WO2014166999A1

WO2014166999A1 - Solid-state composition comprising a hypoiodite salt

Info

Publication number: WO2014166999A1
Application number: PCT/EP2014/057160
Authority: WO
Inventors: Philippe Bordeau; Catherine David
Original assignee: Alaxia Sas; Stragen Pharma Sa
Priority date: 2013-04-09
Filing date: 2014-04-09
Publication date: 2014-10-16

Abstract

The present invention concerns a solid composition comprising at least one hypoiodite salt OI^- associated with a cation and/or the associated form of same, hypoiodous acid HOI, said solid composition being in the form of an amorphous and/or crystalline powder. The invention also concerns the method of producing said solid composition and the use of same.

Description

Solid state composition comprising a hypoiodite salt

FIELD OF THE INVENTION The subject of the present invention is a solid and stable composition comprising at least one cation-associated hypoiodite salt 01 ^' and / or its associated form HOI hypoiodite acid, said solid composition being in the form of An amorphous and / or crystalline powder The invention also relates to the method of manufacturing said composition and its use.

BACKGROUND OF THE INVENTION

The agri-food and pharmaceutical industry show a strong interest in hypoiodite as a bactericidal ion. The iodine ion I ^" is oxidized to hypoiodite and hypoiodous acid according to the equation below:

oxidation

Γ + H ⁺ HOI

Hypoiodite and its hypoiodous acid form are relatively unknown compounds. It is known that the lactoperoxidase system, as well as myeloperoxidase, horseradish peroxidase (HRP horseradish peroxidase) and eosinophil peroxidase can, in the presence of iodides and hydrogen peroxide, generate them in vivo according to the following reaction:

Enzyme (lactoperoxidase)

Nal + H ₂ 0 ₂ ^ 01

These compounds, of unknown toxicity, are highly active on a large number of microorganisms including molds. In addition, hypoiodite compositions with or without enzymes for treating plants (WO 99/22597 Koppert) are developed, which composition may also comprise hypothiocyanites.

A number of publications, highlight the effectiveness of hypoiodite, as a rule with the complete lactoperoxidase system ("The lactoperoxidase System: the influence of iodide and the chemical and antimicrobial stability over the period of about 18 months, EH Bosch et al, Journal of Applied Microbiology 2000, 89, 215-224).

The pharmacological properties of the hypoiodite ion are known in particular its biocidal properties and more particularly microbiocides.

For example, US Patent Application 2009/246146 (BA FI BOTOND et al.) Relates to the use of halides and halide salts for the treatment of microbial infections, including those caused by bacteria, fungi and the like. viruses. It takes advantage of the endogenous immune function and improves this system by using a non-toxic and inexpensive reagent that can be delivered to the surface of the mucous membranes, for example, orally, topically, ophthalmically and by inhalation.

The patent application WO 2008/003688 (PERRAUDIN, Jean-Paul) describes a composition comprising at least one ion selected from hypohalite, hypothiocyanite or a combination thereof and, at least one compound selected from lactoferrin, lactoferrin peptide, lysozyme, immunoglobulins, or a combination thereof.

This invention also relates to the use of said composition for therapeutic applications as well as the protection of plants, in particular for the control of planktonic microorganisms or in bio-films. The application WO2010 / 086530 (ALAXIA SAS) relates to the use of a synergistic combination of at least one ion selected from the group of hypothiocyanites and / or hypohalites and lactoferrin for the preparation of a pharmaceutical composition intended for the treatment of Cystic fibrosis. Said composition being administered by a sprayer, nebulizer or aerolizer.

WO 2012/140272 discloses an antimicrobial system for use in the treatment of microbial infections or microbial contamination control, avoiding the use of antibiotics. These infections include mastitis, tuberculosis, cystic fibrosis and contamination that may result from biofilm formation on medical devices. This microbiocidal composition comprising an oxygen reactive species selected from the group consisting of hypothiocyanate, hypoiodite and hypochlorite produced by the reaction of a peroxidase, a substrate for peroxidase and hydrogen peroxide, wherein the peroxidase enzyme is selected from lactoperoxidase, chloroperoxidase, bromoperoxidase and iodooxidase. The use of halides in these treatments is also described in US 2009/0246146 (BANFI et al).

Almost all the systems used to date concern a liquid solution of OI / HOI comprising an enzyme such as lactoperoxidase. Thus all the applications described use either the production in situ by administration of the complete system, or by the contribution of part of the system using one of the endogenous components present in the action site. Moreover, the use of hypoiodite in solution proves difficult as indicated in US Pat. No. 3,998,751 (Murray W. B.).

Indeed because of the instability of this chemical species whose half-life is less than 24 hours, the uses are delicate, complicated and limited and its storage for prolonged periods is not possible ("Mechanism of Decomposition of The Human Defense Factor Hypothiocyanitis Near Physiological pH "Jozsef Kalmar, Kelemu L. Woldegiorgis, Bernadett Biri, and Michael Thomas Ashby, J. Am Chem Soc, 2011, 133 (49), pp 19911-19921).

