Degenerative diseases are therefore closely linked to intestinal hyperpermeability, like many infectious diseases and in particular viral diseases.

[0006] — In a healthy human intestine, small particles (< 4 Angstrom radius) can migrate through the pores of the Claudins which are the most important component of the tight junctions, but particles up to 10-15 Angstrom (3.5LDa) can transit through the absorption pathway of the paracellular space. The intestine normally presents- normally a certain permeability, which allows nutrients to pass through the intestine, while maintaining a barrier function to prevent potentially harmful substances harmful to leave the intestine and migrate more widely throughout the body. The intestinal flora constantly interacts with the intestinal immune system, with which it is in contact. The interaction between the considerable mass of antigens constituted by the intestinal microflora and the intestinal immune system is extremely complex, but in a balanced organism, this maintains an "immune background noise," an essential balance between the bacteria of the flora and the immune system that regulates them. An unbalanced flora, called dysbiosis, leads to an exacerbated response of the intestinal immune system, increasing inflammation, which results in an alteration of tight junctions. The passage of fragments of walls of bacteria destroyed by the intestine, and passing into the general circulation, endotoxins, is accompanied by the significant secretion by the body of inflammatory cytokines, and if the arrival of endotoxins is massive, can be the starting point of septic shock, respiratory distress, renal ischemia or cytokine storm. The dosage of endotoxins in the blood is also a reliable marker of intestinal hyperpermeability. The causes of intestinal hyperpermeability are extremely numerous. Any disruption of the intestinal biotope, any dysbiosis, triggers a response from the immune system, with the release of inflammatory cytokines, which results in an inflammatory state of the mucosa of the small intestine and colon, with alteration of the epithelium. The causes of this dysbiosis can include: - Stress, which significantly reduces the volume and quality of all digestive juices, - Emotional and psychological shocks, - Significant efforts or physical shocks - Antibiotic therapies, - Viral, bacterial or parasitic infections, - Radiation - Toxic chemical agents: air, water and food pollution; pesticides and heavy metals; medications (statins, anti-inflammatories, immunosuppressants, etc.). Intestinal hyperpermeability, in addition to contributing to the triggering of degenerative diseases in genetically predisposed patients, is the cause of inflammatory, infectious and autoimmune diseases, but also of very disabling food allergies and intolerances. Currently, the solutions proposed to prevent or combat dysbiosis essentially consist of administering probiotics and / or prebiotics, but their effectiveness is very variable and depends on the patient's basic intestinal flora. Furthermore, with regard to degenerative diseases specifically, these are often very burdensome for the patient. Some symptoms can be reduced, But these diseases are never completely cured and there is currently no satisfactory treatment. Many chemical agents have therapeutic properties, but either their toxicity, their lifespan, or their rapid elimination make them unsuitable for the treatment of degenerative diseases. Indeed, while they are multifactorial, current treatments only target one of the factors causing these diseases, and do not seek to act on intestinal hyperpermeability. For example, Lou Gehrig's disease is linked to many factors, in particular oxidative stress, mitochondrial dysfunction, neuroinflammation, excitotoxicity, oligodendrocyte dysfunction and degeneration, impaired proteostasis, an impaired DNA repair system, alterations in nucleocytoplasmic RNA and in RNA linked to transport proteins, defective axonal transport, defective vesicular transport. However, currently, the recommended treatment for Lou Gehrig's disease is Riluzole® which acts only on the inhibition of glutamate release to combat excitotoxicity, and in addition no action on intestinal permeability is envisaged. The observation is the same for other degenerative diseases. There is therefore a need for an effective, non-toxic, easily administered solution capable of acting on different factors to prevent and / or combat the effects of intestinal hyperpermeability and associated multifactorial diseases, in particular against degenerative, autoimmune, inflammatory or infectious diseases. Summary of the invention To meet this need, the invention proposes an active ingredient P1 which both: - reduces the inflammatory process - reduces intestinal permeability - can be administered in a single dose, preferably a single injection - and preferentially rebalances neurological metabolisms causing the degeneration of neurons and motor neurons. To this end, the invention relates to an active principle P1 consisting of the following molecules: - acetic acid, - butyric acid, - lactic acid, - propionic acid, and / or a salt and / or an ester and / or an anhydride of one or more of these molecules, and - optionally at least one pharmaceutically acceptable excipient. Advantageously, the molecules constituting the active principle P1 act together to help restore the function of intestinal permeability disrupted by an imbalance of the microbiota. To increase the effectiveness and bioavailability of these molecules, they are preferably conjugated to specific polymers. The invention also relates to a composition Cl comprising an active ingredient P1 according to the invention. The invention also relates to a method for manufacturing composition C1 according to the invention. The active ingredient P1 and / or the composition CI according to the invention can be used as a medicament alone or combined with the use of at least one other active ingredient and / or another composition. The invention also relates to an active principle P2 consisting of the following molecules: - taurine, - spermine - biotin, - co-enzyme Q10, - Glutathione, - alpha-tocopherol, and / or a salt and / or an ester and / or an anhydride of one or more of these molecules, and - optionally at least one pharmaceutically acceptable excipient, The active ingredient P2 advantageously allows for combined action: - as a neuroprotectant; - as an anti-inflammatory; - as a cell protector; - as a protector of cell membranes; - as an antioxidant; - on the stabilization of cell membranes; and - as a scavenger of free radicals and metals To increase the effectiveness and bioavailability of these molecules, they are preferably conjugated to specific polymers. The invention also relates to a composition C2 comprising an active ingredient P?2 according to the invention. The