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WO2024184369A1 - Formulation pour l'administration buccale d'un système micellaire inverse biocompatible - Google Patents

Formulation pour l'administration buccale d'un système micellaire inverse biocompatible Download PDF

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Publication number
WO2024184369A1
WO2024184369A1 PCT/EP2024/055773 EP2024055773W WO2024184369A1 WO 2024184369 A1 WO2024184369 A1 WO 2024184369A1 EP 2024055773 W EP2024055773 W EP 2024055773W WO 2024184369 A1 WO2024184369 A1 WO 2024184369A1
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Prior art keywords
reverse micelle
water
micelle system
active ingredient
soluble active
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English (en)
Inventor
Léa BALAN
Jean-Claude Maurel
Abdelkader MOURI
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Medesis Pharma SA
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Medesis Pharma SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays

Definitions

  • the present invention relates to a reverse micelle system comprising sterol, acylglycerol, alcohol, water, water-soluble active ingredient, phospholipid or sphingolipid, and a further vegetable oil, said system being adapted for a buccal administration in a subject in need thereof.
  • the invention also relates to the medical uses of said reverse micelle system, and pharmaceutical compositions comprising the same.
  • RNA small RNA
  • miRNA small RNA
  • RNAa RNA-binding protein
  • these molecules are unstable in biological fluids, in vitro and in vivo, and display poor intracellular penetration and low bioavailability.
  • These critical drawbacks have limited their use in therapeutics. Consequently, clinical applications of these nucleic acids have required chemical modifications with the aim of retaining their capacity to knockdown protein expression while increasing their stability and cellular penetration.
  • Research groups have also applied the nanotechnology approach to improve their delivery, to overcome most barriers that hindered the development of nucleic acids delivery-based therapies.
  • To improve bioavailability many researchers have also attempted to use alternative routes of administration: ocular, skin, oral, intramuscular. Those attempts have not been entirely satisfactory so far.
  • the reverse micelle systems mentioned above in the prior art are based on sterols, acylglycerols, phospholipids or sphingolipids, with a specific content of lipids, and comprise at least one active ingredient.
  • the inventors found that the administration of these known system was negatively affected by the occurrence of gelling upon contact with an aqueous medium, such as saliva.
  • the gelling is particularly present when administered through the buccal route, yet it is the preferred administration route as it is less invasive than the rectal route.
  • the gelling of the reverse micelle system leads to a loss of efficiency of said system.
  • the gelling negatively impacts the absorption through the mucosa and the bioavailability of the active ingredient.
  • the gelling decreases patients compliance because the gelled product has an unpleasant texture and a bad taste.
  • the present invention relates to an improvement of the bioavailability of water-soluble active ingredients using reverse micelle system based on sterols, acylglycerols, phospholipids or sphingolipids when administered through the mucosa, in particular the buccal mucosa.
  • the reverse micelle system according to the invention is able to cross mucosa and cellular membranes, even in high humidity environments such as the buccal mucosa. It allows vectorization of both small and large-molecules to target sites.
  • the invention also relates to the improvement of organoleptic properties of said reverse micelle system, allowing a better acceptance of the system when used buccally in humans. It is advantageously useful in the pharmaceutical fields.
  • the inventors found that increasing the contents of unsaturated fatty acids, in particular long-chain unsaturated fatty acids, in the reverse micelle system delays or prevents the phase transition to a gel, while maintaining the stability and efficiency of the system for the delivery of the active ingredient.
  • the unsaturated fatty-acids are preferably unsaturated long-chain fatty acids such as oleic acid and linoleic acid.
  • the inventors also found that vegetable oils are an appropriate source of unsaturated fatty acids in the context of the invention. The addition of a vegetable oil in the reverse micelle system does not interfere with the stability and the efficacy of said system and delays or avoids the gelling in an aqueous medium.
  • the invention also relates to an aromatization of the reverse micro-emulsion.
  • the inventors have selected aromas that do not interfere with the stability of the system and succeed in improving the compliance.
  • the inventors found that hydrophobic (non-polar) aromas and/or aromas have shown to be more effective than hydrophilic aromas.
  • the invention further relates to a reverse micelle system as defined above, for use for preventing and/or treating a disease or disorder selected from the group consisting of pathologies of the central nervous system, neurodegenerative diseases, autoimmune diseases, type 2 diabetes, insulin resistance, metabolic syndrome, cancers such as respiratory tumors or acute promyelocytic leukemia, acquired immunodeficiency syndromes, cancerology, osteoporosis, diseases linked to oxidative stress, bipolar disorders, depression, and inflammatory disorders, wherein the water-soluble active ingredient is a metal ion, preferably selected in the group consisting of lithium, zinc, niobium, vanadium, selenium, molybdenum, chromium, antimony, tin, gold, ruthenium, palladium, platinum, strontium, arsenic and manganese.
  • a disease or disorder selected from the group consisting of pathologies of the central nervous system, neurodegenerative diseases, autoimmune diseases, type 2 diabetes, insulin resistance, metabolic syndrome, cancers such as
  • the invention further relates to a reverse micelle system as defined above, for use for preventing and/or treating pathologies of the CNS such as bipolar disorders and/or neurodegenerative diseases such as Huntington’s disease, Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis, multiple sclerosis, prevention of dementia, ,or disease due to a prion infection, wherein the water-soluble active ingredient is lithium, preferably lithium citrate.
  • pathologies of the CNS such as bipolar disorders and/or neurodegenerative diseases such as Huntington’s disease, Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis, multiple sclerosis, prevention of dementia, ,or disease due to a prion infection
  • the water-soluble active ingredient is lithium, preferably lithium citrate.
  • the invention further relates to a reverse micelle system as defined above, for use for preventing and/or treating Alzheimer disease, wherein the water-soluble active ingredient is lithium, preferably lithium citrate.
  • the invention further relates to a reverse micelle system as defined above, for use for treating a subject exposed to radiation and/or preventing radiation damage in a subject at risk for exposure to radiation, wherein the water-soluble active ingredient is manganese, preferably manganese sulfate.
  • the invention further relates to a reverse micelle system as defined above, for use for treating inflammatory cytokine storms triggered by aggressive viruses, wherein the water-soluble active ingredient is manganese, preferably manganese sulfate.
  • the invention further relates to a reverse micelle system as defined above, for use for treating a subject exposed to radiation therapy of cancers and/or preventing radiation damage in a subject exposed to radiation therapy of cancers, wherein the water-soluble active ingredient is manganese, preferably manganese sulfate.
  • the invention further relates to a reverse micelle system as defined above, for use for preventing and/or treating genetic diseases, cancers, neurodegenerative diseases in particular neurodegenerative genetic diseases, neuromuscular genetic diseases, metabolic diseases in particular metabolic genetic disease infectious and/or inflammatory diseases, or diseases or disorders due to cell proliferation, wherein the water-soluble active ingredient is a nucleic acid, preferably an oligonucleotide, more preferably selected from the group consisting of "short interfering nucleic acid” (siNA), "short interfering RNA” (siRNA), "short interfering nucleic acid molecule", “short interfering oligonucleotide molecule”, “miRNA”, “micro RNA”, and “short hairpin RNA” (shRNA).
  • siNA short interfering nucleic acid
  • siRNA short interfering RNA
  • siRNA short interfering nucleic acid molecule
  • miRNA short interfering oligonucleotide molecule
  • miRNA micro
  • the invention further relates to a reverse micelle system as defined above, for use in inhibiting the expression of pathological or overexpressed genes, wherein the water-soluble active ingredient is siRNA’s.
  • the invention further relates to a reverse micelle system as defined above, for use for the prevention and /or treatment of genetic diseases, cancers, neurodegenerative diseases, neuromuscular genetic diseases, metabolic diseases, infectious and/or inflammatory diseases, or diseases or disorders due to cell proliferation, wherein the water-soluble active ingredient is siRNA’s.
  • the invention further relates to a reverse micelle system as defined above, for use in the treatment of Huntington’s disease, wherein the water-soluble active ingredient is P42 TAT.
  • the invention further relates to a reverse micelle system as defined above, for use in decorporating at least one radionuclide and/or treating at least one metal intoxication, wherein the water-soluble active ingredient is CaNa3DTPA.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a reverse micelle system that comprises sterol, acylglycerol, alcohol, water, water-soluble active ingredient, phospholipid or sphingolipid, wherein the weight ratio phospholipid or sphingolipid/acylglycerol range from 0.05 to 0.55, and a further vegetable oil; and at least a pharmaceutically acceptable vehicle.