Thus one of the major problems of the use of this asset is its instability and therefore the impossibility of storing it for a long time in accordance with the requirements of the pharmaceutical regulations leading to its extemporaneous production.

The document WO 2013/028624 describes a composition comprising a polymer crosslinked with a multivalent metal ion and a hypohalite coordinated with the metal ion, this composition can be used in the treatment of infections of the skin, nails or mucous membranes. The polymer is a carboxylic acid-containing polymer (e.g., an alginate or a carboxylalkylcellulose) and the multivalent metal ion is a divalent metal ion, a trivalent metal ion, or mixtures thereof. Suitable hypohalites include hypofluorites, hypochlorites, hypobromites, hypoiodites. This composition may be in the form of a hydrogel, a dry powder, a solution or a particle of microencapsulated liquid. The use of metal ions makes the mixture particularly explosive knowing that it is well known that metal ions are the "targets" of the oxidizing agents they destabilize and which require this is most often the addition of chelating agents. In addition, there is no indication of how to make hypoiodite powder, or its stability and storage. The examples of embodiments described refer only to the use of hypochlorite in the device of the invention, however hypochlorite is already well known in solid form which is not the case of hypoiodite which has never yet been prepared in a solid form.

US Patent 6,034,138 (Synodis J. et al) relates to a solid or semi-solid concentrated antimicrobial composition which forms a buffered sterilization solution upon the addition of water for the disinfection and sterilization of contaminated surfaces, articles and fluids comprising: a) a glutaraldehyde protected sterilizing agent; b) an oxidizing agent, and c) a buffer system. The sterilizing agent is a protected glutaraldehyde such as an additive glutaraldehyde bisulphite compound (GBS) or a

dioxime glutaraldehyde (GDO), the oxidizing agent is selected from the group consisting of alkali metal and alkaline earth metal salts of percarbonates, persulfates, hypoiodites, perborates, periodates, peroxides, peroxyformates, peroxybenzoates, chlorates, bromites, hypobromites and chloroperoxybenzoates and mixtures thereof. This invention further provides a method of disinfecting or sterilizing a surface or apparatus. Due to the toxicity of glutaraldehyde this composition can not be used in a therapeutic application. Moreover, no embodiment from hypoiodite is presented.

The object of the present invention differs from the known prior art in that the composition of the invention containing the hypoiodite ion is solid, does not have any addition of multivalent metal ions and is devoid of toxic compounds such as glutaraldehyde. Moreover, the problem that the present invention proposes to solve can be considered as the preparation of a solid and stable composition comprising a salt of hypoiodite that can be stored for a prolonged period. SUMMARY OF THE INVENTION

The invention relates to a solid composition comprising at least one salt hypoiodite OI ^"associate of a cation and / or its associated forms the hypoiodous acid HOI form of a powder amorphous and / or crystalline. The solid composition according to the invention has the advantages of being stable and storable in the long term. It is essentially free of multivalent metal ions such as divalent and trivalent as well as toxic compounds such as for example glutaraldehydes and sulfites, the solid composition according to the invention is also characterized by the absence of chelating agents.

The present invention also relates to a method of manufacturing said solid composition, said method comprising the steps of:

a) preparing an aqueous solution containing at least the hypoiodite ion 01 ^" ;

b) adding to said aqueous solution, at least one alcohol or an organic solvent selected from azeotropes of ^water, in a percentage between 10 and 99.9%;

c) adding to said solution an excipient of osidic, polysaccharide or polyol type; d) removing said formed azeotrope containing the alcohol or organic solvent at a pressure between 1 mbar and 120 bar and a temperature between -100 ° C and + 50 ° C to obtain said composition in solid form.

The invention also relates to the use of said composition alone or in combination with other microbiocidal, antimicrobial, antiviral, preservative or antibiotic agents for the treatment of infections of the airways, the lower pulmonary pathways, and / or the high pulmonary pathways .

Another object of the invention is to use said solid composition alone or in combination with other microbiocidal, antimicrobial, antiviral, fungicidal, preservative or antibiotic agents for the treatment of infections selected from the group comprising gastric infections, wounds, mucous membranes, and / or skin.

The invention also relates to the use of said composition, alone or in

combination with other antimicrobial, antiviral, antiparasitic, fungicidal, preservative or antibiotic agents for the treatment of bacteria, yeasts, molds, viruses, prions, parasites, protozoa. Moreover, the invention also relates to the use of said composition, alone or in combination with other agents for the treatment of infections of viruses of the genus Influenzavirus. Another object of the invention is the use of said composition alone or in combination with other compounds as a mucociliary clearance improving compound.

Other objects and advantages of the present invention will appear on reading the description and examples of embodiment.

DETAILED DESCRIPTION OF THE INVENTION

The present invention makes it possible to obtain a composition comprising at least one cation-associated hypoiodite salt 01 ^' of a cation and / or its associated form the HOI hypoiodous acid in solid form, said solid composition being in the form of an amorphous powder and / or crystalline The solid composition according to the invention has the advantages of being stable and storable in the long term.It is essentially devoid of multivalent metal ions (such as divalent and trivalent) as well as toxic compounds such as by Glutaraldehydes, sulfites, etc. The solid composition according to the invention is also characterized by the absence of metal chelating agents, as can easily be found in disinfectant compositions of the prior art.

