Active ingredients and their use for restoring intestinal permeability and / or preventing or combating multifactorial diseases - Patent Application 20070122999

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 compositions comprising said active ingredient, and to their use, in particular as medicines.

Description

[Technical Field]

[0001] The present invention relates to the prevention and / or treatment of multifactorial diseases. In particular, the present invention relates to active ingredients consisting of a plurality of selected specific molecules, compositions containing such active ingredients, and their use in reducing intestinal permeability and / or restoring normal intestinal permeability function and / or in preventing or combating various multifactorial diseases that affect intestinal permeability. [Background technology]

[0002] Most diseases, especially chronic diseases, are multifactorial: they always involve a genetic component as well as immunological and toxic components related to the "environment": bacteria, viruses, chemicals, etc.

[0003] Among the known multifactorial chronic diseases, particular mention may be made 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 progressive deterioration of one or more organs. Often, they are of genetic origin and can be induced by high and long-term exposure to biological and / or toxic products. Specifically, any bacterial components and / or other toxins that pass through the mucosa cause excessive activation of the immune system, which in patients suffering from chronic conditions constantly induces the stimulation of autoreactive clones that attack target tissues (degeneration). Therefore, degenerative diseases, like many infectious diseases, especially viral diseases, are closely related to intestinal hyperpermeability.

[0005] In the healthy human intestine, small particles (radius <4 Å) can move through the pores of claudins, the most important components of tight junctions, while particles up to 10–15 Å (3.5 LDa) can pass via the paracellular absorption pathway. The intestine normally has a certain degree of permeability, which allows nutrients to pass through the intestine while maintaining a barrier function to prevent potentially harmful substances from leaving the intestine and moving further into the body.

[0006] The gut microbiota continuously interacts with the intestinal immune system with which it is in contact. The interplay between the numerous antigens constituted by the gut microbiota and the intestinal immune system is extremely complex, but in a balanced body, this maintains an essential balance between the "immune background noise" - the bacteria of the microbiota and the immune system that regulates them.

[0007] An imbalanced bacterial flora, called dysbiosis, leads to an exacerbated response of the intestinal immune system, increased inflammation, and altered tight junctions. In response to the intestinal destruction of bacterial wall fragments (known as endotoxins) entering the systemic circulation, the body releases substantial amounts of inflammatory cytokines. If endotoxins are introduced in large quantities, this can induce septic shock, respiratory failure, renal ischemia, or cytokine storm. Blood endotoxin assays are also a reliable marker of intestinal hyperpermeability.

[0008] The causes of intestinal hyperpermeability are numerous. Any dysbiosis, a disruption of the intestinal biotope, leads to a response from the immune system with the release of inflammatory cytokines, resulting in an inflamed state of the small intestinal and colonic mucosa and epithelial changes. The causes of such dysbiosis include, inter alia: - stress (which greatly reduces the quantity and quality of all digestive secretions), - emotional and psychological impact, - Substantial strain or physical shock, - antibiotic treatment, - viral, bacterial or parasitic infections, -radiation - Toxic chemical agents: can be air pollution or water or food contamination; pesticides and heavy metals; drugs (statins, anti-inflammatories, immunosuppressants, etc.).

[0009] In addition to playing a role in inducing degenerative diseases in genetically predisposed patients, intestinal hyperpermeability is a cause of inflammatory, infectious and autoimmune diseases, as well as allergies and severe food intolerances.

[0010] Currently, the solutions proposed to prevent or combat dysbiosis essentially consist of administering probiotics and / or prebiotics, but their effectiveness is highly variable and depends on the underlying intestinal flora of the patient.

[0011] Furthermore, especially with regard to degenerative diseases, they are often very difficult for the patient. Although some symptoms may be alleviated, such diseases are never completely cured and currently there are no satisfactory treatments. Many chemical agents have therapeutic properties, but their toxicity, their lifespan, or their rapid elimination make them unsuitable for treating degenerative diseases.

[0012] Specifically, despite their multifactorial nature, current treatments only target one of the causative factors of these diseases and do not attempt to affect intestinal permeability.For example, amyotrophic lateral sclerosis is associated with a number of factors, particularly oxidative stress, mitochondrial dysfunction, neuroinflammation, excitotoxicity, oligodendrocyte dysfunction and degeneration, altered proteostasis, altered DNA repair system, altered nucleocytoplasmic RNA and RNA related to transport proteins, defects in axonal transport, and defects in vesicle transport.Currently, the recommended treatment for amyotrophic lateral sclerosis is Riluzole®, which only acts to inhibit glutamate release to counteract excitotoxicity, and does not consider its effect on intestinal permeability.The same observation can be made for other degenerative diseases.

[0013] Therefore, there is a need for an effective, non-toxic solution that is easy to administer and can act on a variety of factors to prevent and / or combat the effects of intestinal hyperpermeability and related multifactorial diseases, particularly degenerative, autoimmune, inflammatory or infectious diseases. Summary of the Invention

[0014] To address this need, the present invention simultaneously - Reduces inflammatory processes, - Reduces intestinal permeability, - Administered in a single dose, preferentially a single injection, and proposes an active ingredient P1 that rebalances the neurological metabolism that causes preferential degeneration of neurons and motor neurons.

[0015] The active ingredient P1 according to the invention may also be called composition P1 or even drug P1. Indeed, the invention is based on the combination of four specific acids.

[0016] To this end, the present invention provides the following molecule: -acetic acid, -butyric acid, -lactic acid, -propionic acid, and / or salts and / or esters and / or anhydrides of one or more of these molecules, and - for active ingredient P1 optionally consisting of at least one pharmaceutically acceptable excipient.

[0017] Advantageously, the molecules that make up the active ingredient P1 act together to restore the intestinal permeability function disrupted by an imbalanced microflora.

[0018] To enhance the efficacy and bioavailability of these molecules, they are preferentially conjugated to specific polymers.

[0019] The present invention also relates to a composition C1 comprising an active ingredient P1 according to the invention.

[0020] The present invention also relates to a method for producing the composition C1 according to the invention.

[0021] The active ingredient P1 and / or composition C1 according to the invention can be used alone as a medicament or in combination with the use of at least one other active ingredient and / or one other composition.