invention also relates to a method for manufacturing composition C2 according to the invention. The active ingredient P2 and / or the composition C2 according to the invention can be used as a medicament alone or combined with the use of at least one other active ingredient and / or another composition. Preferably, the active ingredient P1 can be used in combination with the active ingredient P2 in a composition C3. Advantageously, composition C3 can be administered in a single dose, preferably a single injection. Other characteristics and advantages will emerge from the detailed description of the invention, the examples and the figures which follow. Brief description of the figures [Fig.1] [Fig.1] represents a scheme of micelle formations according to one embodiment of the invention: 10 = micelles; 12 = polymer (e.g. poly-lysine); 14 = covalently conjugated molecules (e.g. fatty acids); 16 = highly hydrophobic molecules not conjugatable to poly-lysine (e.g. co-enzyme Q10) Detailed description of the invention Defined For the purposes of the invention, the term “animal” means any animal with the exception of human beings. For the purposes of the invention, the term “amphiphilic conjugate” means a conjugate formed by a hydrophobic molecule X and a hydrophilic polymer Y, the conjugate thus having an amphiphilic characteristic. For the purposes of the invention, the term "molecule X conjugated to a polymer Y" means a molecule X linked by a covalent bond to a polymer Y, said bond being preferably able to be an amide, urea or carbamate bond depending on the chemical nature of the molecule X and the polymer Y. Preferably, the covalent bond is made directly between a molecule X and a polymer Y without the intermediary of another molecule such as a linker. For the purposes of the invention, the term "pharmaceutically acceptable excipient" means a component which does not confer therapeutic or preventive properties, but which may play a role in particular in absorption, stability, its formulation, its taste, or its appearance. Pharmaceutically acceptable excipients include gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like, a sweetener, an antiseptic, a flavoring agent, a colorant, dispersing agents, a wetting agent, a suspending agent or a diluent, a buffer. Active ingredient P1 The present invention therefore relates to an active principle PI consisting of the following molecules: - acetic acid, - butyric acid, -lactic acid, - propionic acid, and / or a salt and / or an ester and / or an anhydride of one or more of these molecules, and - optionally at least one pharmaceutically acceptable excipient. Surprisingly, the inventors discovered that the specific combination of molecules constituting the active ingredient PI, namely several specifically selected short-chain fatty acids, makes it possible to prevent and / or combat the effects of intestinal hyperpermeability and associated multifactorial diseases. For all the molecules present in the active ingredient PI, when they are mentioned in the present application, these may be the molecules (example butyric acid) as such and / or a salt (example: butyrate) and / or an ester and / or an anhydride of these molecules (example: butyric acid ester). According to a variant, the active ingredient P1 according to the invention is constituted exclusively by the following molecules: - acetic acid, - butyric acid, -lactic acid, - propionic acid, and / or a salt and / or an ester and / or an anhydride of one or more of these molecules. According to another variant, the active ingredient P1 according to the invention consists exclusively of one or more pharmaceutically acceptable excipients, and of the following molecules: - acetic acid, - butyric acid, -lactic acid, - propionic acid, and / or a salt and / or an ester and / or an anhydride of one or more of these molecules. Preferably, the quantity of butyric acid in the active ingredient PI is greater than that of each of the other molecules taken individually. According to one embodiment, the quantity of butyric acid in the active ingredient P1 is at least twice that of each of the other molecules taken individually. Preferably, each of the active molecules in the active ingredient P1 represents between 0.5 E-05 M and 10 E-05 M. According to one embodiment, to improve the solubility, efficacy and bioavailability of the molecules of the active ingredient P1, at least one of the molecules of the active ingredient P1 chosen from acetic acid, butyric acid, lactic acid, pro- pionic acid, the salts of these acids, the esters of these acids and the anhydrides of these acids, is covalently conjugated to at least one molecule of a polymer selected from poly-lysine, poly-ethylene glycol, poly-ornithine, poly-arginine and poly-histidine. Indeed, the molecules chosen from acetic acid, butyric acid, lactic acid, propionic acid, the salts of these acids, the esters of these acids and the anhydrides of these acids, are all covalently conjugatable with a polymer chosen from poly-lysine, poly-ethylene glycol, poly-ornithine, poly-arginine and poly-histidine, in particular by an amide, urea or carbamate bond. According to a particularly suitable variant, all the molecules constituting the active principle P1 according to the invention are covalently conjugated to at least one molecule of a polymer chosen from poly-lysine, poly-ethylene glycol, poly-ornithine, poly-arginine and poly-histidine. Preferably, the polymer(s) conjugated to the molecules are chosen from poly-L-lysine, poly-ethylene glycol, poly-L-ornithine, poly-L-arginine and poly-L-histidine. According to one embodiment, it is poly-lysine, preferably poly-L-lysine. Preferably, the poly-lysine used is an epsilon poly-L-lysine with a molecular weight of between 12,000 and 20,000 Da. Thus, according to one variant, the active principle P1 is made up of: - 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, and - optionally at least one pharmaceutically acceptable excipient. In this variant, the poly-L-Lysine may be replaced by another poly-lysine or by polyethylene glycol, poly-L-ornithine, poly-L-arginine or poly-L-histidine. According to another variant, the active ingredient P1 is exclusively made up of: - 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. According to one embodiment, the active ingredient P1 consists of the following molecules: - at least 0.72 mg / mL of Acetate-Poly-L-Lysine; - at least 1.5 mg / mL of Butyrate-Poly-L-Lysine; - at least 0.73 mg / mL of Lactate-Poly-L-Lysine; - at least 0.72 mg / mL Propionate-Poly-L-Lysine. The active ingredient Pl optionally comprises at least one pharmaceutically acceptable excipient chosen in particular to meet the pH and osmolarity of injectable solutions in humans or animals. This may be, for example, acids or bases to adjust the pH or NaC] to adjust the osmolarity. The active ingredient