"Chelation" is a physico-chemical process in which a complex, the chelate, is formed between a ligand, called a chelating agent, and a metal cation, then complexed, called chelate.

The "chelate" is distinguished from the simple "complex" by the fact that the metal cation is attached to the chelator by at least two coordination bonds defining a ring with the metal, in the manner of a clamp. The number of metal-ligand bonds that can be formed defines "denticity": we speak of bidentate, tridentate, tetradentic ligands, etc., as well as monodentate, bidentate and polydentate ligands. The central atom is bonded to the neighboring atoms by at least two bonds forming an annular structure, a ring chelate. The most stable chelate rings are 5-membered and 6-membered chelate rings. Thanks to this effect, chelates are more stable complexes than complexes of monodent ligands having the same chemical functions. For example, mention may be made of derivatives of ethylenediamine tetraacetic acid (EDTA) for lead and calcium, D-penicillamine for copper, desferrioxamine for iron, or acid

diethylenetriamine-penta-acetic acid (DTP A).

It is understood by "metal ions" the product of dissolution of a metal salt in a liquid or a solution. In general, an ion is formed when a metal meets a non-metal and they exchange electrons. The metal loses electrons and becomes a cation (ion +) and the non-metal gains electrons and becomes an anion (ion -). As the opposite charges attract each other, the ions remain together to form an ionic compound. An ion never exists alone, it always has a partner with whom it has exchanged electrons. So a cation is always accompanied by an anion and vice versa.

A univalent metal is a metal that will form ions by binding once; on the other hand, the bivalent, trivalent or tetravalent metals will associate with two, three or four atoms respectively of a univalent element.

As used herein, the term "multivalent metal ion" refers to divalent metal ions, trivalent metal ions, and mixtures thereof.

Multivalent metal ions include alkaline earth metal ions, transition metal ions, and Group III metal ions.

Representative divalent metal ions include magnesium, calcium, strontium, and barium ions. Representative transition metal ions include scandium, copper, zinc, tin, iron, titanium, and manganese ions.

Representative trivalent metal ions include aluminum, gallium, indium and thallium.

If they are not absent from the composition, these multivalent metal ions are present in trace amounts in the solid composition of the invention by their presence in trace amounts in the compounds used it is that is, in a minute amount representing about 0.001 to about 0.01 percent by weight based on the total weight of the composition.

The present invention also relates to a solid composition, characterized in that it contains at least one salt hypoiodite OI ^"associate of a cation and / or its associated acid form hypoiodeux HOI, in the form of an amorphous powder and / or crystalline powder in weight percentage between 0.01% and 20% and preferably between 0.01% and 10%>.

In one embodiment, the composition according to the invention is characterized in that it additionally contains a thiocyanate ion salt (SCN) at a mass percentage of between 0.01% and 40% and preferably of between 0.degree. , 01% and 10%.

In another embodiment, the composition according to the invention further comprises gluconic acid at a mass percentage of between 0.01% and 20%.

In an additional embodiment, the composition according to the invention further comprises a phosphate or carbonate salt associated with an alkaline cation at a mass percentage of between 10 and 99.999%.

In a preferred embodiment, the cation according to the invention is chosen from alkaline cations, such as sodium, and potassium, or from the group consisting of calcium and / or magnesium.

In another embodiment, the solid composition according to the invention comprises an excipient of the osidic, polysaccharide or polyol type, and preferably said solid composition comprises a combination of at least two of said saccharide, polysaccharide and polyol excipients.

Said exipients are for example advantageously chosen from glucose, lactose, trehalose, mannitol and / or their mixtures. The solid composition may comprise trehalose and / or mannitol.

In one embodiment, the composition contains mannitol at a mass percentage of between 1 and 50%.

In another embodiment, the composition according to the invention is characterized in that trehalose is present in a mass proportion of between 1 and 45%. In a particular embodiment, the solid composition according to the invention contains lactose present at a mass percentage of between 1 and 60%.

The solid composition according to the invention has the advantage of being substantially devoid of multivalent metal ions, or in the form of minute traces representing approximately 0.001 to about 0.01 percent by weight relative to the total weight of the composition, and than metal chelating agents.

For example, an order of magnitude of a trace of cations (metal ions) for Ba <0.002%, for Fe <5 ppm, for Mg <0.001% and for heavy metals such as Pb <5 ppm.

In the solid composition according to the invention, the hypoiodite ion ΟΓ is stable over a minimum period of 1 month, preferably 2 months (see Example 11), preferably from 3 months and up to 6 months stored under atmosphere. inert.

In a preferred manner, the solid composition of the invention comprising the hypoiodite ion ΟΓ is stable over a minimum period of 2 months and up to 4 months stored under an inert atmosphere. The composition according to the invention will preferably be stored at a temperature of between + 20 ° C. and -80 ° C. in the absence of oxygen, moisture and light.