[0022] The present invention also provides the following molecule: -Taurine, -spermine, -biotin, -Coenzyme Q10, -Glutathione, -alpha-tocopherol, and / or salts and / or esters and / or anhydrides of one or more of these molecules, and - optionally relating to active ingredient P2 consisting of at least one pharmaceutically acceptable excipient.

[0023] The active ingredient P2 is advantageously - as a neuroprotective agent -As an anti-inflammatory agent - as a cytoprotective agent -As a protector of cell membranes -As an antioxidant -for stabilizing cell membranes, and -Can act in a combined manner as a free radical and metal scavenger.

[0024] To enhance the efficacy and bioavailability of these molecules, they are preferentially conjugated to specific polymers.

[0025] The present invention also relates to a composition C2 comprising an active ingredient P2 according to the invention.

[0026] The present invention also relates to a method for producing the composition C2 according to the invention.

[0027] The active ingredient P2 and / or composition C2 according to the invention can be used alone as a medicament or in combination with the use of at least one other active ingredient and / or one other composition.

[0028] Preferentially, active ingredient P1 can be used in combination with active ingredient P2 in composition C3.

[0029] Advantageously, composition C3 can be administered in a single dose, preferentially in a single injection.

[0030] Other features and advantages will become apparent from the following detailed description of the invention, the examples, and the drawings. [Brief explanation of the drawings]

[0031] [Figure 1] 1 shows a diagram of micelle formation according to one embodiment of the present invention: 10 = micelle, 12 = polymer (e.g., polylysine), 14 = covalently conjugated molecule (e.g., fatty acid), 16 = highly hydrophobic molecule (e.g., coenzyme Q10) that cannot be conjugated to polylysine. [Figure 2] 1 is a graphic representation of a comparative study of the cytotoxicity of the molecules present in the active ingredient P1 according to the invention. DETAILED DESCRIPTION OF THE INVENTION

[0032] Definition: For the purposes of the present invention, the term "animal" means any animal except humans.

[0033] For the purposes of the present invention, the term "amphiphilic conjugate" means a conjugate formed by a hydrophobic molecule X and a hydrophilic polymer Y, the conjugate therefore having amphiphilic characteristics.

[0034] For purposes of the present invention, "consisting of" or "consisting of" means that the composition or active ingredient is made up exclusively of the elements listed thereafter.

[0035] For the purposes of the present invention, the term "molecule X conjugated to polymer Y" means a molecule X that is covalently conjugated to polymer Y, which bond is preferably an amide, urea, or carbamate bond, depending on the chemical nature of molecule X and polymer Y. Preferentially, the covalent bond is directly between molecule X and polymer Y, without the intervention of another molecule such as a coupling agent.

[0036] For the purposes of this invention, a "pharmaceutically acceptable excipient" is an ingredient that does not impart therapeutic or prophylactic properties but may play a role in, inter alia, absorption, stability, its formulation, its taste or its appearance. Pharmaceutically acceptable excipients may include gelatin, starch, lactose, magnesium stearate, talc, gum arabic or similar, sweeteners, preservatives, flavoring agents, coloring agents, dispersing agents, wetting agents, suspending agents or diluents, buffers.

[0037] For the purposes of the present invention, a "single dose" or "single injection" means that the active ingredient or composition according to the invention is injected in a single administration. Preferentially, a single administration of the active ingredient or composition according to the invention is carried out once a day. Preferentially, the time between two administrations of the active ingredient or composition according to the invention is at least 24 hours.

[0038] Active ingredient P1 Thus, the present invention provides the following molecule: -acetic acid, -butyric acid, -lactic acid, -propionic acid, and / or salts and / or esters and / or anhydrides of one or more of these molecules, and - an active ingredient P1, optionally consisting of at least one pharmaceutically acceptable excipient. Surprisingly, the inventors have discovered that a particular combination of molecules constituting the 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.

[0039] For all of the active molecules present in the active ingredient P1, when they are mentioned in the present application, they may be the molecules themselves (e.g. butyric acid) and / or salts (e.g. butyrate) and / or esters and / or anhydrides (e.g. butyrate esters) of these molecules.

[0040] According to one variant, the active ingredient P1 according to the invention is a molecule: -acetic acid, -butyric acid, -lactic acid, -propionic acid, and / or consisting exclusively of salts and / or esters and / or anhydrides of one or more of these molecules.

[0041] According to another variant, the active ingredient P1 according to the invention is present in a mixture of one or more pharmaceutically acceptable excipients and the following molecules: -acetic acid, -butyric acid, -lactic acid, -propionic acid, and / or consisting exclusively of salts and / or esters and / or anhydrides of one or more of these molecules.

[0042] Preferably, the amount of butyric acid in the active ingredient P1 is greater than the amount of each of the other molecules taken individually.

[0043] 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 individually.

[0044] Preferentially, each of the active molecules in the active ingredient P1 represents between 0.5E-05M and 10E-05M.

[0045] According to one embodiment, in order to improve the solubility, efficacy and bioavailability of the molecules of active ingredient P1, at least one of the molecules of active ingredient P1 selected from acetic acid, butyric acid, lactic acid, propionic acid, salts of these acids, esters of these acids and anhydrides of these acids is covalently conjugated to at least one molecule of a polymer selected from polylysine, polyethylene glycol, polyornithine, polyarginine and polyhistidine.

[0046] Indeed, 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 covalently conjugated to polymers selected from polylysine, polyethylene glycol, polyornithine, polyarginine, and polyhistidine, in particular via amide, urea, or carbamate bonds.

[0047] According to a particularly preferred variant, all 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.

[0048] Preferentially, the one or more polymers conjugated to the molecule are chosen from among poly-L-lysine, polyethylene glycol, poly-L-ornithine, poly-L-arginine and poly-L-histidine.

[0049] According to one embodiment, the polymer is polylysine, preferentially poly-L-lysine. Preferentially, the polylysine used is epsilon poly-L-lysine with a molecular weight between 12,000 and 20,000 Da.

[0050] Thus, according to one variant, the active ingredient P1 is: 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 consisting of at least one pharmaceutically acceptable excipient.

[0051] In this variation, the poly-L-lysine may be replaced by another polylysine, or polyethylene glycol, poly-L-ornithine, poly-L-arginine, or poly-L-histidine.