P1 can be in liquid or solid form. The solid form is preferably obtained from the liquid form, preferably by lyophilization. When the active ingredient P1 is in liquid form, it may comprise at least one pharmaceutically acceptable excipient, preferably a buffer, in particular water for injection and / or phosphate buffered saline (PBS). When the active ingredient P1 is in solid form, it may not comprise an excipient or it may comprise at least one pharmaceutically acceptable excipient resulting from the lyophilization of the liquid form, such as for example a dehydrated PBS buffer. Also, the invention also relates to a composition C1 comprising the active ingredient P1. Composition C1 may be in liquid form or in solid form. When in liquid form, composition C1 comprises at least water and the active ingredient P1. The solid form is preferably obtained from the liquid form, preferably by lyophilization. Composition C1 preferably comprises at least one pharmaceutically acceptable excipient chosen in particular to meet the pH and osmolarity of injectable solutions in humans or animals. This may be, for example, acids or bases to adjust the pH or NaC] to adjust the osmolarity. Composition C1 may be in liquid form or in solid form. The solid form is preferably obtained from the liquid form, preferably by lyophilization. When composition C1 is in liquid form, it may comprise at least one pharmaceutically acceptable excipient, preferably a buffer, in particular water for injection and / or phosphate buffered saline (PBS). When the composition is in solid form, it may comprise at least one pharmaceutically acceptable excipient resulting from the lyophilization of the liquid form, preferably a dehydrated PBS buffer. Composition C1 according to the invention is intended to be administered to humans or to an animal and is therefore in a form suitable for such administration. When it is in liquid form, it is preferably suitable for administration by subcutaneous or intravenous route, in particular by intravenous infusion, and it is packaged in suitable containers known to those skilled in the art for packaging this type of product. Composition C1 can also be administered in liquid form via a pump, such as insulin pumps. When it comes in solid form, it is preferentially suitable for administration: - by transcutaneous route and it is preferably formulated and packaged in the form of a patch, or - nasally in powder form, or - sublingually in powder or tablet form, or - by transmucosal route and it is preferably formulated and packaged in the form of a mucoadhesive tablet. Advantageously, composition Cl can be administered in a single dose, preferably in a single injection. Manufacturing process active ingredient P The active ingredient P1 according to the invention can be manufactured by any suitable process. If the molecules that constitute the active principle P1 are used as they are in a solvent, they can be mixed all together in said solvent. If the molecules in the active ingredient P1 are conjugated to polymers, the manufacturing process may comprise mixing in an aqueous solution the following compounds - 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. Advantageously, the amphiphilic nature of the components of the active ingredient makes the manufacturing process of the active ingredient P1 easily achievable. Preferably, the active ingredient PI can be lyophilized so as to be in solid form. inci if P2 The present invention also relates to an active principle P2 consisting of the following molecules: - laurine, - sperm - biotin, - co-enzyme Q10, - Glutathione, - alpha-tocopherol, and / or a salt and / or an ester and / or an anhydride of one or more of these molecules, and - optionally at least one pharmaceutically acceptable excipient. For all active molecules present in the active ingredient P2, when mentioned in the present application, these may be the molecules as such and / or a salt and / or an ester of these molecules and / or an anhydride. According to a variant, the active ingredient P2 according to the invention is constituted exclusively by the following molecules: - acetic acid, - butyric acid, -lactic acid, - propionic acid, and / or a salt and / or an ester and / or an anhydride of one or more of these molecules. According to another variant, the active ingredient P2 according to the invention consists exclusively of one or more pharmaceutically acceptable excipients, and of the following molecules: - acetic acid, - butyric acid, -lactic acid, - propionic acid, and / or a salt and / or an ester and / or an anhydride of one or more of these molecules. Preferably, the quantity of butyric acid in the active principle Pl is greater than that of each of the other molecules taken individually. According to one embodiment, all of the molecules constituting the active ingredient P2 have a mass ratio of 1 between them. That is to say that the quantity of each molecule constituting P2 is the same. The active ingredient P2 has a concentration of each of the following molecules: taurine, spermine, biotin, co-enzyme Q10, glutathione and alpha-tocopherol and / or a salt and / or an ester and / or an anhydride of one or more of these molecules is the same in the active ingredient P2. Preferably, each of the active molecules in the active ingredient P2 represents between 6 E-05 M and 18 E-05 M. According to one embodiment, to improve the solubility, efficacy and bioavailability of the molecules of the active ingredient P2, at least one of the molecules of the composition chosen from taurine, spermine, biotin, glutathione and alpha-tocopherol, the salts of these molecules, the esters of these molecules and the anhydrides of these molecules, is covalently conjugated to at least one molecule of a polymer chosen from poly-lysine, polyethylene glycol, poly-ornithine, poly-arginine and poly-histidine. Indeed, the molecules chosen from taurine, spermine, biotin, glutathione and alpha-tocopherol, the salts of these molecules, the esters of these molecules and the anhydrides of these molecules, are all covalently conjugatable with a polymer chosen from poly-lysine, poly-ethylene glycol, poly-ornithine, poly-arginine and poly-histidine, in particular by an amide, urea or carbamate bond. According to a particularly suitable variant, all the molecules chosen from taurine, spermine, biotin, glutathione and alpha-tocopherol, the salts of these molecules, the esters of these molecules and the anhydrides of these molecules, present in the active principle P2 according to the invention are covalently conjugated to at least one molecule of a polymer chosen from poly-lysine, polyethylene glycol, poly-ornithine, poly-arginine and poly-histidine. Among the set of molecules to be conjugated, one of them is highly hydrophobic (LogP values ​​greater than 1, preferably greater than 2 and preferably greater than 