  • said pharmaceutical composition is for buccal administration.
  • the invention also relates to a buccal delivery system comprising a reverse micelle system that comprises sterol, acylglycerol, alcohol, water, phospholipid or sphingolipid, wherein the weight ratio phospholipid or sphingolipid/acylglycerol range from 0.05 to 0.55, a further vegetable oil, and a water- soluble active ingredient intended to be administered within the buccal mucosa.
  • a reverse micelle system that comprises sterol, acylglycerol, alcohol, water, phospholipid or sphingolipid, wherein the weight ratio phospholipid or sphingolipid/acylglycerol range from 0.05 to 0.55, a further vegetable oil, and a water- soluble active ingredient intended to be administered within the buccal mucosa.
  • the invention also relates to the use of a vegetable oil, preferably a vegetable oil comprising unsaturated long-chain fatty acids, in a reverse micelle system comprising sterol, acylglycerol, alcohol, water, water- soluble active ingredient, and phospholipid or sphingolipid, wherein the weight ratio phospholipid or sphingolipid/acylglycerol range from 0.05 to 0.55, for avoiding the occurrence of gelling of said reverse micelle system in an aqueous medium.
  • a vegetable oil preferably a vegetable oil comprising unsaturated long-chain fatty acids
  • the present invention relates to a method for the preparation of a reverse micelle system according to the invention, wherein the method comprises the following steps:
  • step (b) Stirring mixture obtained in step (a), at 40 °C or less, and for a time sufficient to obtain formation of reverse micelles, said stirring being preferably carried out mechanically.
  • Figure 1 Partial pseudotemary phase diagram of the Peceol/Olive oil/B- sitosterol/Lecithin/Ethanol/Water system at Peceol/olive oil ratio of 85/15.
  • the colored area represents the monophasic region (W/O microemulsion).
  • the temperature was 25 °C.
  • mucosa and “mucosal” refer to a mucous tissue such as of the respiratory, digestive, or genital tissue.
  • mucosal delivery refers to the administration of a composition through a mucosal tissue.
  • buccal administration is intended for delivering drugs/active ingredients within/through the buccal mucosa in order to achieve a local or systemic effect.
  • treatment refers to any act intended to ameliorate the health status of patients such as therapy, prevention, prophylaxis and retardation of a disease.
  • amelioration or eradication of the disease, or symptoms associated with it refers to the amelioration or eradication of the disease, or symptoms associated with it.
  • this term refers to minimizing the spread or worsening of the disease, resulting from the administration of one or more therapeutic agents to a subject with such a disease.
  • the terms “subject”, “individual” or “patient” are interchangeable and refer to an animal, preferably to a mammal, even more preferably to a human, including adult and child.
  • the term “subject” can also refer to non-human animals, in particular mammals such as dogs, cats, horses, cows, pigs, sheep and non-human primates, among others.
  • Quantity is used interchangeably herein and may refer to an absolute quantification of a molecule or a product.
  • active principle As used herein, the terms "active principle”, “active ingredient” and “active pharmaceutical ingredient” are equivalent and refers to a component of a pharmaceutical composition having a therapeutic effect.
  • the term “therapeutic effect” refers to an effect induced by an active ingredient, or a pharmaceutical composition according to the invention, capable to prevent or to delay the appearance or development of a disease or disorder, or to cure or to attenuate the effects of a disease or disorder.
  • the term “effective amount” refers to a quantity of an active ingredient or of a pharmaceutical composition which prevents, removes or reduces the deleterious effects of the disease. It is obvious that the quantity to be administered can be adapted by the man skilled in the art according to the subject to be treated, to the nature of the disease, etc. In particular, doses and regimen of administration may be function of the nature, of the stage and of the severity of the disease to be treated, as well as of the weight, the age and the global health of the subject to be treated, as well as of the judgment of the doctor.
  • the percentage values used in the present invention are weight percentages with respect to the total weight of the named compounds or reverse micelle system.
  • the reverse micelle system A first object of the invention is a reverse micelle system comprising sterol, acylglycerol, alcohol, water, water-soluble active ingredient, phospholipid or sphingolipid, wherein the weight ratio phospholipid or sphingolipid/acylglycerol range from 0.05 to 0.55, and a further vegetable oil.
  • the reverse micelle system is characterized as a microemulsion comprising a dispersion of water-nanodroplets in oil.
  • the dispersion is stabilised by two surfactants (acylglycerol, more preferably a diacylglycerol and a phospholipid, more preferably phosphatidylcholine, or a sphingolipid) and a co-surfactant (alcohol) that are most likely at the water/oil interface.
  • the reverse micelle phase can be defined as a system wherein water forms the internal phase and the hydrophobic tails of the lipids form the continuous phase.
  • Reverse micelles containing oil(s), surfactant(s), co-surfactant(s), and an aqueous phase are also characterized as water-in-oil microemulsions. These microemulsions are visually limpid.
  • the size of micelles according to the invention is very small, more particularly, it is less than 10 nm; more specifically it is less than 8 nm and more preferably less than 6 nm.
  • the size may vary with the quantity of added water and phospholipid or sphingolipid.
  • the present invention relates more particularly to reverse micelles presenting a correlation distance from 3 nm to 10 nm, more preferably from 3.5 nm to 6.5 nm, in particular from 3,7 nm to 5,7 nm, including around 4,7 nm.
  • the reverse micelles size can be characterized by various methods known by the one skilled in the art, including Small Angle X-Ray Scattering (SAXS), Neutrons Scattering, Transmission Electron Microscopy (TEM), or Dynamic Light Scattering (DLS)
  • SAXS Small Angle X-Ray Scattering
  • TEM Transmission Electron Microscopy
  • DLS Dynamic Light Scattering
  • the ratios of the lipidic constituents (including sterol, acylglycerol and phospholipid or sphingolipid) in this reverse micelle system according to the invention can vary.
  • the weight ratio sterol/acylglycerol can range from 0,01 to 0,1 more particularly from 0,025 to 0,05.
  • the weight ratio phospholipid or sphingolipid/acylglycerol can range from 0,05 to 0,55, in particular from 0,06 to 0,30.
  • the weight of phospholipid or sphingolipids respectively corresponds to the total weight of the mixture of phospholipids or sphingolipids, for instance the weight of lecithin, used in the formulation.
  • the weight of acylglycerol corresponds to the total weight of the mixture usually containing an acylglycerol, or a mixture of acylglycerols, with glycerol and fatty acids derived from said acylglycerol(s).
  • the compounds of the reverse micelle system can be analysed by appropriate means. More specifically, sterols can be identified by gas chromatographic analysis and acylglycerol by high- performance liquid chromatography (HPLC), in particular with a light scattering detector, on a silica column, in the presence of an eluent, e.g. isocratic acetonitrile. Gas chromatography can also be used to analyse diacylglycerols. Phospholipids and sphingolipids can be analysed by high-performance liquid chromatography (HPLC), with a diol column with a light scattering detector.
  • HPLC high-performance liquid chromatography
  • Reverse micelles are dynamic systems. Brownian motion causes perpetual collisions of micelles, which lead to coalescence of micelles and exchange of the aqueous phases. Separation and regeneration of micelles occur and allow chemical reactions between different solutions.
  • the exchange rate between micelles increases in particular with temperature, the length of hydrocarbon chains of the surfactant, and the ratio water/surfactant.
  • Examples of amounts for different components of the reverse micelle system according to the invention are the following: (percentages by weight according to the total weight of the reverse micelle system)
  • the reverse micelle system may comprise from 1% to 30%, preferably from 1% to 20%, in particular from 5% to 15% phospholipids or sphingolipids, preferably lecithin.
  • the reverse micelle system may comprise from 0. 1% to 20%, preferably from 1% to 15%, in particular from 5% to 15% water.
  • the reverse micelle system may comprise from 0.82% to 4.5% sterol.
  • the reverse micelle system may comprise from 30% to 90%, preferably from 50% to 90% acylglycerol.
  • the reverse micelle system according to the invention comprises a vegetable oil.
  • vegetable oil also called plant oil, are used to refer to a non-animal oil of plant origin, in particular from all or part of a plant.
  • the vegetable oil is preferably a pharmaceutically acceptable vegetable oil.
  • the use of a vegetable oil in the reverse micelle system delays or prevents the phase transition to a gel in an aqueous medium, while maintaining the stability and efficiency of the system for the delivery of the active ingredient.
  • the vegetable oil preferably comprises unsaturated mediumchain fatty acids and/or unsaturated long-chain fatty acids.