[0052] According to another variant, the active ingredient P1 is: one or more acetate-poly-L-lysine conjugates, one or more butyrate-poly-L-lysine conjugates, one or more lactate-poly-L-lysine conjugates - exclusively from one or more propionate-poly-L-lysine conjugates.

[0053] According to one embodiment, the active ingredient P1 is the following molecule: 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 lactate-poly-L-lysine, - consisting of at least 0.72 mg / mL propionate-poly-L-lysine.

[0054] The active ingredient P1 optionally comprises at least one pharmaceutically acceptable excipient selected to suit the pH and osmolality of the injection solution, in particular in humans or animals, for example, they may be an acid or base to adjust the pH, or NaCl to adjust the osmolality.

[0055] The active ingredient P1 may be in liquid or solid form, the latter being preferentially obtained from the liquid form, preferentially by freeze-drying.

[0056] When the active ingredient P1 is in liquid form, it may contain at least one pharmaceutically acceptable excipient, preferentially a buffer, especially water for injection and / or phosphate-buffered saline (PBS).

[0057] When the active ingredient P1 is in solid form, it may be excipient-free or may contain at least one pharmaceutically acceptable excipient obtained, for example, from freeze-drying a liquid form such as dehydrated PBS buffer.

[0058] The present invention also relates to a composition C1 comprising the active ingredient P1.

[0059] Composition C1 can be in liquid or solid form. When in liquid form, composition C1 comprises at least water and active ingredient P1. The solid form is preferentially obtained from the liquid form, preferentially by lyophilization.

[0060] Composition C1 preferentially comprises at least one pharmaceutically acceptable excipient selected in particular to meet the pH and osmolality requirements of a solution for injection into humans or animals, for example, they may be an acid or a base to adjust the pH, or NaCl to adjust the osmolality.

[0061] Composition C1 can be in liquid or solid form, the latter being preferentially obtained from the liquid form, preferentially by lyophilization.

[0062] When composition C1 is in liquid form, it may comprise at least one pharmaceutically acceptable excipient, preferentially a buffer, especially water for injection and / or phosphate buffered saline (PBS).

[0063] When the composition is in solid form, it may comprise at least one pharmaceutically acceptable excipient obtained from freeze-drying a liquid form, preferentially dehydrated PBS buffer.

[0064] Composition C1 according to the present invention is intended to be administered to humans or animals, and is therefore in a form suitable for such administration.When in liquid form, it is preferably suitable for subcutaneous or intravenous administration, particularly intravenous infusion, and is packaged in a suitable container known to those skilled in the art for packaging such products.Composition C1 according to the present invention can also be administered in liquid form via a pump, such as an insulin pump.

[0065] If in solid form, preferentially: -preferentially formulated and packaged in the form of a patch and suitable for transdermal administration, or in powder form and suitable for nasal administration, or - in the form of a powder or tablet suitable for sublingual administration, or - Preferentially formulated and packaged in the form of mucoadhesive tablets, suitable for transmucosal administration.

[0066] Advantageously, composition C1 can be administered in a single dose, preferentially in a single injection.

[0067] According to one variant, composition C1 consists of active ingredient P1.

[0068] Process for preparing the active ingredient P1 The active ingredient P1 according to the invention can be prepared by any suitable method.

[0069] If the molecules that make up the active ingredient P1 are used as such in a solvent, they can all be mixed together in said solvent.

[0070] If the molecule in the active ingredient P1 is conjugated to a polymer, the preparation method may comprise 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.

[0071] Advantageously, the amphiphilic nature of the components of the active ingredient makes the process for preparing the active ingredient P1 easy to carry out.

[0072] Preferably, the active ingredient P1 can be lyophilized into a solid form.

[0073] Active ingredient P2 The present invention also provides the following molecule: -Taurine, -spermine, -biotin, -Coenzyme Q10, -Glutathione, -alpha-tocopherol, and / or salts and / or esters and / or anhydrides of one or more of these molecules, and - optionally relating to active ingredient P2 consisting of at least one pharmaceutically acceptable excipient.

[0074] For all of the active molecules present in the active ingredient P2, when they are mentioned in the present application, they may be the molecules themselves and / or the salts and / or esters and / or anhydrides of these molecules.

[0075] According to one variant, the active ingredient P2 according to the invention is the following molecule: -acetic acid, -butyric acid, -lactic acid, -propionic acid, and / or consisting exclusively of salts and / or esters and / or anhydrides of one or more of these molecules.

[0076] According to another variant, the active ingredient P2 according to the invention is present in the presence of one or more pharmaceutically acceptable excipients, as well as the following molecules: -acetic acid, -butyric acid, -lactic acid, -propionic acid, and / or consisting exclusively of salts and / or esters and / or anhydrides of one or more of these molecules.

[0077] Preferably, the amount of butyric acid in the active ingredient P1 is greater than the amount of each of the other molecules taken individually.

[0078] According to one embodiment, all molecules constituting the active ingredient P2 have a mass ratio to one another of 1. In other words, the amount of each molecule constituting P2 is the same.

[0079] Active ingredient P2 has a concentration of each of the following molecules: taurine, spermine, biotin, coenzyme Q10, glutathione and alpha-tocopherol, and / or salts and / or esters and / or anhydrides of one or more of these molecules are the same in active ingredient P2.

[0080] Preferentially, each of the active molecules in the active ingredient P2 represents between 6E-05M and 18E-05M.

[0081] According to one embodiment, in order to improve the solubility, efficacy and bioavailability of the molecules of the active ingredient P2, at least one of the molecules of the composition selected from taurine, spermine, biotin, glutathione and alpha-tocopherol, salts of these molecules, esters of these molecules and anhydrides of these molecules is covalently conjugated to at least one molecule of a polymer selected from polylysine, polyethylene glycol, polyornithine, polyarginine and polyhistidine.

[0082] Indeed, molecules selected from taurine, spermine, biotin, glutathione and alpha-tocopherol, salts of these molecules, esters of these molecules, and anhydrides of these molecules can all be covalently conjugated to polymers selected from polylysine, polyethylene glycol, polyornithine, polyarginine and polyhistidine, in particular via amide, urea, or carbamate bonds.