An important advantage of the solid composition according to the invention is that it is now possible to increase the concentration of hypoiodite OI ^- in the ready-to-use reconstituted solution to be administered to the patient. possible to have a dose of hypoiodite OI ^"most important and therefore administered to patients of lower volumes of product, which is faster, more cost effective and comfortable for the patient. Furthermore, the invention also relates to a ready-to-use solution characterized in that it comprises the solid composition according to the invention, solubilized in a physiologically acceptable medium. The solid composition will, for example, be solubilized in an acceptable organic solvent chosen from hydroalcoholic solvents or from among compounds carrying hydroxyl functions or any other physiologically acceptable solvent known to those skilled in the art.

Preferably, the hydroalcoholic solvent comprises an alcohol representing from 0.01% to 100% by weight of said solvent.

The invention also relates to a method of manufacturing said solid composition comprising the steps of:

a) preparing an aqueous solution containing at least the hypoiodite ion ΟΓ;

c) adding to said solution an excipient of osidic, polysaccharide or polyol type;

d) removing said formed azeotrope containing the alcohol or organic solvent at a pressure between 1 mbar and 120 bar and a temperature between -100 ° C and + 50 ° C to obtain said composition in solid form.

In one embodiment, the process according to the invention is characterized in that the organic solvent is chosen from the classically described water azeotropes, as well as their combination.

An "azeotropic or azeotropic" mixture is a liquid mixture that boils at a fixed temperature while keeping a fixed composition. An azeotropic mixture is a mixture which has, for a particular composition, a vapor phase having the same composition as the liquid phase with which it is in equilibrium.

In one embodiment, the process according to the invention is characterized in that said alcohol is selected from ethanol, propanol, isopropanol, tert-butanol, or mixtures thereof.

In one embodiment, the process according to the invention is characterized in that an association of at least two of said alcohols is added to the aqueous solution. In a particular embodiment, the proportions of alcohol or organic solvent may vary from 1 to 99% relative to the aqueous solution containing ΓΟΓ / ΗΟΙ. In a preferred embodiment, the process according to the invention is characterized in that the alcohol is ethanol at a percentage of between 1% and 99%.

In one embodiment, the excipient is of the osidic, polysaccharide or polyol type. Preferably, the excipient is selected from the group of mannitol, trehalose, lactose, glycerol of PEG (polyethylene glycol) and / or mixtures thereof.

In a particular embodiment, the process according to the invention is characterized in that the excipient of the polyol type is glycerol at a mass percentage of between 10% and 50%.

In another embodiment, the process according to the invention is characterized in that the polyol type excipient is polyethylene glycol (PEG) at a mass percentage of between 10% and 50%.

In a different embodiment, the process according to the invention is characterized in that the excipient of the polyol type is mannitol at a mass percentage of between 1 and 50%. In a complementary embodiment, the process according to the invention is characterized in that the excipient of the polysaccharide type is trehalose at a mass percentage of between 1 and 45%.

In another embodiment, the process according to the invention is characterized in that the polysaccharide excipient is lactose at a mass percentage of between 1 and 60%.

In one embodiment, the method according to the invention is characterized in that the temperature in step d) is adjusted between 0 ° C and -100 ° C. Preferably the temperature is adjusted between -10 ° C and -80 ° C. In another preferred embodiment the temperature is adjusted to -20 ° C. In a particular embodiment, the temperature is adjusted to -80 ° C. In one embodiment, the process according to the invention is characterized in that the solvents are removed simultaneously.

According to another embodiment, the process according to the invention is characterized in that said alcohol or the organic solvent is removed consecutively.

In one embodiment of the invention, the water is removed first.

In another embodiment, said alcohol or organic solvent is removed by evaporation as an azeotrope under reduced pressure. Preferably, the evaporation is carried out at a temperature between 20 and 45 ° C.

In one embodiment, the method according to the invention is characterized in that the evaporation is carried out at ambient temperature.

In a particular embodiment, the process according to the invention is characterized in that the evaporation is carried out at low temperature, for example at a temperature below -80 ° C. Preferably, the evaporation is carried out under reduced pressure. According to another embodiment, said alcohol or the organic solvent is removed by sublimation at low temperature and reduced pressure.

In one embodiment, the process according to the invention is characterized in that said alcohol or the organic solvent is removed by lyophilization.

In a particular embodiment, said alcohol or the organic solvent is removed by exclusion through ^the use of fluids in their supercritical state or sub critical used as antisolvents. In one embodiment of the invention, for example, the super-critical form of C0 _{2 is used} .

In one embodiment the method according to the invention is characterized in that the solvents are removed to couples pressure / temperature for ^obtaining ^the super critical state or sub critical. In one embodiment, the method according to the invention is characterized in that the supercritical or subcritical fluids are used in the GAS (gas anti-solvent) modality.

In another embodiment, the method according to the invention is characterized in that the supercritical or subcritical fluids are used in the SAS (Super critical anti-solvent) modality. In a particular embodiment, the method according to the invention is characterized in that the supercritical or subcritical fluids are used in the SEDS (Solution Enhanced Dispersion by Supercritical Fluids) modalities.