3) and chemically not suitable for covalent conjugation, due to the absence of reactive functional groups and due to chemical incompatibilities. This is coenzyme Q10. On the other hand, considering both the hydrophilic character of certain polymers (such as poly-lysine, polyethylene glycol, poly-ornithine, poly-arginine or poly-histidine) and the hydrophobic character of alpha-tocopherol suitable for covalent conjugation, according to the invention these particular conjugates behave as surfactants in aqueous solution.In this way, some of these conjugates (amphiphiles) act as polymeric micelles in aqueous media, generating a hydrophobic pocket, capable of encapsulating the hydrophobic coenzyme Q10, thus considerably improving their solubility and stability in aqueous solution. Co-enzyme Q10, and the esters, salts and anhydrides of co-enzyme Q10 cannot in fact bind covalently, cannot be conjugated, to a polymer chosen from poly-lysine, polyethylene glycol, poly-ornithine, poly-arginine and poly-histidine. Also, preferably co-enzyme Q10 and / or the esters and salts of co-enzyme Q10 are encapsulated in micelles. Thus, the active ingredient P2 preferably comprises micelles in which at least co-enzyme Q10 and / or esters and / or salts and / or anhydrides of co-enzyme Q10 are encapsulated. According to a particularly suitable embodiment, at least one of the micelles of the active principle P2 is formed by amphiphilic conjugates each consisting of at least one molecule covalently conjugated to a molecule of a polymer chosen from poly-lysine, polyethylene glycol, poly-ornithine, poly-arginine and poly-histidine. Even more preferably, as shown in [Fig. 1], at least one of the micelles 10 of the active principle P2 is formed by amphiphilic conjugates phiphiles each consisting of at least one molecule 14 chosen from taurine, biotin, glutathione, and alpha-tocopherol, the salts of these molecules, the esters of these molecules and the anhydrides of these molecules, covalently conjugated to a molecule of a polymer 12 chosen from poly-lysine, polyethylene glycol, poly-ornithine, poly-arginine and poly-histidine, thus encapsulating co-enzyme Q10 and / or esters and / or salts and / or anhydrides of co-enzyme Q10 16. Indeed, taurine, spermine, biotin, glutathione, and alpha-tocopherol, the salts of these molecules, the esters of these molecules and the anhydrides of these molecules, are hydrophobic and poly-L-lysine, polyethylene glycol, Poly-ornithine, poly-arginine or poly-histidine are hydrophilic polymers. Thus, the active principle P2 is preferentially made up of: - conjugates of taurine, spermine, biotin, glutathione, and alpha-tocopherol, salts of these molecules, esters of these molecules and / or anhydrides of these molecules, with poly-lysine, poly-ethylene glycol, poly-ornithine, poly-arginine or poly-histidine, and - micelles formed by at least one of these conjugates, said micelles encapsulating the coenzyme QI10. This configuration allows in particular: - to increase the half-life of the molecules of the active ingredient P2 in the body, - to target the tissues or cells on which the molecules of the active ingredient P2 must act, - to allow the molecules of the active ingredient P2 to pass the blood-brain barrier and penetrate into the cells - to increase the stability and bioavailability of the active ingredient. The effectiveness of the active ingredient P2 is therefore greater and it is possible to administer lower doses and reduce the acute or chronic toxicity of the active molecules contained in the composition. Preferably, the polymer(s) conjugated to the molecules are chosen from poly-L-lysine, poly-ethylene glycol, poly-L-ornithine, poly-L-arginine and poly-L-histidine. According to one embodiment, it is poly-lysine, preferably poly-L-lysine. Preferably, the poly-lysine used is a poly-L-lysine with a molecular weight of between 12,000 and 20,000 Da. Thus, according to one variant, the active principle P2 is made up of: - To. the following conjugates, each conjugate consisting of a molecule covalently linked to a poly-lysine: - one or more Taurine-Poly-L-Lysine conjugates - one or more Spermine-Poly-L-Lysine conjugates - one or more Alpha tocopherol-Poly-L-Lysine conjugates - one or more Biotinyl-Poly-L-Lysine conjugates - one or more Glutathione-Poly-L-Lysine conjugates, and B. Co-enzyme Q10, and / or an ester and / or a salt of Co-enzyme Q10, encapsulated in micelles, preferably in micelles formed by one or more of the conjugates listed in point A; and C. Optionally at least one pharmaceutically acceptable excipient. According to another variant, the active principle P2 is constituted exclusively by: - To. the following conjugates, each conjugate consisting of a molecule covalently linked to a poly-lysine: - one or more Taurine-Poly-L-Lysine conjugates - one or more Spermine-Poly-L-Lysine conjugates - one or more Alpha tocopherol-Poly-L-Lysine conjugates - one or more Biotinyl-Poly-L-Lysine conjugates - one or more Glutathione-Poly-L-Lysine conjugates, and B. Co-enzyme Q10, and / or an ester and / or a salt of Co-enzyme Q10, encapsulated in micelles, preferably in micelles formed by one or more of the conjugates listed in point A. In this composition, poly-L-Lysine may be replaced by another poly-lysine or by polyethylene glycol, poly-L-ornithine, poly-L-arginine or poly-L-histidine. According to one embodiment, the active ingredient P2 consists of the following molecules: - at least 0.86 mg / mL of Taurine-Poly-L-Lysine; - at least 0.86 mg / mL of Spermine-Poly-L-Lysine; - at least 0.86 mg / mL of Alpha tocopherol-Poly-L-Lysine; - at least 0.86 mg / mL of Biotinyl-Poly-L-Lysine; - at least 0.86 mg / mL of Glutathione-Poly-L-Lysine; and - at least 0.86 mg / mL of Coenzyme QI0. The active ingredient P2 optionally comprises pharmaceutically acceptable excipients chosen in particular to meet the pH and osmolarity of injectable solutions in humans or animals. These may be, for example, acids or bases to adjust the pH or NaC] to adjust the osmolarity. The active ingredient P2 can be in liquid or solid form. The solid form is preferably obtained from the liquid form, preferably by lyophilization. When the active ingredient P2 is in liquid form, it may comprise at least one pharmaceutically acceptable excipient, preferably a buffer, in particular water for injection and / or phosphate buffered saline (PBS). When the active ingredient P2 is in solid form, it may not comprise an excipient or it may comprise at least one pharmaceutically acceptable excipient resulting from the lyophilization of the liquid form, such as for example a dehydrated PBS buffer. Also, the invention also relates to a composition C2 comprising the active ingredient P2. Composition C2 according to the invention may be in liquid form or in solid form. When it is in liquid form, composition C2 comprises at least water