[0083] According to one particularly preferred variant, all of the molecules present in the active ingredient P2 according to the invention selected 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 covalently conjugated to at least one molecule of a polymer selected from polylysine, polyethylene glycol, polyornithine, polyarginine and polyhistidine.

[0084] Among all the conjugated molecules, one is highly hydrophobic (logP value greater than 1, preferentially greater than 2, preferentially greater than 3) and chemically unsuitable for covalent conjugation due to the absence of reactive functional groups and chemical incompatibility. This is coenzyme Q10. However, taking into account both the hydrophilic properties of certain polymers (e.g., polylysine, polyethylene glycol, polyornithine, polyarginine, or polyhistidine) and the hydrophobic properties of alpha-tocopherol, which are suitable for covalent conjugation, according to the present invention, these particular conjugates behave as surfactants in aqueous solution. Thus, some of these (amphiphilic) conjugates act as polymeric micelles in aqueous media, forming hydrophobic pockets that can encapsulate the hydrophobic coenzyme Q10, thus significantly improving its solubility and stability in aqueous solution.

[0085] Specifically, coenzyme Q10 and its esters, salts and anhydrides cannot be covalently bound to a polymer selected from polylysine, polyethylene glycol, polyornithine, polyarginine and polyhistidine, i.e., cannot be conjugated.Preferentially, coenzyme Q10 and / or coenzyme Q10 esters and salts are encapsulated in micelles.Therefore, active ingredient P2 preferably comprises micelles in which at least coenzyme Q10 and / or coenzyme Q10 esters and / or salts and / or anhydrides are encapsulated.

[0086] According to a particularly preferred embodiment, at least one of the micelles of the active ingredient P2 is formed by amphiphilic conjugates, each consisting of at least one molecule covalently conjugated to a molecule of a polymer selected from polylysine, polyethylene glycol, polyornithine, polyarginine, and polyhistidine. Even more preferentially, as shown in Figure 1, at least one of the micelles 10 of the active ingredient P2 is formed by amphiphilic conjugates, each consisting of at least one molecule 14 selected from taurine, biotin, glutathione, and alpha-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, thus encapsulating coenzyme Q10 and / or esters and / or salts and / or anhydrides of coenzyme Q10 16. Indeed, taurine, spermine, biotin, glutathione and alpha-tocopherol, salts of these molecules, esters of these molecules and anhydrides of these molecules are hydrophobic, while poly-L-lysine, polyethylene glycol, polyornithine, polyarginine or polyhistidine are hydrophilic polymers.

[0087] Thus, the active ingredient P2 is preferentially conjugates of taurine, spermine, biotin, glutathione and alpha-tocopherol with polylysine, polyethylene glycol, polyornithine, polyarginine or polyhistidine, salts of these molecules, esters of these molecules and / or anhydrides of these molecules, and - consisting of micelles formed by at least one of these conjugates, said micelles encapsulating Coenzyme Q10.

[0088] In particular, this configuration - increasing the half-life of the active ingredient P2 molecule in the body; - targeting the tissues or cells on which the molecules of the active ingredient P2 act; - allowing the active molecules of the active ingredient P2 to cross the blood-brain barrier and enter cells; -Enables to increase the stability and bioavailability of the active ingredient.

[0089] Thus, the effectiveness of the active ingredient P2 is enhanced, making it possible to administer lower doses and to reduce the acute or chronic toxicity of the active molecule contained in the composition.

[0090] Preferentially, the one or more polymers conjugated to the molecule are chosen from among poly-L-lysine, polyethylene glycol, poly-L-ornithine, poly-L-arginine and poly-L-histidine.

[0091] According to one embodiment, the polymer is polylysine, preferentially poly-L-lysine. Preferentially, the polylysine used is poly-L-lysine with a molecular weight between 12,000 and 20,000 Da.

[0092] Thus, according to one variant, the active ingredient P2 is selected from the group consisting of: A. the following conjugates, each consisting of a molecule covalently bound to polylysine: 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. Coenzyme Q10 and / or esters and / or salts of coenzyme Q10 encapsulated in micelles, preferentially micelles formed by one or more of the conjugates listed in paragraph A, and C. Optionally, at least one pharmaceutically acceptable excipient.

[0093] According to another variant, the active ingredient P2 is: A. The following conjugates, each consisting of a molecule covalently bound to polylysine: 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. Micelles, preferentially consisting exclusively of coenzyme Q10 and / or esters and / or salts of coenzyme Q10 encapsulated in micelles formed by one or more of the conjugates listed in section A.

[0094] In this composition, the poly-L-lysine may be replaced by another polylysine, or by polyethylene glycol, poly-L-ornithine, poly-L-arginine, or poly-L-histidine.

[0095] According to one embodiment, the active ingredient P2 is the following molecule: at least 0.86 mg / mL of taurine-poly-L-lysine, at least 0.86 mg / mL 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 -Consists of at least 0.86 mg / mL of coenzyme Q10.

[0096] The active ingredient P2 optionally comprises pharmaceutically acceptable excipients selected in particular to meet the pH and osmolality requirements of the solution for injection into humans or animals, for example, they can be acids or bases to adjust the pH, or NaCl to adjust the osmolality.

[0097] The active ingredient P2 may be in liquid or solid form, the latter being preferentially obtained from the liquid form, preferentially by freeze-drying.

[0098] When the active ingredient P2 is in liquid form, it may comprise at least one pharmaceutically acceptable excipient, preferentially a buffer, especially water for injection and / or phosphate buffered saline (PBS).

[0099] When the active ingredient P2 is in solid form, it may be excipient-free or may contain at least one pharmaceutically acceptable excipient obtained, for example, from freeze-drying a liquid form such as dehydrated PBS buffer.

[0100] The present invention also relates to a composition C2 comprising an active ingredient P2.

[0101] Composition C2 according to the present invention can be in solid or liquid form. When in liquid form, composition C2 contains at least water and active ingredient P2. The solid form is preferably obtained from the liquid form, preferably by lyophilization. Thus, when composition C2 in liquid form contains micelles and is lyophilized into a solid form, the micelles are reformed when composition C2 in solid form is returned to an aqueous solution.

[0102] Composition C2 may also contain at least one pharmaceutically acceptable excipient. The excipient may be selected to meet the pH and osmolality requirements of the solution for injection into humans or animals. For example, they may be an acid or base to adjust the pH, or NaCl to adjust the osmolality.