In a preferred embodiment the fluid in its super-critical form is CC or dimethyl ether.

In one embodiment, the process according to the invention is characterized in that said alcohol or the organic solvent is removed at a temperature between 4 ° C and 50 ° C. In one embodiment, step a) comprises preparing the aqueous solution containing the hypoiodite ion ΟΓ by contacting a peroxidase, a halogen and optionally a pseudohalogen, and / or a oxygen donor.

In this embodiment, the peroxidase is lactoperoxidase, the pseudohalogen is thiocyanate, halogen is iodine. In this embodiment, the hydrogen peroxide is generated in situ by the glucose / glucose oxidase pair.

In one embodiment, the oxygen donor is selected from the group consisting of hydrogen peroxide, or sodium percarbonate. In one embodiment, the aqueous solution is buffered and the pH is in the range [6; 11]. In this embodiment, the aqueous solution is buffered with a phosphate buffer whose concentration is between 50 mM and 200 mM. In another embodiment, the aqueous solution is buffered with a carbonate buffer whose concentration is between 50 mM and 1M.

In one embodiment, the method further comprises between steps a) and b) a membrane filtration step whose cutoff threshold is less than or equal to 30 kDa for retaining the enzymes.

In one embodiment, said membrane is a membrane whose cutoff threshold is 10 kDa. Preferably the membrane has a cutoff threshold of 5 kDa.

In one embodiment, the process according to the invention is characterized in that the aqueous solution available (in step b) additionally contains carbohydrates such as glucose, gluconic acid, carbonates or their salts. mixtures.

In one embodiment, the process according to the invention is characterized in that the aqueous solution which is available further contains the thiocyanate ion.

In one embodiment, the process according to the invention is characterized in that the aqueous solution which is available is buffered. Preferably, the pH of the aqueous solution available is in the range [6; 11].

In a preferred embodiment, the aqueous solution available is buffered with a phosphate buffer ranging from 50 mM to 200 mM. Preferably, the aqueous solution which is available is buffered with a carbonate buffer ranging from 50 mM to 1M. In one embodiment, the method according to the invention is characterized in that the ion ΟΓ is obtained at a temperature between 0 ° C and 40 ° C.

In one embodiment, the process according to the invention is characterized in that the ion ΟΓ of said aqueous solution is obtained by electrolysis.

In one embodiment, the ion ΟΓ of said aqueous solution is obtained by chemical synthesis. In one embodiment, the process according to the invention is characterized in that the composition in solid form obtained in step d) is a powder.

In one embodiment, the resulting powder is amorphous.

In one embodiment, the powder obtained is partially crystalline.

In one embodiment, the resulting powder is crystalline.

The invention also relates to the use of the solid composition according to the invention, alone or in combination with other anti-infective, antimicrobial, antiviral, antifungal or antibiotic agents, or preservatives for the treatment of aerial infections, pathways lower pulmonary and / or upper pulmonary

In particular, the invention also relates to the use of said solid composition, alone or in combination with other anti-infective, antimicrobial, antiviral, antifungal, antibiotic or preservative agents for the treatment of infections associated with cystic fibrosis, COPDs (Chronic Obstructive Pulmonary Disease) and any pathology of the airways. Preferably, the solid composition according to the invention will be used alone or in combination with other active agents as a mucociliary clearance improving compound. Mucociliary clearance is a critical inborn defense mechanism of the airways made of a coordinated set of epithelial transport of water and ions, secretion of mucins, ciliary function and cough. Failure of mucociliary clearance leads to obstruction and predisposes to chronic bacterial infection.

The invention also relates to the use of said solid composition of the invention, alone or in combination with other anti-infective, antimicrobial, antiviral, antibiotic, antifungal or preservative agents for the treatment of infections, in particular but not exclusively infections. gastric, wounds, mucous membranes and / or skin. Another subject of the invention is the use of the solid composition alone or in combination with other anti-infective, antimicrobial, antiviral, antiparasitic, antibiotic, antifungal or preservative agents in the treatment of infections caused by bacteria and and / or yeasts and / or molds and / or viruses and / or prions and / or parasites and / or protozoa. In particular, the treatment of viral infections caused by viruses of the genus Influenza virus will be mentioned. Furthermore, the solid composition according to the invention is advantageously used alone or in combination with other antimicrobial agents and / or anti-viral agents for the treatment or prophylaxis of viral infections caused by viruses of the genus Influenza virus.

The solid composition or its reconstituted solution is especially used as a prophylactic in sensitive areas for example by vaporization or application of said zones. The solid composition is advantageously combined with proteins or peptides having antimicrobial activity. The proteins or peptides of interest having an antimicrobial activity which are combined with the solid composition according to the invention are for example chosen from lactoferrin, lactoferricin and / or lysozyme. The invention also relates to the use of said solid composition, alone or in combination with other anti-infective, antimicrobial, antiviral, anti-fungal, anti-parasitic, or preservative agents by direct use of the powder or after resolubilization of the powder. in a physiologically acceptable environment. Another subject of the invention also relates to the use of the solid composition, alone or in combination with other anti-infective, antimicrobial, antiviral, antibiotic, antifungal or preservative agents for the treatment and / or disinfection, sanitization of the care equipment and medical devices. The solid composition according to the invention, alone or in combination with other anti-infective, antimicrobial, antiviral, antibiotic, antifungal, anti-parasitic or preservative agents, is intended to be administered by inhalation, orally, topically or by injection. The invention also relates to the use of the composition according to the invention, alone or in combination with other anti-infective, antimicrobial, antiviral, antibiotic, antifungal, anti-parasitic or preservative agents for the treatment of air, by decontamination of the air (passive), decontamination environment (active) and environmental remediation.