and the active ingredient P2. The solid form is preferably obtained from the liquid form, preferably by lyophilization. Thus, when composition C2 in liquid form comprises micelles and is lyophilized in solid form, the micelles reform when composition C2 in solid form is again placed in an aqueous solution. Composition C2 may also comprise at least one pharmaceutically acceptable excipient. These excipients may be chosen in particular to meet the pH and osmolarity of injectable solutions in humans or animals. These may be, for example, acids or bases to adjust the pH or NaCl to adjust the osmolarity. Composition C2 may be in liquid form or in solid form. The solid form is preferably obtained from the liquid form, preferably by lyophilization. When composition C2 is in liquid form, it may comprise at least one pharmaceutically acceptable excipient, preferably a buffer, in particular water for injection and / or phosphate buffered saline (PBS). When the composition is in solid form, it may comprise at least one pharmaceutically acceptable excipient resulting from the lyophilization of the liquid form, preferably a dehydrated PBS buffer. Composition C2 according to the invention is intended to be administered to humans or animals and is therefore in a form suitable for such administration. When it is in liquid form, it is preferably suitable for administration by subcutaneous or intravenous route, in particular by intravenous infusion, and it is packaged in suitable containers known to those skilled in the art for packaging this type of product. Composition C2 can also be administered in liquid form via a pump, such as insulin pumps. When it comes in solid form, it is preferentially suitable for administration: - by transcutaneous route and it is preferably formulated and packaged in the form of a patch, or - nasally in powder form, or - sublingually in powder or tablet form, or - by transmucosal route and it is preferably formulated and packaged in the form of a mucoadhesive tablet. Advantageously, composition C2 can be administered in a single dose, preferably in a single injection. According to a particularly preferred variant, the invention relates to a composition C3 comprising the active principle P1 and the active principle P2 and optionally one or more excipients. Manufacturing process of the active ingredient P2 The active ingredient P2 according to the invention can be manufactured by any suitable process. If the molecules that constitute the active principle P2 are used as they are in a solvent, they can be mixed all together in said solvent. If the molecules in the active ingredient P2 are conjugated to polymers for some part and in micelles for others, the manufacturing process can include the following steps: - to create an amphiphilic premix: mix in an aqueous solution one or more conjugates chosen from: - one or more Taurine-Poly-L-Lysine conjugates - one or more Spermine-Poly-L-Lysine conjugates - one or more Alpha tocopherol-Poly-L-Lysine conjugates - one or more Biotinyl-Poly-L-Lysine conjugates - one or more Glutathione-Poly-L-Lysine conjugates - b. adding at least co-enzyme Q10 to the amphiphilic premix, and stirring to form micelles formed by one or more of the conjugates of the amphiphilic premix encapsulating co-enzyme Q10. Indeed, a variant of the invention consists in taking advantage of the amphiphilic nature of most of the individual components, to create an amphiphilic premix which allows the controlled solubilization of the hydrophobic co-enzyme Q10. The solubilization process according to a preferred embodiment consists of a controlled addition of the hydrophobic molecules to the amphiphilic premixes and allowing the necessary time for their dissolution under stirring. Poly-L-lysine can be replaced by another poly-lysine or by polyethylene glycol, poly-L-ornithine, poly-L-arginine or poly-L-histidine. Preferably, the stirring is carried out for at least 5 minutes, even more preferably between 5 and 20 minutes, and preferably at a stirring speed less than or equal to 900 revolutions per minute, in particular at a stirring speed of between 50 and 800 revolutions per minute. According to a preferred embodiment, the manufacturing process according to the invention also comprises a step c. of separation of the soluble and insoluble phases, to recover the soluble phase. In this case the insoluble phase is eliminated and the soluble phase constitutes the active ingredient P2 according to the invention. Indeed, a physical separation process (filtration, ultrafiltration) is preferentially carried out to ensure the isolation of the soluble fraction, containing both the amphiphilic premix, the copolymers and the solubilized molecules. The active ingredient P2 in liquid form can then be lyophilized or dehydrated to be in solid form, preferably by slow lyophilization for example between 12 and 36 hours. Furthermore, if molecule-polymer conjugates of the active ingredient P2 are not integrated into the premix of step a, these can be added to the mixture after step b, i.e. after the formation of the micelles and the encapsulation of the co-enzyme Q10. Active molecule-polymer conjugates can be manufactured by any means known to those skilled in the art for covalently conjugating a molecule to a polymer depending on their chemical nature. Thus: - spermine and taurine are conjugated to a polymer by a urea bond. - glutathione, biotin, alpha tocopherol are conjugated to a polymer by an amide bond. Examples of the production of urea and carbamate bonds are described for example in: - Zhuxian Z, Jianbin T, Qihang S, William J. À multifunctional PEG-PLL drug conjugate forming redox-responsive nanoparticles for intracellular drug delivery Issue 38, 2015. Journal of Materials Chemistry B (amide bonds), - Scheper V, Wolf M, Scholl M, Kadlecova Z, Perrier T, Klok HA, Saulnier P, Lenarz T, Stôver T. Potential novel drug carriers for inner ear treatment: hyper-branched polylysine and lipid nanocapsules. Nanomedicine (Lond). 