  • long -chain fatty acids refer to fatty acids containing from 13 to 21 carbon atoms.
  • intermediate-chain fatty acids refer to fatty acids containing from 6 to 12 carbon atoms such as caproic acid, caprylic acid, capric acid or lauric acid.
  • the vegetable oil comprises unsaturated long-chain fatty acids.
  • the vegetable oil is rich in unsaturated long-chain fatty acids.
  • the vegetable oil comprises at least 50%, preferably at least 70%, unsaturated long -chain fatty acids, by weight of the total weight of the vegetable oil.
  • the unsaturated long-chain fatty acids can be for example Myristoleic acid (C14), Palmitoleic acid (C16), Sapienic acid (C16), Oleic acid (C18), Elaidic acid (Cl 8), Vaccenic acid (Cl 8), Linoleic acid (Cl 8), Linoelaidic acid (Cl 8), a-Linolenic acid (Cl 8), Arachidonic acid (C20), and Eicosapentaenoic acid (C20).
  • the unsaturated long-chain fatty acids comprises 18 to 21 carbon atoms, more preferably 18 carbon atoms.
  • the unsaturated fatty acid is oleic acid and/or linoleic acid
  • the vegetable oil comprises at least 50 %, preferably at least 70%, of oleic acid and/or linoleic acid, by weight of the total weight of the vegetable oil.
  • the vegetable oil is selected from the group consisting of olive oil, sunflower oil, safflower oil, soya oil, sesame oil, and mixtures thereof.
  • the vegetable oil is olive oil.
  • the olive oil used is refined olive oil. The inventor uncovered that refined olive oil contributes to improving the organoleptic properties of the reverse micelle system.
  • the content of the vegetable oil in the reverse micelle system is higher than 3 %, preferably at least 4%, by weight of the total weight of the reverse micelle system.
  • the content of the vegetable oil in the reverse micelle system is between 4% and 20 %, between 5% and 20%, between 6% and 20%, between 7% and 20%, between 8% and 20%, between 9% and 20%, or between 10% and 20%, by weight of the total weight of the reverse micelle system.
  • the content of the vegetable oil in the reverse micelle system can also be for example between 4% and 19 %, between 4% and 18%, between 4% and 17%, between 4% and 16%, between 4% and 17%, between 4% and 16%, between 4% and 15%, between 4% and 14%, between 4% and 13%, between 4% and 12%, between 4% and 11%, or between 4% and 10%, by weight of the total weight of the reverse micelle system.
  • the reverse micelle system according to the invention comprises a vegetable oil content of between 4% and 20%, preferably between 6% and 10%, by weight of the total weight of the reverse micelle system.
  • the content of the olive oil in the reverse micelle system is higher than 3 %, preferably at least 4%, by weight of the total weight of the reverse micelle system.
  • the content of the olive oil in the reverse micelle system is between 4% and 20 %, between 5% and 20%, between 6% and 20%, between 7% and 20%, between 8% and 20%, between 9% and 20%, or between 10% and 20%, by weight of the total weight of the reverse micelle system.
  • the content of the olive oil in the reverse micelle system can also be for example between 4% and 19 %, between 4% and 18%, between 4% and 17%, between 4% and 16%, between 4% and 17%, between 4% and 16%, between 4% and 15%, between 4% and 14%, between 4% and 13%, between 4% and 12%, between 4% and 11%, or between 4% and 10%, by weight of the total weight of the reverse micelle system.
  • the reverse micelle system according to the invention comprises an olive oil content of between 4% and 20%, preferably between 6% and 10%, by weight of the total weight of the reverse micelle system
  • the vegetable oil in particular the olive oil
  • the vegetable oil in particular the olive oil
  • the vegetable oil leads to a loss of the micelle structure.
  • Acylglycerols used in the reverse micelle system according to the invention can be isolated from the majority of animals, and more preferably plants.
  • Acylglycerols used according to the invention include mono-, di- and tri -acylglycerols.
  • acylglycerols used according to the invention are of the following formula (I): wherein:
  • - Ri is an acyl residue of a linear or branched unsaturated fatty acid having between 14 and 24 carbon atoms
  • - R2 is an acyl residue of a linear or branched unsaturated fatty acid having between 2 and 18 carbon atoms, or a hydrogen atom
  • R3 is an acyl residue of a linear or branched unsaturated fatty acid having between 14 and 24 carbon atoms, or a hydrogen atom.
  • R2 has one unsaturated bond (e.g., ethylenic bond) and has advantageously 18 carbon atoms, preferably R2 is an oleic acid residue (oleoyl group), one of its positional isomers with respect to the double bond (cis-6,7,9,11 and 13) or one of its iso-branched isomers.
  • Ri represents an oleoyl group.
  • R2 represents an acetyl group.
  • R3 is a hydrogen atom.
  • R2 and R3 are hydrogen atoms.
  • oil containing a high concentration of oleic acid will be chosen as a useful source of acylglycerols according to the invention.
  • Such oil usually contains a high proportion of acylglycerols useful according to the invention.
  • the preferred diglycerols of fatty acids are selected in the group consisting of 1 -monooleate, 1,2-diolein glycerol (also called glycerol 1,2 -dioleate) and 1 -oleoyl -2 -acetyl glycerol.
  • glycerol monooleate 40 contains about 32 to 52% of monoacylglycerol, 30 to 50% of diacylglycerol, 5 to 20% of triacylglycerol and is pharmaceutically accepted (European Pharmacopeia (8 th Edition), USP 25/NF20, and Japanese Standard of food Additives). Such product is for instance commercially available by Gattefosse Company under the name Peceol®.
  • Peceol® may comprise around 45.3 wt% of monoacyl glycerol, around 44.5 wt% of diacylglycerol and around 8.6 wt% of triacyl glycerol (the acyl fraction of Peceol® is mainly made of oleoyl - usually around 80% of the acyl residue is oleoyl fraction).
  • the weight of acylglycerol corresponds to the total weight of the mixture usually containing an acylglycerol, or a mixture of acylglycerols, with glycerol and fatty acids derived from said acylglycerol(s), such as Peceol® described above.
  • the acylglycerols are preferably incorporated or comprised in the composition or reversemicelle system in an amount by weight ranging from 50 g to 90 g with respect to 100 g of the total weight of the composition or reverse-micelle system according to the invention.
  • the amounts specified herein will be adapted with respect to the other compounds as to correspond more specifically to the weight ratios identified below.
  • Acylglycerols are natural compounds, and may be extracted and/or derived from renewable vegetable sources. Their use is thus favoured in terms of biocompatibility and environmental concerns when compared to synthetic compounds.
  • the reverse micelle system according to the invention comprises at least one sterol, preferably natural sterol, such as cholesterol or phytosterol (vegetable sterols).
  • sterol preferably natural sterol, such as cholesterol or phytosterol (vegetable sterols).
  • Sitosterol and cholesterol are the preferred sterols that can be present in a reverse micelle system according to the invention.
  • the reverse micelle system comprises sitosterol, such beta-sitosterol.
  • Sitosterol and cholesterol are commercially available. More particularly, commercial sitosterol, which is extracted from soya, can be used. In such a product, the sitosterol generally represents from 50 to 80% by weight of the product and is generally found in a mixture with campesterol and sitostanol in respective proportions in the order of 15% each. Commercial sitosterol, which is extracted from a variety of pine called tall oil, can also be used. In general, it will be possible to use sitosterol in mixture with sitostanol. Preferably, said mixture comprises at least 50% sitosterol by weight of the mixture.
  • the sterols are preferably incorporated or comprised in the composition or reverse micelle system in an amount by weight ranging from 0.825 g to 4.5 g with respect to 100 g of the total weight of the composition or reverse micelle system according to the invention.
  • the amounts specified herein will be adapted with respect to the other compounds as to correspond more specifically to the weight ratios identified above and/or below.
  • Phospholipids are formed of a glycerol linked to 2 fatty acids and to a phosphate group.
  • the variability of phospholipids relies on the fatty acids that are attached to the glycerol and on the chemical groups that are susceptible to link to the phosphate group.
  • Phospholipids are, with sphingolipids, the major lipidic constituents of biological membranes.
  • Phosphatidylcholine is formed from a choline, a phosphate group, a glycerol and two fatty acids. It is actually a group of molecules, wherein the fatty acid compositions varies from one molecule to another.
  • Phosphatidylcholine may be obtained from commercial lecithin that contains phosphatidylcholine in weight concentrations of 20 to 98%.