The invention also relates to the use of the solid composition of the invention, alone or in combination with other anti-infective, antimicrobial, antiviral, antibiotic, antifungal, anti-parasitic or preservative agents for the treatment of food or drinking water, recreational water and water used for subsequent antimicrobial applications. The invention also relates to the use of said solid composition, alone or in combination with other anti-infective, antimicrobial, antiviral, antibiotic, antifungal, anti-parasitic or preservative agents for the stabilization and / or preservation of cosmetics. The invention also relates to the use of said solid composition according to the invention, alone or in combination with other anti-infective, antimicrobial, antiviral, antibiotic, antifungal, anti-parasitic or preservative agents for the treatment and / or the sanitization of materials and equipment. The invention also relates to the use of the solid composition, alone or in combination with other anti-infective, antimicrobial, antiviral, antibiotic, antifungal, anti-parasitic or preservative agents for the treatment of packaging.

Another subject of the invention relates to the use of said solid composition, alone or in combination with other anti-infective, antimicrobial, antiviral, antibiotic, antifungal, anti-parasitic or preservative agents for the treatment of textiles.

The invention also relates to the use of said composition, alone or in

combination with other anti-infective, antimicrobial, antiviral, antibiotic, antifungal, anti-parasitic or preservative agents for the treatment of plants. The invention also relates to the use of said composition, alone or in

combination with other anti-infective, antimicrobial, antiviral, antibiotic, antifungal, anti-parasitic or soil-preserving agents. The invention also relates to the use of said composition, alone or in

combination with other anti-infective, antimicrobial, antiviral, antibiotic, antifungal, anti-parasitic or preservative agents for its co-use with cleaning or disinfecting agents. Another object of the invention relates to the use of said composition alone or in combination with other anti-infective agents, antimicrobials, antivirals, antibiotics, antifungals, anti-parasitic or preservatives for ^the elimination of bacteria, yeasts, molds, viruses, parasites, protozoa. The solid composition according to the invention is preferably used as an antimicrobial, antiviral, antifungal or anti-parasitic agent and intended for administration by inhalation, orally, topically or by injection.

The solid composition according to the invention can also be used for the preparation of a sustained-release formulation.

In one embodiment, said sustained-release solid composition is preferably encapsulated in combination with other antimicrobial and / or antifungal agents, for the treatment of infections selected in a non-limiting manner from mucosal and / or skin infections, as well as respiratory, oral, gastric, intestinal, vaginal infections, wounds and burns.

In another embodiment, said solid sustained-release composition is preferably encapsulated in combination with other antiviral and / or antifungal and / or antiparasitic agents, for the treatment of infections selected in a non-limiting manner among infections or with mucous membranes. , skin and integuments.

In one embodiment and / or use, said composition is used as a disinfecting agent. The invention is described in more detail by the examples below. Other aspects and advantages of the present invention will appear on reading the examples, which should be considered as illustrative and not limiting.

EXAMPLES

Example 1 Enzymatic Production of OI ^" According to Two Successive Enzymatic Reactions

Enzymatic production according to the two successive enzymatic reactions below:

D-Glucose + ½ 02 - -► H ₂ 0 ₂ + gluconic acid

LP

H ₂ 0 ₂ + r> ■ 01 + H, 0

With GOD: Glucose Oxidase; H2O2: hydrogen peroxide; LP: Lactoperoxidase; I ^" Iode 01 ^" Hypoiodite

To a solution of carbonate buffer (100 mL, 50 mM, pH 9.2) are added 0.4 g of D-glucose, 0.04 g of GOD, 0.15 g of LP and 5.4 mM NaI. The solution is stirred at room temperature at 200 rpm for 10 minutes. After reaction, the solution is filtered through an ultrafiltration membrane at 10 kDa. A solution containing:

H ₂ 0 + glucose + gluconic acid + OI ^" + I ^" + Na ⁺

The concentration obtained in OI ^" is 520 μΜ.