[0103] Composition C2 can be in liquid or solid form, the latter being preferentially obtained from the liquid form, preferentially by lyophilization.

[0104] When composition C2 is in liquid form, it may comprise at least one pharmaceutically acceptable excipient, preferentially a buffer, especially water for injection and / or phosphate buffered saline (PBS).

[0105] When the composition is in solid form, it may comprise at least one pharmaceutically acceptable excipient obtained from freeze-drying a liquid form, preferentially dehydrated PBS buffer.

[0106] 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 in liquid form, it is preferably suitable for subcutaneous or intravenous administration, particularly intravenous infusion, and is packaged in a suitable container known to those skilled in the art for packaging such products. Composition C2 according to the invention can also be administered in liquid form via a pump, such as an insulin pump.

[0107] If in solid form, preferentially -preferentially formulated and packaged in the form of a patch and suitable for transdermal administration, or in powder form and suitable for nasal administration, or - in the form of a powder or tablet suitable for sublingual administration, or - Preferentially formulated and packaged in the form of mucoadhesive tablets, suitable for transmucosal administration.

[0108] Advantageously, composition C2 can be administered in a single dose, preferentially in a single injection.

[0109] According to one variant, composition C2 consists of active ingredient P2.

[0110] According to another variant, the invention relates to a composition C3 comprising an active ingredient P1, an active ingredient P2 and, optionally, one or more excipients.

[0111] Process for preparing the active ingredient P2 The active ingredient P2 according to the invention can be prepared by any suitable method.

[0112] If the molecules that make up the active ingredient P2 are used as such in a solvent, they can all be mixed together in said solvent.

[0113] If the molecules in the active ingredient P2 are partly conjugated to a polymer and partly conjugated in micelles, the preparation method comprises the following steps: -a. Making an amphiphilic premix: mixing in an aqueous solution one or more conjugates selected 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 oleyl-poly-L-lysine conjugates, -b. adding at least Coenzyme Q10 to the amphiphilic premix and stirring to form micelles formed by one or more of the conjugates of the amphiphilic premix encapsulating Coenzyme Q10.

[0114] Specifically, one variant of the present invention utilizes the amphiphilic nature of most of the individual components to create an amphiphilic premix that allows controlled solubilization of hydrophobic coenzyme Q10. The solubilization process according to a preferred embodiment involves controlled addition of hydrophobic molecules to the amphiphilic premix and allowing the necessary time for their dissolution under stirring.

[0115] The poly-L-lysine can be replaced by another polylysine, or polyethylene glycol, poly-L-ornithine, poly-L-arginine, or poly-L-histidine.

[0116] Preferentially, stirring is carried out for at least 5 minutes, even more preferably between 5 and 20 minutes, and preferably at a stirring speed of up to 900 revolutions / min, in particular between 50 and 800 revolutions / min.

[0117] According to a preferred embodiment, the process according to the invention also comprises a step c. of separating the soluble and insoluble phases in order to recover the soluble phase, which in this case is removed and constitutes the active ingredient P2 according to the invention. In practice, a physical separation process (filtration, ultrafiltration) is preferentially carried out to ensure the isolation of a soluble fraction containing both the amphiphilic premix, the copolymer and the solubilizing molecule.

[0118] The active ingredient P2 in liquid form can then be freeze-dried or dehydrated to a solid form, preferably by slow freeze-drying for, for example, 12 to 36 hours.

[0119] 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, i.e., after the formation of micelles and the encapsulation of coenzyme Q10.

[0120] The active molecule-polymer conjugate can be prepared by any means known to those skilled in the art for covalently attaching a molecule to a polymer, depending on its chemical nature. -Spermine and taurine are conjugated to the polymer via urea bonds. -Glutathione, biotin and alpha-tocopherol are conjugated to the polymer via amide bonds.

[0121] Exemplary embodiments of urea and carbamate linkages are described, for example, below: -Zhuxian Z, Jianbin T, Qihang S, William JA multifunctional PEG-PLL drug conjugate forming redox-responsive nanoparticles for intracellular drug delivery, Issue 38, 2015. Journal of Materials Chemistry B (amide bond), -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).2009 Aug;4(6):623-35(urea bonds), -Stephanie Gac-Breton, Jean Coudane, Mahfoud Boustta & Michel Vert(2004)Norfloxacin-Poly(l-Lysine Citramide Imide)Conjugates and Structure-dependence of the Drug Release,Journal of Drug Targeting,12:5,297-307,(carbamate conjugation), -Elmore, WM(2013).Nanoparticles Stabilized with MPEG-Polylysine Carbamate: Synthesis and Characterization, (Carbamate Bond), -Ning-Ping Huang, Janos Voros, 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 bond).

[0122] Use of active ingredient P1 The present invention also relates to the active ingredient P1 for use as a medicament, in particular for the prevention and / or treatment of multifactorial diseases, especially chronic multifactorial diseases, in particular diseases affecting intestinal permeability.

[0123] The active ingredient P1 is -As a synergistic cell substrate, especially with the presence of butyrate - Particularly due to the presence of acetate, lactate, propionate and butyrate, they are able to act in a combined manner to modulate the mucous membranes and the intestinal flora.

[0124] The various molecules present act synergistically, making it possible to restore the function, in particular of intestinal permeability.

[0125] Advantageously, the presence of these four short chain fatty acids is sufficient to restore intestinal permeability function.

[0126] The active ingredient P1 can therefore be used to restore the function of the intestinal membrane and / or to maintain intestinal permeability and / or to prevent or counteract intestinal mucosal hyperpermeability.

[0127] According to one variant, the invention relates to the use of the active ingredient P1 as a dietary supplement in healthy humans or healthy animals, in particular to reduce intestinal permeability in the humans or animals to which it is given.

[0128] Therefore, intestine plays an important role in the initiation and regulation of the chronicity of disease.Therefore, active ingredient P1 can be administered to humans or animals to prevent or combat the diseases that intestine plays an important role, especially chronic diseases, especially degenerative chronic diseases, such as neurodegenerative diseases such as amyotrophic lateral sclerosis.Active ingredient P1 can also be used as an immune system activator to prevent or combat autoimmune disease and infectious disease.