  • the lecithin preferably used for the preparation of the reverse micelles according to the invention is preferably Lipoid SI 00® and contains phosphatidylcholine at a concentration of more than 90%, in particular more than 94%.
  • Sphingolipids are a class of lipids derived from the aliphatic amino alcohol sphingosine.
  • sphingolipids that may be used in the present invention may be cited acylsphingosin, sphingomyelins, glycosphingolipids, and gangliosides.
  • the reverse micelles system of the invention may comprise phospholipids, sphingolipids, or a mixture of both types of compounds.
  • the reverse micelles system of the invention comprises phospholipids.
  • the reverse micelles system of the invention comprises lecithin.
  • the weight ratio phospholipid and/or sphingolipid/acylglycerol in compositions or reverse micelle systems according to the invention is from 0,05 to 0,55 in particular from 0,06 to 0,30.
  • the phospholipids or sphingolipids are preferably incorporated or comprised in the composition or reverse micelle system in an amount by weight ranging from 1 g to 30 g, preferably from 5 to 20 g with respect to 100 g of the total weight of the composition or reverse micelle system according to the invention.
  • the amounts specified herein will be adapted with respect to the other compounds as to correspond more specifically to the weight ratios identified above.
  • the water useful for the preparation of the reverse micelle system according to the invention is preferably purified water; more particularly distilled or deionized water.
  • Water is preferably incorporated or comprised in the composition in an amount by weight ranging from 1 g to 15 g, preferably from 5 g to 15 g, with respect to 100 ml of the total volume of the composition or reverse micelle system according to the invention.
  • One of ordinary skill in the art will adapt the amount of phospholipid or sphingolipid in the systems to the desired amount of water. For instance, increasing amount of water should imply increasing amount of phospholipid or sphingolipid in the systems.
  • the reverse micelle system of the invention comprises at least one water-soluble active ingredient.
  • the water-soluble active ingredient is selected from the group consisting of metal ions, chelating and/or sequestering agents, nucleic acids, oligonucleotides, small molecules, biomolecules, and peptides. More particularly, the water-soluble active ingredient is selected from the group consisting of metal ions (such as lithium, manganese), chelating and/or sequestering agents (such as DTP A), nucleic acids/antisense oligonucleotides, nucleotides, peptides (such as P42 TAT), small molecules or biomolecules.
  • metal ions such as lithium, manganese
  • chelating and/or sequestering agents such as DTP A
  • nucleic acids/antisense oligonucleotides such as nucleotides, peptides (such as P42 TAT)
  • small molecules or biomolecules such as P42 TAT
  • the water-soluble active ingredient is a metal ion, preferably selected in the group consisting of lithium, zinc, niobium, vanadium, selenium, molybdenum, chromium, antimony, tin, gold, ruthenium, palladium, platinum, strontium, arsenic, manganese, and mixtures thereof.
  • Metal ions may be metal salts.
  • particularly useful metal salts according to the invention are selected from sulfates, hydrates, halides, in particular chlorides, citrates, carbonates and any other water-soluble salt.
  • the metal ion is lithium or manganese, in particular lithium citrate or manganese sulfate.
  • the water-soluble active ingredient is lithium, preferably lithium citrate.
  • the invention further relates to a reverse micelle system as defined above, for use for preventing and/or treating a disease or disorder selected from the group consisting of pathologies of the central nervous system, neurodegenerative diseases, autoimmune diseases, type 2 diabetes, insulin resistance, metabolic syndrome, cancers such as respiratory tumors or acute promyelocytic leukemia, acquired immunodeficiency syndromes, cancerology, osteoporosis, diseases linked to oxidative stress, bipolar disorders, depression, and inflammatory disorders, wherein the water-soluble active ingredient is a metal ion, preferably selected in the group consisting of lithium, zinc, niobium, vanadium, selenium, molybdenum, chromium, antimony, tin, gold, ruthenium, palladium, platinum, strontium, arsenic and manganese.
  • a disease or disorder selected from the group consisting of pathologies of the central nervous system, neurodegenerative diseases,
  • the invention further relates to a reverse micelle system as defined above, for use for preventing and/or treating pathologies of the CN S such as bipolar disorder, and/or neurodegenerative diseases such as Huntington’s disease, Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis, multiple sclerosis, prevention of dementia, ,or disease due to a prion infection, wherein the water-soluble active ingredient is lithium, preferably lithium citrate.
  • pathologies of the CN S such as bipolar disorder, and/or neurodegenerative diseases such as Huntington’s disease, Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis, multiple sclerosis, prevention of dementia, ,or disease due to a prion infection
  • the water-soluble active ingredient is lithium, preferably lithium citrate.
  • the invention further relates to a reverse micelle system as defined above, for use for preventing and/or treating Alzheimer disease, wherein the water-soluble active ingredient is lithium, preferably lithium citrate.
  • the invention further relates to a method for preventing and/or treating a disease or disorder selected from the group consisting of pathologies of the central nervous system, neurodegenerative diseases, autoimmune diseases, type 2 diabetes, insulin resistance, metabolic syndrome, cancers such as respiratory tumors or acute promyelocytic leukemia, acquired immunodeficiency syndromes, cancerology, osteoporosis, diseases linked to oxidative stress, bipolar disorders, depression, and inflammatory disorders, in a subject in need thereof, said method comprising the administration, preferably buccal administration, to a subject in need thereof of an effective amount of the reverse micelle system as defined above, wherein the water-soluble active ingredient is a metal ion, preferably selected in the group consisting of lithium, zinc, niobium, vanadium, selenium, molybdenum, chromium, antimony, tin, gold, ruthenium, palladium, platinum, strontium, arsenic and manganese.
  • a disease or disorder selected from the group consisting
  • the invention further relates to a method for preventing and/or treating pathologies of the CNS such as bipolar disorder, and/or neurodegenerative diseases such as Huntington’s disease, Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis, multiple sclerosis, prevention of dementia, or disease due to a prion infection, in a subject in need thereof, said method comprising the administration, preferably buccal administration, to a subject in need thereof of an effective amount of the reverse micelle system as defined above, wherein the water-soluble active ingredient is lithium, preferably lithium citrate.
  • the invention further relates to a method for preventing and/or treating Alzheimer disease in a subject in need thereof, said method comprising the administration, preferably buccal administration, to a subject in need thereof of an effective amount of the reverse micelle system as defined above wherein the water-soluble active ingredient is lithium, preferably lithium citrate.
  • the invention further relates to the use of the reverse micelle system as defined above, in the manufacture of a medicament for the prevention and/or the treatment of a disease or disorder selected from the group consisting of pathologies of the central nervous system, neurodegenerative diseases, autoimmune diseases, type 2 diabetes, insulin resistance, metabolic syndrome, cancers such as respiratory tumors or acute promyelocytic leukemia, acquired immunodeficiency syndromes, cancerology, osteoporosis, diseases linked to oxidative stress, bipolar disorders, depression, and inflammatory disorders, wherein the water-soluble active ingredient is a metal ion, preferably selected in the group consisting of lithium, zinc, niobium, vanadium, selenium, molybdenum, chromium, antimony, tin, gold, ruthenium, palladium, platinum, strontium, arsenic and manganese.
  • a disease or disorder selected from the group consisting of pathologies of the central nervous system, neurodegenerative diseases, autoimmune diseases, type 2 diabetes, insulin
  • the invention further relates to the use of the reverse micelle system as defined above, in the manufacture of a medicament for the prevention and/or the treatment of pathologies of the CNS such as bipolar disorder, and/or neurodegenerative diseases such as Huntington’s disease, Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis, multiple sclerosis, prevention of dementia, ,or disease due to a prion infection, wherein the water-soluble active ingredient is lithium, preferably lithium citrate.
  • the invention further relates to the use of the reverse micelle system as defined above, in the manufacture of a medicament for the prevention and/or the treatment of Alzheimer disease, wherein the water-soluble active ingredient is lithium, preferably lithium citrate.
  • antimony or tin examples of metals adapted to other types of activity are indicated below: antimony or tin, if the treatment of autoimmune diseases concerning, in particular, the nervous system, for example multiple sclerosis and cancerology, is desired, gold, in autoimmune diseases affecting the locomotor system, for example in rhumatoid arthritis, vanadium in diabetes type 2, insulin resistance and metabolic syndrome, ruthenium or palladium in respiratory tumors or neoplasias, tin, in acquired immunodeficiency syndroms, selenium in cancerology, strontium in osteoporosis, arsenic in cancers, in particular acute promyelocytic leukemia, manganese in disease linked to oxidative stress.