Example 2: Enzymatic Production of OI ^" Using Hydrogen Peroxide, Iodine and Thiocyanate and a Lactoperoxidase

SCN, I, H ₂ O ₂ Lactoperoxidase OSCN, OI, SCN, I

To an isotonic solution, neutral pH, 5.4 mM KI / 5.4 mM KSCN / 10.8 mM H ₂ O ₂ and 150 mg of lactoperoxidase are added. After reaction, the solution is filtered through an ultrafiltration membrane at 10 kDa. A solution containing:

OSCN + OI ^" + SCN + I ^" + K ⁺ The concentration obtained in 01 ^" is 460 μΜ Example 3: ΟΓ in hydroalcoholic solution

To a dilute solution obtained according to Example 1, having a concentration of 0.1 ^" of 570 μl, 20% by weight of absolute ethanol is added, the temperature is then lowered to -30 ° C. The solution passes from the liquid phase to the solid phase. the IM-ion content was 550 μΜ after a period of 1 month 545 μΜ after a period of 2 months. the difference observed is in the range ^of precision error of the method of measurement (spectrophotometry).

Example 4: OSCN- in hydroalcoholic solution

To a solution obtained according to example 1 having a concentration OI ^"600 μΜ are added 50% by weight of absolute ethanol. The temperature is then lowered to -30 ° C. The solution does not freeze. It is a measure ion concentration OSCN ^"590 μΜ after a period of 1 month as well as 580 μΜ after a period of 2 months. The observed difference is due to the accuracy of the measurement method (spectrophotometry).

Example 5: OI- in hydroalcoholic solution

A solution obtained according to Example 4, having a concentration of OI- 500 μΜ is stored at a temperature of -80 ° C. The solution freezes. An OI- ion concentration of 520 μΜ is measured after a period of 1 month and 490 μΜ after a period of 2 months. The observed difference is due to the accuracy of the measurement method (spectrophotometry). The results observed in Examples 3 to 5 are shown in Table 1:

Table 1: OI ^" in hydroalcoholic solution. Example 6: Sodium salt OI ^"solid obtained by freeze-drying

To a dilute solution obtained according to Example 1, having a concentration of 520 μΜ of Μ are added 20% by weight of absolute ethanol. The temperature is then lowered to -30 ° C. The frozen hydroalcoholic solution of the example is freeze-dried at a pressure of between 1 and 10 mbar for 24 hours. Is obtained 0.5 ug of OI ^"Na salt.

Example 7: Sodium salt of OSCN ^" solid obtained by evaporation of solvents

A solution obtained according to Example 1 ([OI-] = 520 μιηο1.1-1) is diluted with absolute ethanol (EtOH / H 2 O 9: 1) containing Lactose Immole. The solvent is then evaporated as azeotrope under reduced pressure using a rotary evaporator (bath temperature 40 ° C.) until the solvents are completely evaporated. The product obtained is in the form of a white powder. The content of OI- is controlled., Obtain 20 micrograms of OI-. EXAMPLE 8 Solid IO Sodium Salt Obtained by Evaporation of Solvents

A solution obtained according to Example 1 ([OI-] = 640 μιηο1.1-1) is diluted with absolute ethanol (EtOH / H 2 O of 9: 1) containing Lactose Immole. The solvent is then evaporated as azeotrope under reduced pressure using a rotary evaporator (bath temperature 40 ° C.) until the solvents are completely evaporated. The product obtained is in the form of a white powder. The content of OI- is controlled, We obtain 100 μg of OI-.

EXAMPLE 9 Solid IO Sodium Salt Obtained by Use of CO2 as Anti-Solvent

A solution obtained according to Example 1 ([OI-] = 610 μιηο1.1-1) is diluted with absolute ethanol (EtOH / H 2 O of 9: 1) containing 1 mmol of Lactose. The solvent is then indroduit in the cell reaction pressure of 73 bar at 35 ° C ^using ^a capillary, the solution is disperséee form ^of a jet in the supercritical phase flowing co-current. Precipitation makes it possible to obtain a product in the form of a white powder in the precipitation cell after depressurization.

We obtain 70 μ§ of OI-.

Example 10: Stability of solid composition No. 2 containing hypoiodite.

In order to study the stability of the solid composition of the present invention, stocks we have been prepared. Hypoiodite was generated in solution by the lactoperoxidase system according to the procedure described above. . the solution was diluted with ethanol (190 mL) and evaporated to dryness under reduced pressure (40 mbar) at 25 ° C. Two lots were prepared according to the same procedure. The powders were collected and 0.15 g were prepared in closed plastic bottles.

The samples were stored at -25 ° C. and the amount of 01 ^" was measured after storing the solid composition for different periods of time (0, 138, 1440 hours) .The measurement of the amount of hypoiodite by spectrophotometry was carried out The measurements were duplicated and the results show that the solid composition according to the present invention is stable over time, the stability being practically identical to zero time than at time 0 or 1440 hours (Table 2).

Table 2: Quantity of RO ^" measured from two samples 1 and 2 of the solid composition of the invention after storage at -25 ° C. for a variable time.

Sample 1 Sample 2

Time (i

(h) iimol

0 0.4S0 0.01 5 0.550 0.008

ÉliiiÈiiià

13S 0.450 0.050 0.555 0.01 5

1440 0.460 0.012 0.535 0.010

Example 11: Measurement of OI

This measurement was carried out according to the DTNB method (5,5'-dithio-bis (2-nitrobenzoic acid) described by Thomas and Aulne, "Aune, T.M. and E.L. Thomas, Accumulation of

hypothiocyanite ion during peroxidase-catalyzed oxidation of thiocyanate ion. European Journal of Biochemistry, 1977. 80 (1): p. 209-214. "

OI production from Nal, H202 catalyzed by lactoperoxidase.