[0129] The active ingredient P1 can be used in particular to reduce the chronicity of chronic diseases.

[0130] Preferentially, the active ingredient P1 is used in prophylaxis or therapy as soon as the first symptoms of intestinal hyperpermeability or chronic disease appear, in order to prevent the onset of chronicity of said disease and thus to prevent the cytokine storm resulting from long-term intestinal hyperpermeability.

[0131] In particular, the active ingredient P1 comprises at least: - reducing inflammatory processes, and / or -reducing autoimmune processes, and / or -Particularly useful in reducing intestinal permeability.

[0132] In particular, the present invention relates to the active ingredient P1 for use 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.

[0133] According to one particular embodiment, the present invention relates to the active ingredient P1 for use in the prevention and / or treatment of a disease selected from eczema, psoriasis, chronic inflammatory bowel diseases (in particular Crohn's disease and celiac disease), Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis.

[0134] According to one embodiment, the active ingredient P1 is administered in a single dose, preferentially in a single injection.

[0135] The present invention therefore also relates to a composition C1 comprising or consisting of an active ingredient P1 according to the invention, in particular for use as a medicine in humans or animals, ie for human or animal subjects.

[0136] In particular, the present invention relates to a composition C1 for use 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.

[0137] According to one particular embodiment, the present invention relates to composition C1 for use in the prevention and / or treatment of a disease selected from eczema, psoriasis, chronic inflammatory bowel diseases (in particular Crohn's disease and celiac disease), Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis.

[0138] According to one embodiment, composition C1 is administered in a single dose, preferentially in a single injection.

[0139] Composition C1 can be used alone or together with one or more other compositions.

[0140] According to another embodiment, composition C1 is preferentially used together with composition C2. Composition C2 comprising or consisting of active ingredient P2.

[0141] Compositions C1 and C2 can also be used, alone or in combination, to treat or prevent diseases associated with pathological dysbiosis of the intestinal microflora. In particular, compositions C1 and C2 can be used, alone or in combination, to prevent or treat: - neurodegenerative diseases associated with a pathological dysbiosis of the intestinal microbiota, for example a disease selected from amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease and Alzheimer's disease, Intestinal diseases associated with a pathological dysbiosis of the intestinal microflora, such as Crohn's disease, chronic inflammatory bowel disease, hemorrhagic proctocolitis, irritable bowel syndrome, ulcerative colitis, rheumatoid arthritis and food intolerance, in particular gluten intolerance.

[0142] According to another embodiment, the active ingredient P1 is used in combination with an active ingredient P2 in a composition C3. The composition C3 according to the invention comprises or consists of the active ingredient P1 and the active ingredient P2.

[0143] Advantageously, composition C3 can be administered in a single dose, preferentially in a single injection.

[0144] Use of the active ingredient P2 The present invention also relates to the active ingredient P2 for use as a medicine, particularly for the prevention and / or treatment of multifactorial diseases, especially chronic multifactorial diseases, in particular for the treatment of neurodegenerative diseases, autoimmune diseases, infectious diseases, or cancer. In particular, the active ingredient P2 is highly effective in the prevention and treatment of amyotrophic lateral sclerosis. The active ingredient P2 intervenes in conventionally known processes to reduce the chronicity of the disease. Its action is particularly suitable for neurodegenerative diseases, autoimmune diseases, cancer, and infectious diseases.

[0145] In particular, the active ingredient P2 as a neuroprotective agent, especially due to the presence of taurine and coenzyme Q10 -Anti-inflammatory agent, especially due to the presence of spermine - as a cytoprotective agent (especially at the level of mitochondrial chains), especially due to the presence of coenzyme Q10; - as a cell membrane protector, especially due to the presence of alpha-tocopherol as an antioxidant, especially due to the presence of taurine, spermine, alpha-tocopherol, coenzyme Q10 and glutathione; -For stabilizing cell membranes - The presence of taurine, spermine, coenzyme Q10 and glutathione in particular allows it to act in a combined manner as a scavenger of free radicals and metals.

[0146] The various molecules present act synergistically, making it possible to prevent or combat factors at the root of, among other things, chronic diseases, especially amyotrophic lateral sclerosis.

[0147] The active ingredient P2 can therefore be used to prevent and / or combat chronic diseases, in particular by acting on disease-specific metabolism, and in particular to reduce the chronicity of chronic diseases.

[0148] Preferentially, the active ingredient P2 is used for the prevention or treatment of chronic diseases, in particular neurodegenerative diseases, in particular amyotrophic lateral sclerosis, as soon as the first symptoms appear.

[0149] According to one embodiment, the active ingredient P1 is administered in a single dose, preferentially in a single injection.

[0150] The present invention therefore also relates to a composition C2 comprising or consisting of an active ingredient P2 according to the invention, in particular for use as a medicament in humans or animals, ie for human or animal subjects.

[0151] In particular, the present invention relates to composition C2 for use 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, in particular amyotrophic lateral sclerosis.

[0152] According to one particular embodiment, the present invention relates to composition C2 for use in the prevention and / or treatment of a disease selected from eczema, psoriasis, chronic inflammatory bowel disease (in particular Crohn's disease and celiac disease), Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis.

[0153] According to one embodiment, composition C2 is administered in a single dose, preferentially in a single injection. Composition C2 is very preferentially used together with composition C1.

[0154] One particular object of the present invention is therefore composition C1 for use together with composition C2 as a medicament, in particular in the prevention and / or treatment of multifactorial diseases, in particular chronic multifactorial diseases, especially diseases chosen from inflammatory diseases, neurodegenerative diseases, bacterial diseases, viral diseases, autoimmune diseases, allergies and food intolerances, and especially in the prevention and / or treatment of diseases chosen from eczema, psoriasis, Crohn's disease, celiac disease, chronic inflammatory bowel disease, Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis.

[0155] Composition C1 and composition C2 are used medicinally simultaneously in a single administration, preferentially a single injection.

[0156] Composition C3 The present invention also relates to a composition C3 comprising or consisting of active ingredients P1 and P2.

[0157] Composition C3 according to the present invention can be in solid or liquid form. In the liquid form, composition C3 contains at least water and active ingredients P1 and P2. The solid form is preferably obtained from the liquid form, preferably by lyophilization. Thus, if composition C3 in liquid form contains micelles and is lyophilized into a solid form, the micelles will be reformed when composition C3 in solid form is returned to an aqueous solution.