  • antimony or tin if the treatment of autoimmune diseases concerning, in particular, the nervous system, for example multiple sclerosis and cancerology, is desired, gold, in autoimmune diseases affecting the locomotor system, for example in rhumatoid arthritis, vanadium in diabetes
  • the invention further relates to a reverse micelle system as defined above, for use for treating a subject exposed to radiation and/or preventing radiation damage in a subject at risk for exposure to radiation, wherein the water-soluble active ingredient is manganese, preferably manganese sulfate.
  • the invention further relates to a reverse micelle system as defined above, for use for treating inflammatory cytokine storms triggered by aggressive viruses, wherein the water-soluble active ingredient is manganese, preferably manganese sulfate.
  • the invention further relates to a reverse micelle system as defined above, for use for treating a subject exposed to radiation therapy of cancers and/or preventing radiation damage in a subject exposed to radiation therapy of cancers, wherein the water-soluble active ingredient is manganese, preferably manganese sulfate.
  • the invention further relates to a method for treating a subject exposed to radiation and/or preventing radiation damage in a subject at risk for exposure to radiation, said method comprising the administration, preferably buccal administration, to a subject in need thereof of an effective amount of a reverse micelle system as defined above, wherein the water-soluble active ingredient is manganese, preferably manganese sulfate.
  • the invention further relates to a method for treating inflammatory cytokine storms triggered by aggressive viruses, said method comprising the administration, preferably buccal administration, to a subject in need thereof of an effective amount of a reverse micelle system as defined above, wherein the water-soluble active ingredient is manganese, preferably manganese sulfate.
  • the invention further relates to a method for treating a subject exposed to radiation therapy of cancers and/or preventing radiation damage in a subject exposed to radiation therapy of cancers, said method comprising the administration, preferably buccal administration, to a subject in need thereof of an effective amount of a reverse micelle system as defined above, wherein the water-soluble active ingredient is manganese, preferably manganese sulfate.
  • the invention further relates to the use of a reverse micelle system as defined above, wherein the water-soluble active ingredient is manganese, preferably manganese sulfate, for the manufacture of a medicament for the treatment of a subject exposed to radiation and/or preventing radiation damage in a subject at risk for exposure to radiation.
  • the water-soluble active ingredient is manganese, preferably manganese sulfate
  • the invention further relates to the use of a reverse micelle system as defined above, wherein the water- soluble active ingredient is manganese, preferably manganese sulfate, for the manufacture of a medicament for the treatment of inflammatory cytokine storms triggered by aggressive viruses.
  • the water- soluble active ingredient is manganese, preferably manganese sulfate
  • the invention further relates to the use of a reverse micelle system as defined above, wherein the water- soluble active ingredient is manganese, preferably manganese sulfate, for the manufacture of a medicament for the treatment of a subject exposed to radiation therapy of cancers and/or the prevention of radiation damage in a subject exposed to radiation therapy of cancers.
  • the water- soluble active ingredient is manganese, preferably manganese sulfate
  • the metal ions and the associated medical uses are preferably as disclosed in the international application WO2011/117333.
  • the invention further relates to a reverse micelle system as defined above, for use for treating and/or preventing paludism, wherein the water-soluble active ingredient is methylene blue.
  • the invention further relates to a method for treating and/or preventing paludism in a subject in need thereof, said method comprising the administration, preferably buccal administration, to the subject in need thereof of an effective amount of a reverse micelle system as defined above, wherein the water- soluble active ingredient is methylene blue.
  • the invention further relates to the use of a reverse micelle system as defined above, wherein the water- soluble active ingredient is methylene blue, for the manufacture of a medicament for the treatment and/or the prevention of paludism.
  • the water-soluble active ingredient is a nucleic acid, preferably an oligonucleotide, more preferably selected from the group consisting of "short interfering nucleic acid” (siNA), “short interfering RNA” (siRNA), “short interfering nucleic acid molecule”, “short interfering oligonucleotide molecule”, “miRNA”, “micro RNA”, and “short hairpin RNA” (shRNA).
  • siRNA short interfering nucleic acid
  • siRNA short interfering RNA
  • siRNA siRNA
  • Nucleic acid includes any DNA (deoxyribonucleic acid) and RNA (ribonucleic acid).
  • the terms include single-stranded RNA, single -stranded DNA, double-stranded RNA, double -stranded DNA, plasmid DNA, isolated RNA such as partially purified RNA, essentially pure RNA, synthetic RNA, recombinantly produced RNA, aptamers, as well as nucleic acids comprising non-standard nucleotides, such as non-naturally occurring nucleotides or chemically synthesized nucleotides or deoxynucleotides.
  • oligonucleotide is meant a nucleic acid comprising from 5 to 100 nucleotides, preferably from 10 to 90 nucleotides, more preferably from 13 to 80 nucleotides, more particularly from 13 to 25 nucleotides.
  • antisense oligonucleotides refer to any nucleic acid molecule capable of modulating gene expression by up or down regulating (for instance gene silencing) target protein expression in a sequence-specific manner.
  • the invention further relates to a reverse micelle system as defined above, for use for preventing and/or treating genetic diseases, cancers, neurodegenerative diseases in particular neurodegenerative genetic diseases, neuromuscular genetic diseases, metabolic diseases in particular metabolic genetic diseases, infectious and/or inflammatory diseases, or diseases or disorders due to cell proliferation, wherein the water-soluble active ingredient is a nucleic acid, preferably an oligonucleotide, more preferably selected from the group consisting of "short interfering nucleic acid” (siNA), "short interfering RNA” (siRNA), "short interfering nucleic acid molecule", “short interfering oligonucleotide molecule”, “miRNA”, “micro RNA”, and “short hairpin RNA” (shRNA).
  • siNA short interfering nucleic acid
  • siRNA short interfering RNA
  • siRNA short interfering nucleic acid molecule
  • miRNA short interfering oligonucleotide molecule
  • miRNA
  • the invention further relates to a reverse micelle system as defined above, for use in inhibiting the expression of pathological or overexpressed genes, wherein the water-soluble active ingredient is siRNA’s.
  • the invention further relates to a reverse micelle system as defined above, for use for the prevention and /or treatment of genetic diseases, cancers, neurodegenerative diseases in particular neurodegenerative genetic disease, neuromuscular genetic diseases, metabolic diseases in particular metabolic genetic diseases, infectious and/or inflammatory diseases, or diseases or disorders due to cell proliferation.
  • the invention further relates to a method for preventing and/or treating genetic diseases, cancers, neurodegenerative diseases in particular neurodegenerative genetic diseases, neuromuscular genetic diseases, metabolic diseases in particular metabolic genetic diseases, infectious and/or inflammatory diseases, or diseases or disorders due to cell proliferation in a subject in need thereof, said method comprising the administration, preferably buccal administration, to the subject in need thereof of an effective amount of a reverse micelle system as defined above, wherein the water- soluble active ingredient is a nucleic acid, preferably an oligonucleotide, more preferably selected from the group consisting of "short interfering nucleic acid” (siNA), "short interfering RNA” (siRNA), "short interfering nucleic acid molecule", “short interfering oligonucleotide molecule”, “miRNA”, “micro RNA”, and “short hairpin RNA” (shRNA).
  • siNA short interfering nucleic acid
  • siRNA short interfering RNA
  • the invention further relates to a method for inhibiting the expression of pathological or overexpressed genes in a subject in need thereof, said method comprising the administration, preferably buccal administration, to the subject in need thereof of an effective amount of a reverse micelle system as defined above wherein the water-soluble active ingredient is siRNA’s.
  • the invention further relates to a method for the prevention and /or treatment of genetic diseases, cancers, neurodegenerative diseases in particular neurodegenerative genetic disease, neuromuscular genetic diseases, metabolic diseases in particular metabolic genetic diseases, infectious and/or inflammatory diseases, or diseases or disorders due to cell proliferation in a subject in need thereof, said method comprising the administration, preferably buccal administration, to the subject in need thereof of an effective amount of a reverse micelle system as defined above.
  • the invention further relates to the use of a reverse micelle system as defined above wherein the water-soluble active ingredient is a nucleic acid, preferably an oligonucleotide, more preferably selected from the group consisting of "short interfering nucleic acid” (siNA), “short interfering RNA” (siRNA), “short interfering nucleic acid molecule”, “short interfering oligonucleotide molecule”, “miRNA”, “micro RNA”, and “short hairpin RNA” (shRNA), for the manufacture of a medicament for the prevention and/or treatment of genetic diseases, cancers, neurodegenerative diseases in particular neurodegenerative genetic diseases, neuromuscular genetic diseases, metabolic diseases in particular metabolic genetic diseases, infectious and/or inflammatory diseases, or diseases or disorders due to cell proliferation.