UF membrane filtration (ultrafiltration) at 30 kDa. No. Test 1 2 3

100.38 mg 278.8 mg 278.8 mg

Na l

(5.4 mM) (15 mM) (15 mM)

H2O2

260μί 750μΙ. 1200μΙ.

(solution

(2.6 mM) (7.5 mM) (12 mM)

1M)

Results

01 in solution only

3 bottles of 15ml produced for each category 1, 2, 3

S denotes the solution, C for -30 ° C.

Storage at room temperature, pH 7.5 for 1S, 2S, 3S solution samples.

The sample stored at -30 ° C

Storage at -30 ° C during the period

The sample powder: A solution obtained according to Example 3S ([OI-] = 2094μιηο1.1-1) is diluted with absolute ethanol (EtOH / H 2 O 9: 1) containing Lactose Immole. The solvent is then evaporated as azeotrope under reduced pressure using a rotary evaporator (bath temperature 40 ° C.) until the solvents are completely evaporated. The product obtained is in the form of a white powder. The content of 01- is controlled. 300 μg of OI- are obtained.

Part of the powder is stored under an inert atmosphere for 2 months. The concentration of hypoiodite at To, T2 months is checked by putting the same amount of powder back into solution and the same concentration is obtained 2050 μιη at To, 2040 μιη at T + 2 months.

Claims

A solid composition comprising at least one cation-associated hypoiodite salt and / or its associated form HOI hypoiodous acid, said solid composition being in the form of an amorphous and / or crystalline powder.

2. The solid composition according to claim 1, characterized in that the weight percentage of hypoiodite salt 01 ^" and / or its associated form HOI hypoiodous acid in the composition is between 0.01 and 20%.

3. The solid composition according to any one of claims 1 to 2, characterized in that the cation is selected from the group comprising sodium, potassium, calcium and / or magnesium.

4. The solid composition according to any one of claims 1 to 3, characterized in that it further comprises a thiocyanate ion SCN salt ^", by percentage weight of between 0.01% and 40%.

5. The solid composition according to claims 1 to 4, characterized in that it further comprises gluconic acid in weight percentage between 0.01% and 20%.

6. The solid composition according to any one of claims 1 to 5, characterized in that it further comprises a phosphate or carbonate salt (associated with an alkaline cation) in weight percentage between 10% and 99.999%.

7. The solid composition according to any one of claims 1 to 6, characterized in that it further comprises an excipient of osidic type, polysaccharide or polyol.

8. The solid composition according to claim 7, characterized in that it comprises a combination of at least two of said excipients osidic, polysaccharides and polyols.

9. The solid composition according to claims 7 and 8, characterized in that it comprises glucose.

10. The solid composition according to claims 7 and 8, characterized in that it comprises lactose.

11. The solid composition according to claims 7 and 8, characterized in that it comprises trehalose and / or mannitol.

12. The solid composition according to claims 7 and 8, characterized in that it is stable over a minimum period of 2 months stored under an inert atmosphere.

13. The solid composition according to any one of claims 1 to 12, characterized in that it is essentially free of multivalent metal ions and metal chelating agents.

The method of manufacturing the solid composition according to any one of claims 1 to 13, comprising the steps of:

a) preparing an aqueous solution containing at least the hypoiodite ion 01 ^" ;

15. The manufacturing method according to claim 14, characterized in that said alcohol or the organic solvent is removed by exclusion of the solvent by using a fluid in its supercritical or subcritical form.

16. The manufacturing method according to any one of claims 14 to 15, characterized in that step a) comprises the preparation of the aqueous solution containing the hypoiodite ion ΟΓ by contacting a peroxidase, a halogen and optionally a pseudohalogen and an oxygen donor.

A solid composition according to any one of claims 1 to 13, alone or in combination with other anti-infective, antimicrobial, antiviral, antibiotic, antifungal or preservative agents for its use in the treatment of airway infections, lower pulmonary tract, and / or upper pulmonary tract.

18. Solid composition according to one of claims 1 to 13, alone or in

combination with other anti-infective, antimicrobial, antiviral, antibiotic, antifungal or preservative agents for its use in the treatment of infections selected from the group consisting of gastric infections, wounds, mucous membranes, and / or skin.

19. Solid composition according to one of claims 1 to 13, alone or in

combination with other anti-infective, antimicrobial, antiviral, antibiotic, antifungal or preservative agents for its use in the treatment of infections caused by bacteria and / or yeasts and / or molds and / or viruses and / or parasites and / or protozoa.

20. Solid composition according to one of claims 1 to 13, alone or in

combination with other antimicrobial agents and / or antiviral agents for use in the treatment or prophylaxis of viral infections caused by viruses of the genus Influenza virus.

A solid composition according to any one of claims 1 to 13 for use as an antimicrobial, antifungal, antiviral or anti-parasitic agent for administration by inhalation, orally, topically or by injection.