[0158] Composition C3 can be obtained by mixing active ingredient P1 with active ingredient P2.

[0159] Composition C3 may also contain at least one pharmaceutically acceptable excipient. The excipient may be selected to meet the pH and osmolality requirements of the solution for injection into humans or animals. For example, they may be an acid or base to adjust the pH, or NaCl to adjust the osmolality.

[0160] Composition C3 may be in liquid or solid form, the latter being preferentially obtained from the liquid form, preferentially by lyophilization.

[0161] When composition C3 is in liquid form, it may comprise at least one pharmaceutically acceptable excipient, preferentially a buffer, especially water for injection and / or phosphate buffered saline (PBS).

[0162] When the composition is in solid form, it may comprise at least one pharmaceutically acceptable excipient obtained from freeze-drying a liquid form, preferentially dehydrated PBS buffer.

[0163] Composition C3 according to the invention is intended to be administered to humans or animals and is therefore in a form suitable for such administration. When in liquid form, it is preferably suitable for subcutaneous or intravenous administration, particularly intravenous infusion, and 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.

[0164] If in solid form, preferentially -preferentially formulated and packaged in the form of a patch and suitable for transdermal administration, or in powder form and suitable for nasal administration, or - in the form of a powder or tablet suitable for sublingual administration, or - Preferentially formulated and packaged in the form of mucoadhesive tablets, suitable for transmucosal administration.

[0165] Advantageously, composition C3 can be administered in a single dose, preferentially in a single injection.

[0166] According to a particularly preferred variant, the present invention relates to a composition C3 comprising an active ingredient P1, an active ingredient P2 and, optionally, one or more excipients. The present invention also relates to a composition C3 comprising an active ingredient P1 and an active ingredient P2 according to the present invention, in particular for use as a medicament in humans or animals, i.e. for human or animal subjects.

[0167] In particular, the present invention relates to composition C3 for use 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, in particular amyotrophic lateral sclerosis.

[0168] According to one particular embodiment, the present invention relates to composition C3 for use in the prevention and / or treatment of a disease selected from eczema, psoriasis, chronic inflammatory bowel disease (in particular Crohn's disease and celiac disease), Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis.

[0169] According to one embodiment, composition C3 is administered in a single dose, preferentially in a single injection.

[0170] Composition C3 can also be used to treat or prevent diseases associated with pathological dysbiosis of the intestinal microflora. In particular, composition C3 can be used to prevent or treat: - neurodegenerative diseases associated with a pathological dysbiosis of the intestinal microbiota, for example a disease selected from amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease and Alzheimer's disease, Intestinal diseases associated with a pathological dysbiosis of the intestinal microflora, such as Crohn's disease, chronic inflammatory bowel disease, hemorrhagic proctocolitis, irritable bowel syndrome, ulcerative colitis, rheumatoid arthritis and food intolerance, in particular gluten intolerance.

[0171] Composition C4: According to one variant, the invention also relates to the following molecule: -acetic acid, -butyric acid, -lactic acid, -propionic acid, and / or salts and / or esters and / or anhydrides of one or more of these molecules, and - optionally relating to composition C4 consisting of at least one pharmaceutically acceptable excipient.

[0172] Advantageously, the embodiments described for active ingredient P1 can be replaced by composition C4. [Example]

[0173] Example 1: Analysis of the cytotoxicity of the active ingredients according to the invention on colon cells.

[0174] This example represents an analysis of the cytotoxicity of the active ingredients according to the invention on human epithelial cells of the colonic mucosa, namely CACO-2 cells.

[0175] These cells are one of the therapeutic targets for combating dysbiosis and restoring intestinal permeability.

[0176] Cytotoxicity tests are performed on three different plates, with each sample in triplicate per plate, to limit cell bias.

[0177] The concentrations tested follow a serial dilution starting from 1000 μg / mL down to 2 μg / mL.

[0178] The analysis and determination of the LD50 is carried out as the % survival from the OD obtained using the tetrazolium salt MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) after incubation with the molecules for 48 hours at 37°C and 5% CO2. a) Analysis of the cytotoxicity of each molecule present in the active ingredient according to the invention

[0179] Cytotoxicity tests were carried out to evaluate the cytotoxicity of each molecule present in the active ingredient according to the present invention, as well as the association of each molecule with poly-L-lysine. The results are shown in Table 1 below.

[0180] [Table 1]

[0181] The compounds exhibit lower cytotoxicity when combined with poly-L-lysine. b) Analysis of the cytotoxicity of different combinations of molecules present in the active ingredient according to the invention.

[0182] The results for the various combinations of molecules present in the active ingredient according to the invention are presented in Table 2 below.

[0183] [Table 2]

[0184] The active ingredient according to the invention exhibits the lowest toxicity compared to the various combinations of molecules considered.

[0185] A thorough analysis of all the results shows that the IC50 of the active ingredient according to the invention is in the range of 7.5 μg / mL to 12.8 μg / mL, close to the literature values ​​for polylysine.

[0186] These results, summarized in FIG. 1, show that the addition of the conjugate does not alter the inherent cytotoxicity of polylysine, nor the inter-molecular combinations present in the active ingredient according to the invention.

[0187] The LD50 in animal models is defined as 220 mg / kg to 273 mg / kg, according to extrapolation according to the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM).

[0188] Example 2: Evaluation of the effectiveness of composition C1 according to the invention.

[0189] A. Materials and Methods 1-Setting up the chronic inflammation model Upon arrival, animals (Wistar rats, 280–300 g) were placed in a 900 cm 2 Animals were housed in cages (3 animals per cage). During this acclimation period, animals had free access to water and food. After this period, animals (n=9) were given free access to a solution of 2, 3, or 4% (w / v) dextran sulfate sodium (DSS) in food and drinking water.

[0190] Oral ingestion of DSS induces inflammation in rats that leads to defects in intestinal permeability.

[0191] The induction of intestinal inflammation is monitored on days 3, 5 and 7 after the start of DSS addition. A control group (n=3) has free access to food and water.

[0192] These results indicate that the 2% concentration is optimal for inducing intestinal inflammation without causing animal death. Concentrations of 3% or 4% are not suitable for measuring intestinal permeability.