  • siNA short interfering nucleic acid
  • siRNA short interfering RNA
  • miRNA short interfering nucleic acid molecule
  • miRNA short interfering oligonucleo
  • the invention further relates to the use of a reverse micelle system as defined above wherein the water-soluble active ingredient is siRNA’s, for the manufacture of a medicament for the inhibition of the expression of pathological or overexpressed genes.
  • the invention further relates to the use of a reverse micelle system as defined above, for the manufacture of a medicament for use for the prevention and /or treatment of genetic diseases, cancers, neurodegenerative diseases in particular neurodegenerative genetic disease, neuromuscular genetic diseases, metabolic diseases in particular metabolic genetic diseases, infectious and/or inflammatory diseases, or diseases or disorders due to cell proliferation.
  • nucleic acid and the associated medical uses are preferably as disclosed in the international application WO2011/117334.
  • the water-soluble active ingredient is a compound appropriate for chelating and/or sequestering at least one radionuclide and/or metal, preferably selected from the group consisting of DTPA, bisphosphonates, Prussian blue, EDTA, Trientine, D-penicillamine, Deferoxamine, BAL, DMSA, DMPS, Phytic acid, Hydroxypyridonates (HOPO), mercaptoacetyltriglycine (MAG3), chelating peptides, derivatives thereof and combinations thereof.
  • the appropriate compound for chelating and/or sequestering at least one radionuclide and/or metal is CaNa3DTPA.
  • the invention further relates to a reverse micelle system as defined above, for use as an imaging agent and/or as a diagnosis agent, wherein the water-soluble active ingredient is a compound appropriate for chelating and/or sequestering at least one radionuclide and/or metal.
  • the invention further relates to a reverse micelle system as defined above, for use in the treatment of at least one disease linked to the accumulation and/or overload of at least one radionuclide or metal in a patient in need thereof, wherein the water-soluble active ingredient is a compound appropriate for chelating and/or sequestering at least one radionuclide and/or metal.
  • the invention further relates to a method for the treatment of at least one disease linked to the accumulation and/or overload of at least one radionuclide or metal in a subject in need thereof, said method comprising the administration, preferably buccal administration, to the subject in need thereof of an effective amount of a reverse micelle system as defined above wherein the water- soluble active ingredient is a compound appropriate for chelating and/or sequestering at least one radionuclide and/or metal.
  • the invention further relates to the use of a reverse micelle system as defined above wherein the water-soluble active ingredient is a compound appropriate for chelating and/or sequestering at least one radionuclide and/or metal, for the manufacture of a medicament for the treatment of at least one disease linked to the accumulation and/or overload of at least one radionuclide or metal in a subject in need thereof.
  • the water-soluble active ingredient is a compound appropriate for chelating and/or sequestering at least one radionuclide and/or metal, for the manufacture of a medicament for the treatment of at least one disease linked to the accumulation and/or overload of at least one radionuclide or metal in a subject in need thereof.
  • the diseases (or pathologies) linked to the accumulation and/or overload of at least one metal may vary depending on the metal and radiation exposure (duration and/or amount), it can include Wilson’s disease; haemochromatosis; or a pathology or symptom due to a metal accumulation from an external origin such as anxiety, memory loss, depression, suicidal tendencies, loss of strength and coordination, bleeding gums and tooth loss, abdominal cramps, diarrhea or chronic constipation, abnormal heart rate or blood pressure, repeated infections or cancer, chronic migraines, allergies, dermatitis, heart palpitations, sinus congestion, loss of appetite, chronic obesity and Alzheimer's disease.
  • the diseases (or pathologies) linked to the accumulation and/or overload of at least one radionuclide may vary depending on the radiation exposure (duration and/or amount), it can include gastrointestinal disorders, such as nausea or vomiting, symptoms related to falling blood counts, such as predisposition to infection or bleeding, neurological disorders, or different types of cancers (such as blood cancers or thyroid cancer).
  • the invention further relates to a reverse micelle system as defined above, for use for use in decorporating at least one radionuclide and/or treating at least one metal intoxication, wherein the water-soluble active ingredient CaNa3DTPA.
  • the invention further relates to a method for decorporating at least one radionuclide and/or treating at least one metal intoxication in a subject in need thereof, said method comprising the administration, preferably buccal administration, to the subject in need thereof of an effective amount of a reverse micelle system as defined above, wherein the water-soluble active ingredient CaNa3DTPA.
  • the invention further relates to the use of a reverse micelle system as defined above wherein the water-soluble active ingredient CaNa3DTPA, for the manufacture of a medicament for use for decorporating at least one radionuclide and/or treating at least one metal intoxication.
  • the compound appropriate for chelating and/or sequestering at least one radionuclide and/or metal, and the associated medical uses are preferably as disclosed in the international application WO2015/124581.
  • the water-soluble active ingredient is a peptide, preferably P42 TAT.
  • the invention further relates to a reverse micelle system as defined above, for use in the treatment of Huntington’disease, wherein the water-soluble active ingredient is P42 TAT.
  • the invention further relates to a method for the treatment of Huntington’disease in a subject in need thereof, said method comprising the administration, preferably buccal administration, to the subject in need thereof of an effective amount of a reverse micelle system as defined above wherein the water- soluble active ingredient is P42 TAT.
  • the invention further relates to the use of a reverse micelle system as defined above wherein the water-soluble active ingredient is P42 TAT, for the manufacture of a medicament for the treatment of Huntington’disease.
  • the reverse micelle system comprises cyano-bridged metal nanoparticles.
  • the invention further relates to the reverse micelle system according to the invention, for use for being substituted by and/or sequestering radionuclide and/or metal cations, wherein said reverse micelle system comprises cyano-bridged metal nanoparticles.
  • the cyano-bridged metal nanoparticles and the associated uses are preferably as disclosed in the international application W02017/005899.
  • the water-soluble active ingredient is preferably a small molecule.
  • a small molecule refer preferentially to molecules smaller than 1 KDalton.
  • the reverse micelle system further comprises a hydrophobic aroma compound.
  • the reverse micelle system have a pronounced taste of rancid oil. This unpleasant taste can be responsible for patient non-compliance, particularly in young subjects or in the case of long-term treatment. Aromas can thus be used to mask this taste but must not interfere with the stability and effectiveness of the reverse micelle system.
  • Aromas used for the present invention are hydrophobic aromas, preferably lipophilic aromas.
  • a molecule in the context of the invention, is said to be hydrophobic or lipophilic when it is soluble in fats, but insoluble in water.
  • a hydrophobic molecule does not have the capacity to create hydrogen bonds with water molecules. It is also often said to be apolar, or of low polarity, which means that it cannot create electrostatic interactions with water. Indeed, the solubility of a molecule in a solvent depends generally on the interactions it can have with the solvent.
  • a hydrophobic molecule is therefore a molecule that cannot physically interact with water.
  • the hydrophobic aromas used according to the invention are selected in the group consisting of menthol, peppermint essential oil, eucalyptol, and mixtures thereof.
  • Aromas are preferably incorporated in the composition in an amount by weight ranging from 0, 1 g ,to 4,0 g preferably from 0,5 g to 2,0 g, with respect to 100 g of the total weight of the composition or reverse micelle system according to the invention.
  • the reverse micelle system according to the invention may comprise any type of additional components.
  • the amounts of the components of the reverse micelle system can be adapted by anyone of ordinary skill in the art depending on the desired properties for the phase or system, such as visual appearance, viscosity, and/or concentration of active agent for instance.
  • the reverse micelle system does not comprise liposomes.
  • the amounts of the components of the reverse micelle system are adjusted so that the reverse micelle system is in the form of a liquid.
  • One of ordinary skill in the art can adapt the relative amounts of acylglycerol, sterol, lecithin, ethanol and water in the reverse micelle systems for obtaining a liquid with the desired properties, such as the visual appearance, the viscosity, and/or the concentration of the active agent for instance.
  • the invention relates to a method for preparing reverse micelles as defined above wherein said method comprises the following steps:
  • step (b) Stirring mixture obtained in step (a), at 40 °C or less, and for a time sufficient to obtain formation of reverse micelles.