2009 Aug:4(6):623-35 (urea bonds), - Stéphanie Gac-Breton, Jean Coudane, Mahfoud Boustta & Michel Vert (2004) Norfloxacin-Poly(-Lysine Citramide Imide) Conjugates and Structure-dependence of the Drug Release, Journal of Drug Targeting, 12:5, 297-307, (carbamate bonds), -Elmore, W.M. (2013). Nanoparticles Stabilized with MPEG-Polylysine Carbamate: Synthesis and Characterization, (carbamate bonds), - Ning-Ping Huang, Janos Vôrôs, 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 (carbamate bonds). Use of the active ingredient P1 The invention also relates to the active ingredient P1 for its use as a medicament, in particular for preventing and / or treating multifactorial diseases, in particular chronic multifactorial diseases, and in particular diseases involving intestinal permeability. The active ingredient P1 is capable of acting in a combined manner: - as a cellular synergistic substrate, in particular thanks to the presence of butyrate, - to regulate the mucous membranes and intestinal flora, in particular thanks to the presence of acetate, lactate, propionate and butyrate The different molecules present act in synergy and in particular help to restore the function of intestinal permeability. Advantageously, the presence of these 4 short-chain fatty acids is sufficient to restore the function of intestinal permeability. Thus, the active ingredient P1 can be used to restore the function of the intestinal membrane and / or to maintain intestinal permeability and / or prevent or combat hyperpermeability of the intestinal mucosa. According to one variant, the invention relates to the use of the active ingredient Pl as a food supplement in a healthy person or a healthy animal, in particular to reduce the intestinal permeability of the person or animal for whom it is intended. The intestine therefore plays a key role as an initiator and regulator of the chronicity of diseases. Thus, the active ingredient Pl can be administered to humans or animals to prevent or combat diseases in which the intestine plays an important role, including chronic diseases, and in particular chronic degenerative diseases, such as neurodegenerative diseases such as, for example, Lou Gehrig's disease. The active ingredient P1 can also be used as an activator of the immune system to prevent or combat autoimmune and infectious diseases. The active ingredient P1 can be used in particular to reduce the chronicity of chronic diseases. Preferably, the active ingredient P1 is used for prevention or treatment from the first symptoms of intestinal hyperpermeability or a chronic disease, so as to prevent the development of the chronicity of said disease and thus avoid the inflammatory storm which results from prolonged intestinal hyperpermeability. Specifically, the active ingredient P1 is particularly useful for at least: - reduce the inflammatory process, and / or - reduce the autoimmune process, and / or - reduce intestinal permeability. In particular, the invention relates to an active ingredient P1 for its use in the prevention and / or treatment of a multifactorial pathology, in particular a chronic multifactorial pathology, in particular a pathology chosen from inflammatory diseases, neurodegenerative diseases, bacterial diseases, viral diseases, autoimmune diseases, food allergies and intolerances. According to a particular embodiment, the invention relates to an active ingredient P1 for its use in the prevention and / or treatment of a pathology chosen from eczema, psoriasis, chronic inflammatory intestinal diseases (in particular Crohn's disease and Celiac disease), Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot's disease. According to one embodiment, the active ingredient P1 is administered in a single dose, preferably a single injection. The invention therefore also relates to a composition C1 comprising the active ingredient P1 according to the invention for its use as a medicament, in particular in humans or animals, i.e. for a human or animal subject. In particular, the invention relates to a composition Cl for its use in the prevention and / or treatment of a multifactorial pathology, in particular a chronic multifactorial pathology, in particular a pathology chosen from inflammatory diseases, neurodegenerative diseases, bacterial diseases, viral diseases, autoimmune diseases, food allergies and intolerances. According to a particular embodiment, the invention relates to a composition C1 for its use in the prevention and / or treatment of a pathology chosen from eczema, psoriasis, chronic inflammatory intestinal diseases (in particular Crohn's disease and Celiac disease), Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot's disease. According to one embodiment, composition C1 is administered in a single dose, preferably a single injection. Composition C1 can be used alone or with one or more other compositions. According to another embodiment, composition C1 is preferentially used with a composition C2. Compositions C1 and C2 can also be used alone or in combination to treat or prevent diseases associated with pathological dysbiosis of the mi- intestinal microbiota. In particular, compositions C1 and C2 can be used alone or in combination to prevent or treat: - a neurodegenerative disease associated with pathological dysbiosis of the intestinal microbiota, for example a disease selected from amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, and Alzheimer's disease; - an intestinal disease associated with pathological dysbiosis of the intestinal microbiota, for example a disease selected from Crohn's disease, chronic inflammatory bowel diseases, ulcerative colitis, irritable bowel syndrome, ulcerative colitis, rheumatoid arthritis and food intolerance, in particular gluten intolerance. According to another embodiment, the active ingredient P1 is used in combination with the active ingredient P2 in a composition C3. Advantageously, composition C3 can be administered in a single dose, preferably a single injection. Utilisati active ingredient P2 The invention also relates to the active ingredient P2 for its use as a medicament, in particular for preventing and / or treating multifactorial diseases, in particular chronic multifactorial diseases, and in particular the treatment of neurodegenerative, autoimmune, infectious diseases or cancers. In particular, it is highly effective in the prevention and treatment of Charcot's disease. The active ingredient P2 acts on the classic processes known to reduce the chronicity of diseases. Its action is particularly suited to neurodegenerative, autoimmune, cancer and infectious diseases. In particular, it is capable of acting in a combined manner: - as a neuroprotectant, in particular thanks to the presence of taurine and co-enzyme Q10 - as an anti-inflammatory, in particular thanks to the presence of spermine, - as a cellular protector, in particular thanks to the presence of co-enzyme Q10 (protection in particular at the level of the mitochondrial chain) - as a protector of cell membranes, in particular thanks to the presence of alpha-tocopherol, - as an antioxidant, in particular thanks to the presence of taurine, spermine, alpha-tocopherol, co-enzyme Q10 and glutathione - on the stabilization of cell membranes, - as a scavenger of free radicals and metals, in particular thanks to the presence of taurine, spermine, co-enzyme Q10 and glutathione. The different molecules present act in synergy and in particular make it possible to prevent or combat the factors causing chronic diseases and in particular particular of Charcot's disease. Thus, the active ingredient P2 can be used to prevent and / or combat chronic diseases, particularly to act on the specific metabolisms of the pathology. The active ingredient