[0193] 2-Permeability test To determine the effectiveness of composition C1 according to the invention in restoring intestinal permeability, a permeability test is carried out on isolated organs (jejunum or colon).

[0194] a) Composition C1 according to the invention The composition C1 used in this example comprises the following elements: -1.17 g / L acetate-PLL, -1.88 g / L butyrate-PLL, -1.17 g / L lactate-PLL, -Contains 1.18g / L propionate-PLL.

[0195] b) Sampling of digestive tract fragments This ex vivo approach used fragments of jejunum or colon taken from the rat digestive tract.

[0196] The serosal and mucosal compartments of the organ were quickly rinsed with saline (37°C) and the organ was turned inside out. A ligation was performed on one of the ends. The second end allowed for the introduction of 1 mL of Krebs-Henseleit medium. This end was then ligated, the organ was weighed, and then placed in a container containing 10 mL of Krebs-Henseleit survival medium + 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 agitated by performing three suction-discharge cycles with a 1 mL micropipette. After a 2-hour incubation, a 1 mL sample was taken from the mucosal side.

[0197] The organ is removed from the glass container and one of the ends is cut. The serosal medium is sampled and placed in a pre-weighed tube. After sampling, the tube is weighed again to assess the movement of viability medium over the course of the experiment. After weighing, FITC-dextran is assayed in duplicate by fluorometry (excitation, 490 nm; emission, 530 nm).

[0198] After weighing the organs, they are cut longitudinally and rapidly frozen in liquid nitrogen. The frozen organs are then placed in ziplock bags, frozen in liquid nitrogen, and stored at -80°C.

[0199] B-Results a) In vivo approach For the implementation of this approach, the experiment was divided into three groups, namely: - FITC force-fed control group, - Two groups of rats force-fed with FITC+2% DSS and treated subcutaneously with composition C1 for 3 days.

[0200] Plasma samples were collected 10 days after DSS injection. The results of the FITC measurements are shown below.

[0201] [Table 3]

[0202] These results demonstrate that treatment of rats with composition C1 according to the invention restores intestinal permeability.

[0203] b) Ex vivo approach For the implementation of this approach, the experiment was also divided into three groups, i.e. - FITC force-fed control group, - Two groups of rats force-fed with FITC+2% DSS and treated subcutaneously with composition C1 for 3 days.

[0204] As described in the experimental section, the ex vivo approach was based on the use of ileal and jejunal fragments collected from rats belonging to the above three groups 10 days after the injection of DSS in the treatment group. Thus, samples were taken from the mucosal side every 30 minutes to measure FITC. The results are shown in the table below.

[0205] [Table 4]

[0206] These results demonstrate that treatment of rats with composition C1 according to the invention restores intestinal permeability.

Claims

1. The following molecule: -acetic acid, -butyric acid, - lactic acid, -propionic acid, and / or salts and / or esters and / or anhydrides of one or more of these molecules, and - an active ingredient optionally consisting of at least one pharmaceutically acceptable excipient, characterized in that at least one of said molecules of the composition selected from acetic acid, butyric acid, lactic acid, propionic acid, salts of these acids, esters of these acids, and 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. 2. The active ingredient according to claim 1, wherein the polylysine is poly-L-lysine having a molecular weight of 12,000 to 20,000 Da.

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

4. The composition according to claim 3, characterized in that the composition is in liquid or solid form.

5. 5. The composition according to claim 3 or 4, characterized in that the composition also comprises at least one pharmaceutically acceptable excipient.

6. A process for producing an active ingredient according to any one of claims 1 to 2, comprising the following compound: one or more acetate-poly-L-lysine conjugates, one or more butyrate-poly-L-lysine conjugates, one or more lactate-poly-L-lysine conjugates - mixing one or more propionate-poly-L-lysine conjugates in an aqueous solution.

7. An active ingredient according to any one of claims 1 to 2 or a composition according to any one of claims 3 to 5 for use as a medicine.

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

9. 6. The active ingredient according to any one of claims 1 to 2 or the composition according to any one of claims 3 to 5 for use in the prevention and / or treatment of a disease 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 any one of claims 1 to 2 or the composition according to any one of claims 3 to 5, for the use according to any one of claims 7 to 9, characterized in that the composition is administered in a single dose.

11. The following molecule: - taurine, -spermine, -biotin, - coenzyme Q10, - glutathione, - alpha-tocopherol, and / or salts and / or esters and / or anhydrides of one or more of these molecules, and optionally at least one pharmaceutically acceptable excipient, The active ingredient according to any one of claims 1 to 2 or the composition according to any one of claims 4 to 6, for the use according to any one of claims 7 to 10 in conjunction with the use of a second active ingredient consisting of

12. 12. The active ingredient according to claim 1 or the composition according to claim 3, for use according to claim 11, characterized in that in the second active ingredient, at least one of the molecules of the composition selected from taurine, spermine, biotin and glutathione, salts of these molecules, esters of these molecules and 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 any one of claims 1 to 2 or the composition according to any one of claims 3 to 5, for use according to any one of claims 11 or 12, characterized in that in the second active ingredient, the coenzyme Q10 is encapsulated in a micelle.

14. 14. The active ingredient according to any one of claims 1 to 2 or the composition according to any one of claims 3 or 4, for use according to claim 13, characterized in that at least one micelle of the second active ingredient is formed by amphiphilic conjugates, each consisting of at least one molecule covalently conjugated to a molecule of a polymer selected from polylysine, polyethylene glycol, polyornithine, polyarginine and polyhistidine.

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

16. 16. An active ingredient according to any one of claims 1 to 2 or a composition according to any one of claims 3 or 4 for use according to any one of claims 6 to 15 in the prevention and / or treatment of pathological dysbiosis of the intestinal microflora.

17. 18. The active ingredient according to any one of claims 1 to 2 or the composition according to any one of claims 3 to 5 for use according to any one of claims 7 to 17 in the prevention and / or treatment of intestinal diseases associated with pathological dysbiosis of the intestinal microflora.

18. 18. The active ingredient according to any one of claims 1 to 2 or the composition according to any one of claims 3 to 4 for use according to any one of claims 6 to 17 in the prevention and / or treatment of intestinal diseases 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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