  • Step (b) of the process is of particular importance since it allows reverse micelles to be obtained, said reverse micelles being then useful as a transport system for delivering active ingredients into the target sites.
  • Target sites may for instance be cells of a specific tissue.
  • the water-soluble active ingredient is first solubilised in water, preferably purified water, to form an aqueous mixture. Said aqueous mixture is then introduced into the oily mixture (according to step (a)).
  • the oily mixture preferably comprises at least a sterol, an acylglycerol, a phospholipid or sphingolipid, an alcohol and the further vegetable oil. All these compounds are as defined above.
  • Stirring of the mixture obtained by step (a) is carried out at a temperature less than or equal to 40°C, preferably ranging from 15 °C to 40°C, more preferably from 25 °C to 40 °C, or more specifically from 30 °C to 37 °C, for a time sufficient to form of reverse micelles.
  • the time sufficient can vary in particular upon the used stirring techniques, i.e., mechanical stirring.
  • the time of mechanical stirring is more specifically the time needed to convert the initial mixture into a visually transparent reverse micelle solution.
  • glycerol can, when introduced in large amount, prevent the formation of reverse micelles or break the reverse micelle system. More specifically, no more than 2.5%, and preferably no glycerol (percent expressed by weight of glycerol / weight of acylglycerol) is used for the preparation of the reverse micelles of the present invention.
  • the aroma when the reverse micelle system further comprises a hydrophobic aroma, the aroma can also be introduced in step (a).
  • step (a) One can cite for instance colouring agents.
  • the compounds cited above or the commercially available mixtures containing them are the only ingredients introduced to prepare the micelle system and consequently the only ones present in the micelle system of the invention.
  • Stirring of step (b) may for instance be performed by mechanical stirring.
  • the common materials may be propellers whose fast movements generate turbulences and swirls allowing interpenetration of particles and formation of reverse micelles within the mixture.
  • Mechanical stirring speed is preferably ranging from 100 to 2 000 r/minute, more preferably from 300 to 700 r/minute.
  • the implemented volumes, device, and stirring speed depend on and should be adapted with the reactants and amounts thereof. Temperature is more specifically ranging from 15°C to 40°C, or from 25 °C to 40 °C, or even more specifically from 30 °C to 37 °C.
  • composition comprising the reverse micelle system
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the reverse micelle system according to the invention, and at least a pharmaceutically acceptable vehicle.
  • the pharmaceutical composition of the invention comprises a therapeutically effective amount of the reverse micelle system.
  • the pharmaceutical composition of the invention is preferably for mucosal administration, more preferably for buccal administration.
  • the pharmaceutical composition according to the invention comprises from 5 to 20 g of phospholipid or sphingolipid with respect to 100 g of composition, and from 5 to 15 g of water with respect to 100 ml of composition.
  • pharmaceutically acceptable vehicle is intended to include any and all carriers, solvents, diluents, excipients, adjuvants, dispersion media, coatings, antibacterial and antifungal agents, absorption agents and the like, well-known by the person skilled in the art, and compatible with administration in mammals and in particular human subjects.
  • Other additives well-known to the person skilled in the art such as stabilisers, drying agents, binders or pH buffers may also be used.
  • Preferred excipients in accordance with the invention promote adherence of the finished product to the mucosa.
  • the pharmaceutical composition is in the form of vial, airless bottle, non-airless bottle, unidose syringe, stick liquid, a capsule, a caplet, an aerosol, a spray, a solution or a soft elastic gelatin capsule.
  • the invention also relates to a buccal delivery system comprising a reverse micelle system according to the invention or a composition according to the invention, wherein the water-soluble active ingredient is intended to be administered within the buccal mucosa.
  • the reverse micelle system or pharmaceutical composition of the invention can be administered in different ways, in particular via the oral, nasal, vaginal or rectal route, preferably with a buccal, nasal, vaginal or digestive absorption, or more generally via mucosal tissue absorption.
  • the reverse micelle system or pharmaceutical composition of the invention is administered by buccal route.
  • the reverse micelle system or pharmaceutical composition of the invention is administered via mucosa.
  • “Mucosal delivery”, “mucosal administration” and analogous terms include, but are not limited to, the delivery of a composition through preferably buccal administration, bronchi, gingival, lingual, nasal, oral, vaginal, rectal, and gastro-intestinal mucosal tissue. Administration according to the invention is more preferably carried out via buccal mucosa.
  • a further aspect of the invention is the use of a vegetable oil, preferably a vegetable oil comprising long-chain fatty acids, in a reverse micelle system comprising sterol, acylglycerol, alcohol, water, water-soluble active ingredient, and phospholipid or sphingolipid, wherein the weight ratio phospholipid or sphingolipid/acylglycerol range from 0.05 to 0.55, for avoiding the occurrence of gelling of said reverse micelle system in an aqueous medium.
  • a vegetable oil preferably a vegetable oil comprising long-chain fatty acids
  • the invention relates to the use of more than 3 %, preferably at least 4%, of a vegetable oil in a reverse micelle system comprising sterol, acylglycerol, alcohol, water, water-soluble active ingredient, and phospholipid or sphingolipid, wherein the weight ratio phospholipid or sphingolipid/acylglycerol range from 0.05 to 0.55, for avoiding the occurrence of gelling of said reverse micelle system in an aqueous medium.
  • the invention relates to the use of more than 3 %, preferably at least 4%, of an olive oil in a reverse micelle system comprising sterol, acylglycerol, alcohol, water, water-soluble active ingredient, and phospholipid or sphingolipid, wherein the weight ratio phospholipid or sphingolipid/acylglycerol range from 0.05 to 0.55, for avoiding the occurrence of gelling of said reverse micelle system in an aqueous medium.
  • the vegetable oil and its content are preferably as defined above, in particular in the section “vegetable oil”.
  • 0,3384 g of lecithin were dissolved in 0,2030 g absolute ethanol by magnetic stirring at 300 r/min for 15 minutes at room temperature.
  • 0,0564 g B-sitosterol were added thereto and magnetic stirring at 300 r/min for 15 minutes at room temperature.
  • 0,1354 g of olive oil were thereto and magnetic stirring at 300 r/min for 15 minutes at room temperature.
  • 1,2588 g of glycerol monooleate were then added and magnetic stirring was carried out at 500 r/min for 45 minutes at 37°C to form oil mixture.
  • Example 2 Preparation of reverse micelle formulated with lithium citrate used as treatment for Alzheimer disease.
  • Example 3 Preparation of reverse micelle formulated with Calcium Diethylenetriaminepentaacetic Acid trisodium (CaNa3DTPA).
  • 0,2850 g of lecithin were dissolved in 0,1710 g absolute ethanol by magnetic stirring at 300 r/min for 15 minutes at room temperature.
  • 0,0475 g B-sitosterol were added thereto and magnetic stirring at 300 r/min for 15 minutes at room temperature.
  • 0,1140 g of olive oil were thereto and magnetic stirring at 300 r/min for 15 minutes at room temperature.
  • 1,0625 g of glycerol monooleate were then added and magnetic stirring was carried out at 500 r/min for 45 minutes at 37°C to form oil mixture.
  • Three pharmaceutical vegetable oils have been selected to be incorporated into the reverse micelle system: i) refined sesame oil (39% of oleic acid and 41% of linoleic acid), ii) refined soybean oil (21% of oleic acid and 55% of linoleic acid) and iii) refined olive oil (78% of oleic acid and 5,5% of linoleic acid).
  • 6 gr of reverse micelle system has been titrated by oil until apparition of turbidity.
  • Rheology measurements were performed using an Anton Paar Rheometer MCR92, Cone plates with 6 cm in diameter and an angle of 0,5° was used. Temperature was maintained at 25°C ⁇ 0. 1°C. Shear rate measurements were performed between 0.01 and 1000s 1 . A sample volume of 1 ml was used.
  • Blood samples 400 pL per time-point were collected at 2h, 3h, 4h and 24h after the treatment in the sinus retro-orbital using a capillary tube and stored in test tubes with anticoagulant. Animal were sacrificed 24 hours after the treatment and the brain will be collected, weighed, divided in two hemispheres and each half of brain will be stored frozen at target temperature of -20°C until shipment. Lithium concentration in blood and brain were determined by Inductively Coupled Plasma Mass Spectrometry (I CP -MS).
  • I CP -MS Inductively Coupled Plasma Mass Spectrometry
  • the aim of this study is to evaluate the impact of oil incorporation on the stability of microemulsion after dilution.