P2 can be used in particular to reduce the chronicity of chronic diseases. Preferably, the active ingredient P2 is used for prevention or treatment from the first symptoms of a chronic disease, in particular a neurodegenerative disease and specifically Charcot's disease. According to one embodiment, the active ingredient P1 is administered in a single dose, preferably a single injection. The invention therefore also relates to a composition C2 comprising the active ingredient P2 according to the invention for its use as a medicament, in particular in humans or animals, that is to say for a human or animal subject. In particular, the subject of the invention is a composition C2 for its use in the prevention and / or treatment of a multifactorial pathology, in particular a chronic multifactorial pathology, in particular a pathology chosen from inflammatory diseases, neurodegenerative diseases, bacterial diseases, viral diseases, autoimmune diseases, food allergies and intolerances, and in particular Charcot's disease. According to a particular embodiment, the invention relates to a composition C2 for its use in the prevention and / or treatment of a pathology chosen from eczema, psoriasis, chronic inflammatory intestinal diseases (in particular Crohn's disease and Celiac disease), Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot's disease. According to one embodiment, composition C2 is administered in a single dose, preferably a single injection. Composition C2 is very preferentially used with composition C1. A particular subject of the invention is therefore composition C1 for its use with composition C2 as a medicament, in particular in the prevention and / or treatment of a multifactorial pathology, in particular a chronic multifactorial pathology, in particular a pathology chosen from inflammatory diseases, neurodegenerative diseases, bacterial diseases, viral diseases, autoimmune diseases, food allergies and intolerances, and in particular in the prevention and / or treatment of a pathology chosen from eczema, psoriasis, Crohn's disease, celiac disease, chronic inflammatory bowel diseases, Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot's disease. This use as a medicine of composition C1 and composition C2 is simultaneous, in a single administration, preferably a single injection. Composition C3 Also, the invention also relates to a composition C3 comprising the active ingredient P1 and the active ingredient P2. The composition C3 according to the invention may be in liquid form or in solid form. When it is in liquid form, the composition C3 comprises at least water and the active ingredients P1 and P2. The solid form is preferably obtained from the liquid form, preferably by lyophilization. Thus, when the composition C3 in liquid form comprises micelles and is lyophilized in solid form, the micelles reform when the composition C3 in solid form is again placed in an aqueous solution. Composition C3 can be obtained by mixing active ingredient P1 and active ingredient P2. Composition C3 may also comprise at least one pharmaceutically acceptable excipient. These excipients may be chosen in particular to meet the pH and osmolarity of injectable solutions in humans or animals. These may be, for example, acids or bases to adjust the pH or NaCl to adjust the osmolarity. Composition C3 may be in liquid form or in solid form. The solid form is preferably obtained from the liquid form, preferably by lyophilization. When composition C3 is in liquid form, it may comprise at least one pharmaceutically acceptable excipient, preferably a buffer, in particular water for injection and / or phosphate buffered saline (PBS). When the composition is in solid form, it may comprise at least one pharmaceutically acceptable excipient resulting from the lyophilization of the liquid form, preferably a dehydrated PBS buffer. The composition C3 according to the invention is intended to be administered to humans or to an animal and is therefore in a form suitable for such administration. When it is in liquid form, it is preferably suitable for administration by subcutaneous or intravenous route, in particular by intravenous infusion, and it is packaged in suitable containers known to those skilled in the art for packaging this type of product. The composition C3 can also be administered in liquid form via a pump, such as insulin pumps. When it comes in solid form, it is preferentially suitable for administration: - by transcutaneous route and it is preferentially formulated and packaged under in the form of a patch, or - nasally in powder form, or - sublingually in powder or tablet form, or - by transmucosal route and it is preferably formulated and packaged in the form of a mucoadhesive tablet. Advantageously, composition C3 can be administered in a single dose, preferably in a single injection. According to a particularly preferred variant, the invention relates to a composition C3 comprising the active principle P1 and the active principle P2 and optionally one or more excipients. The invention also relates to a composition C3 comprising the active ingredient P1 and the active ingredient P2 according to the invention for its use as a medicament, in particular in humans or animals, that is to say for a human or animal subject. In particular, the subject of the invention is a composition C3 for its use in the prevention and / or treatment of a multifactorial pathology, in particular a chronic multifactorial pathology, in particular a pathology chosen from inflammatory diseases, neurodegenerative diseases, bacterial diseases, viral diseases, autoimmune diseases, food allergies and intolerances, and in particular Charcot's disease. According to a particular embodiment, the invention relates to a composition C3 for its use in the prevention and / or treatment of a pathology chosen from eczema, psoriasis, chronic inflammatory intestinal diseases (in particular Crohn's disease and Celiac disease), Alzheimer's disease, Parkinson's disease, multiple sclerosis, Charcot's disease. According to one embodiment, composition C3 is administered in a single dose, preferably a single injection. Composition C3 can also be used to treat or prevent diseases associated with pathological dysbiosis of the intestinal microbiota. In particular, composition C3 can be used to prevent or treat: - a neurodegenerative disease associated with pathological dysbiosis of the intestinal microbiota, for example a disease chosen from amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, and Alzheimer's disease; - an intestinal disease associated with pathological dysbiosis of the intestinal microbiota, for example a disease chosen from Crohn's disease, chronic inflammatory bowel diseases, ulcerative colitis, irritable bowel syndrome, ulcerative colitis, rheumatoid arthritis and food intolerance, in particular gluten intolerance.

Claims

Claims

1. Active ingredient consisting of the following molecules: - Acetic acid - Butyric Acid - Lactic acid - Propionic acid and / or a salt and / or an ester and / or an anhydride of one or more of these molecules, and - optionally at least one pharmaceutically ac- acceptable.

2. Active ingredient according to the preceding claim, characterized in that at at least one of the molecules of the composition chosen from the acid acetic acid, butyric acid, lactic acid, propionic acid, salts of these acids, the esters of these acids and the anhydrides of these acids, is covalently conjugated to at least one molecule of a polymer selected from poly-lysine, poly-ethylene glycol, poly-ornithine, poly-arginine and poly-histidine.

3. Active ingredient according to the preceding claim, characterized in that the poly-lysine is a poly-L-lysine with a molecular weight between 12,000 and 20,000 Da.

4. Composition comprising an active ingredient according to one of the claims- indications 1 to 3.

5. Composition according to the preceding claim, characterized in that whether it is in liquid form or in solid form.

6. Composition according to one of claims 4 or 5, characterized in that it also includes at least one pharmaceutically acceptable excipient acceptable.

7. Method of manufacturing an active ingredient according to one of the claims 1 to 3, characterized in that it comprises the mixture in a solution aqueous of the following compounds: - 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.

8. Active ingredient according to one of claims 1 to 3 or composition according to one of claims 4 or 6, for its use as a me- medicine.

9. Active ingredient according to one of claims 1 to 3 or composition according to one of claims 4 to 6, for its use in the prevention and / or the treatment of a pathology chosen from inflammatory diseases- matoriums, neurodegenerative diseases, bacterial diseases, viral diseases, autoimmune diseases, allergies and into- food sensitivities.

10. Active ingredient according to one of claims 1 to 3 or composition according to one of claims 4 to 6, for its use in the prevention and / or the treatment of a pathology chosen from eczema, psoriasis, inflammatory bowel disease, disease Alzheimer's, Parkinson's disease, multiple sclerosis, disease of Charcot.

11. Active ingredient according to one of claims 1 to 3 or composition according to one of claims 4 to 6 for its use according to one of the res- indications 8 to 10, associated with the use of a second active ingredient made up of the following molecules: - taurine, - spermine - biotin, - co-enzyme Q10, - Glutathione, - alpha-tocopherol and / or a salt and / or an ester and / or an anhydride of one or more of these molecules; and -- optionally at least one pharmaceutically ac- acceptable.

12. Active ingredient according to one of claims 1 to 3 or composition according to one of claims 4 to 6 for its use according to claim 11, characterized in that in the second active ingredient at least one molecules of the composition chosen from taurine, spermine, biotin and glutathione, the salts of these molecules, the esters of these molecules, and the anhydrides of these molecules, is conjugated with covalently to a molecule of a polymer chosen from poly- lysine, polyethylene glycol, polyornithine, polyarginine and polyhistidine.

13. Active ingredient according to one of claims 1 to 3 or composition according to one of claims 4 to 6 for its use according to one of the res- indications 11 or 12, characterized in that in the second principle active coenzyme Q10 is encapsulated in micelles.

14. Active ingredient according to one of claims 1 to 3 or composition according to one of claims 4 or 5 for its use according to the resale- dication 13, characterized in that at least one micelle of the second active ingredient is formed by amphiphilic conjugates consisting each by at least one molecule covalently conjugated to a molecule of a polymer chosen from poly-lysine, poly- ethylene glycol, poly-ornithine, poly-arginine and poly-histidine.

15. Active ingredient according to one of claims 1 to 3 or composition according to one of claims 4 to 6 for its use according to claim 13 or 14, characterized in that at least one micelle of the second active ingredient is formed by amphiphilic conjugates consisting each by at least one molecule chosen from taurine, spermine, biotin, glutathione and alpha-tocopherol, the salts of these molecules, the esters of these molecules, and the anhydrides of these molecules, covalently conjugated to a molecule of a chosen polymer among poly-lysine, poly-ethylene glycol, poly-ornithine, poly- arginine and polyhistidine.

16. Active ingredient according to one of claims 1 to 3 or composition according to one of claims 4 or 5 for its use according to one of the re- claims 7 to 15, in the prevention and / or treatment of a pathological dysbiosis of the intestinal microbiota.

17. Active ingredient according to one of claims 1 to 3 or composition according to one of claims 4 to 6 for its use one of the res- indications 7 to 16, in the prevention and / or treatment of a disease of the intestine associated with pathological dysbiosis of the intestinal microbiota.

18. | Active ingredient according to one of claims 1 to 3 or composition according to one of claims 4 or 5 for its use one of the res- indications 7 to 17, in the prevention and / or treatment of the intestine chosen from Crohn's disease, inflammatory diseases chronic bowel disease, ulcerative colitis, syndrome of irritable bowel, ulcerative colitis, rheumatoid arthritis and gluten intolerance.