  • Three pharmaceutical oils sesame, soybean and olive oils have been tested by the titration method. Oil has been added gradually to the microemulsion until apparition of turbidity. The results shown that 26,3 wt% of sesame oil, 26,6 wt% of soybean and 29,2 wt% of olive oil can be incorporated into the microemulsion.
  • the solubilization efficiency of the five -component system Peceol/olive oil/B-sitosterol/lecithin/ethanol was evaluated by the preparation of partial pseudo-ternary phase diagram at constant Peceol/olive oil ratio of 85/15 (Fig 1).
  • the colored area in the explored zone of the phase diagram represents the monophasic reverse microemulsion region.
  • the extension of the microemulsion zone toward the water rich comer increases slightly in the Peceol rich region up to 10wt% of lecithin/ethanol and then increases gradually with the amount of lecithin/ethanol to reach a maximum at 24 wt% of water.
  • the area of the olive oil based microemulsion and the olive oil free microemulsion represents respectively 23% and 23,3% of the total explored zone in the phase diagram.
  • the impact of olive oil incorporation on the extent of the monophasic domain studied in comparison with the olive oil free system doesn’t seem to be significant.
  • the phase behavior and the in-situ gelling properties of the system were significantly affected by addition olive oil in the water rich region of the phase diagram.
  • the olive oil free microemulsions demixed first into a clear liquid (fully hydrated microemulsion) with excess water and then forms a turbid gel with high capacity of drug retention, formulations with higher values of consistency and viscosity impose resistance to the movement of internal phase of the system and which can impact strongly their drug release properties.
  • Our finding show that adding olive oil to the system disturbed the formation of this gel liquid crystal in the water rich region of the phase diagram, increased the dilution rate of the microemulsion and consequently its ability to sustain drug release upon contact with saliva in the oral cavity.
  • results of viscosity measurement of the olive oil free system achieved in the upper microemulsion phase showed a strong increment in viscosity to reach a value of 1065 mPas.
  • the shift in the viscosity beyond the water saturation point cannot be interpreted in terms of water content (dispersed phase volume) and may be related to a structural transition mechanism from microemulsion to liquid crystalline phases (gels).
  • Microemulsions exhibit lower viscosities whereas liquid crystalline phases exhibit higher viscosities and complex rheology.
  • 1,4250 g of lecithin was dissolved in 0,8550 g absolute ethanol by magnetic stirring at 300 r/min for 15 minutes at room temperature.
  • 0,2375 g B-sitosterol were added thereto and magnetic stirring at 300 r/min for 15 minutes at room temperature.
  • 0,610 g of olive oil were thereto and magnetic stirring at 300 r/min for 15 minutes at room temperature.
  • 5,1725 g of glycerol monooleate were then added and magnetic stirring was carried out at 500 r/min for 45 minutes at 37°C to form oil mixture.
  • 1,2 g of a lithium citrate solution containing 8,12 mg of lithium were added to 8,3 g of the oil mixture and stirred at room temperature by magnetic stirring at 700 r/min for 15 minutes to form reverse micelles containing 600 pg of Li/ml.
  • 1,4250 g of lecithin was dissolved in 0,8550 g absolute ethanol by magnetic stirring at 300 r/min for 15 minutes at room temperature.
  • 0,2375 g B-sitosterol were added thereto and magnetic stirring at 300 r/min for 15 minutes at room temperature.
  • 5,7825 g of glycerol monooleate were then added and magnetic stirring was carried out at 500 r/min for 45 minutes at 37°C to form oil mixture.
  • 1,2 g of a lithium citrate solution containing 8,12 mg of lithium were added to 8,3000 g of the oil mixture and stirred at room temperature by magnetic stirring at 700 r/min for 15 minutes to form reverse Results
  • the aim of this study was to evaluate the pharmacokinetic of metal lithium in the blood and the delivery of lithium in the brain as a function of reverse microemulsion formulated with and without olive oil, composition of formulation and procedure of preparation are detailed above.
  • the formulations were administrated via muco-buccal route.
  • Example 5 Texture assessment of olive oil based reverse micelle system (microemulsion) in contact with buccal mucosa
  • microemulsions (reverse micelle system according to the invention) containing increasing quantity of olive oil (up to 10 wt%) were tested.
  • the formulations were applied by each participant on the buccal mucosa (in contact with cheek) using plastic pipette of approximately 1,5 mb of microemulsion so that each participant could evaluate the same amount of product.
  • Table 1 The formulation composition and preparation are detailed hereafter (Table 1), the results are presented in Table 2: 1,4250 g of lecithin was dissolved in 0,8550 g absolute ethanol by magnetic stirring at 300 r/min for 15 minutes at room temperature. 0,2375 g B-sitosterol were added thereto and magnetic stirring at 300 r/min for 15 minutes at room temperature. (Y) g of olive oil were thereto and magnetic stirring at 300 r/min for 15 minutes at room temperature. (X) g of glycerol monooleate were then added and magnetic stirring was carried out at 500 r/min for 45 minutes at 37°C to form oil mixture. 1,2 g of purified water were added to 8,3 g of the oil mixture and stirred at room temperature by magnetic stirring at 700 r/min for 15 minutes to form empty reverse micelles.
  • Table 2 results of texture assessment of olive oil based microemulsions in contact with buccal mucosa
  • the formulation including 3% oil prevents partially the gelling but leads to the formation of a persistent film on the palate and inside the cheeks. Above this percentage the formulations do not form a gel in contact with saliva into the oral cavity.

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Abstract

La présente invention concerne un système micellaire inverse comprenant du stérol, de l'acylglycérol, de l'alcool, de l'eau, un principe actif soluble dans l'eau, un phospholipide ou un sphingolipide, le rapport pondéral phospholipide ou sphingolipide/acylglycérol allant de 0,05 à 0,55 et une autre huile végétale. L'invention concerne également le procédé de préparation dudit système micellaire inverse, son utilisation et une composition pharmaceutique le comprenant.
PCT/EP2024/055773 2023-03-06 2024-03-06 Formulation pour l'administration buccale d'un système micellaire inverse biocompatible Pending WO2024184369A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1652512A1 (fr) * 2004-11-02 2006-05-03 Medesis Pharma Composition à base de micelles inverses pour l'administration de cations métalliques comprenant un diglycéride et un phytostérol, et procédé de préparation
WO2011117334A2 (fr) 2010-03-24 2011-09-29 Medesis Pharma Système de micelle inverse comprenant des acides nucléiques et son utilisation
WO2011117333A2 (fr) 2010-03-24 2011-09-29 Medesis Pharma Système de micelle inverse comprenant des ions métalliques et son utilisation
WO2015124581A1 (fr) 2014-02-18 2015-08-27 Medesis Pharma Utilisation d'un système micellaire inverse dans la libération de chélateurs de radionucléides et de métaux
WO2017005899A1 (fr) 2015-07-09 2017-01-12 Medesis Pharma Préparation in situ de nanoparticules à pont cyano, à l'intérieur d'un système micellaire inverse biocompatible
WO2020008032A1 (fr) * 2018-07-06 2020-01-09 Medesis Pharma Traitement et prévention d'une lésion provoquer par une exposition à un rayonnement

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1652512A1 (fr) * 2004-11-02 2006-05-03 Medesis Pharma Composition à base de micelles inverses pour l'administration de cations métalliques comprenant un diglycéride et un phytostérol, et procédé de préparation
WO2011117334A2 (fr) 2010-03-24 2011-09-29 Medesis Pharma Système de micelle inverse comprenant des acides nucléiques et son utilisation
WO2011117333A2 (fr) 2010-03-24 2011-09-29 Medesis Pharma Système de micelle inverse comprenant des ions métalliques et son utilisation
EP2549980A2 (fr) 2010-03-24 2013-01-30 Medesis Pharma Compositions a base de micelles inverses contenant d'acides nucléiques et leur applications
EP2550020A2 (fr) 2010-03-24 2013-01-30 Medesis Pharma Microemulsion de micelles inverses contenant des ions metalliques et leur utilisation
WO2015124581A1 (fr) 2014-02-18 2015-08-27 Medesis Pharma Utilisation d'un système micellaire inverse dans la libération de chélateurs de radionucléides et de métaux
WO2017005899A1 (fr) 2015-07-09 2017-01-12 Medesis Pharma Préparation in situ de nanoparticules à pont cyano, à l'intérieur d'un système micellaire inverse biocompatible
WO2020008032A1 (fr) * 2018-07-06 2020-01-09 Medesis Pharma Traitement et prévention d'une lésion provoquer par une exposition à un rayonnement

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