Classifications

• • C—CHEMISTRY; METALLURGY
  • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
  • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
  • C09K19/00—Liquid crystal materials
  • C09K19/04—Liquid crystal materials characterised by the chemical structure of the liquid crystal components, e.g. by a specific unit
  • C09K19/06—Non-steroidal liquid crystal compounds
  • C09K19/061—Linear compounds without any rings
• • 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
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
• • 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
  • A61K31/12—Ketones
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
• • 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
  • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• • 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
  • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites

Definitions

• the low water-soluble power of these active molecules is a challenge for the development of solid and effective oral compositions, in particular in terms of formulation, bioavailability, control of the release of the active ingredient and the marketing of new pharmaceutical products. .
• the LFCS classification system Lipid Formulation Classification System
• lipid formulations can be classified into four different categories: types I, II, III (A and B) and IV (Table 1):
• Type I made up of mono, di or triglycerides in which the active substance is dissolved. These systems must be digested by gastric or pancreatic enzymes to form amphiphilic products and thus maintain the active substance dissolved in the gastrointestinal fluids.
• Type II these formulations incorporate 20 to 60% of surfactants with a Hydrophilic / lipophilic balance (Hydrophilic Lipophilie Balance, HLB) of less than 12. They constitute in particular, self-emulsifying systems (Self-Emulsifying Drug).
• HLB Hydrophilic / lipophilic balance
• SEDDS oil-in-water emulsions with low agitation and independent of enzymatic digestion.
• SEDDS oil-in-water emulsions with low agitation and independent of enzymatic digestion.
• the SEDDS form opaque emulsions with emulsion droplets larger than 100 nm.
• Type III containing a lipid part, hydrophilic surfactants (HLB> 12) and co-solvents, they can form SEDDS but also SMEDDS (Self-Micro Emulsifying Drug Delivery Systems) or SNEDDS (Self-Nano Emulsifying Drug Delivery Systems).
• SMEDDS Self-Micro Emulsifying Drug Delivery Systems
• SNEDDS Self-Nano Emulsifying Drug Delivery Systems.
• the emulsions formed by the SMEDDS have particle sizes less than 100 nm and are opalescent or transparent.
• the nanoemulsions formed by SNEDDS are transparent with droplets smaller than lOnm.
• type III formulations there are types III a, exhibiting a lipid content of 40 to 80%, and types III b, which are more soluble in water (less than 20% oil). The latter have better dispersion but an increased risk of API precipitation, due to the large proportion of hydrophilic co-solvent (20 to 50%).
• Type IV devoid of lipid part, these systems consist only of mainly hydrophilic surfactants, and co-solvents. They make it possible to dissolve a large amount of active substance and thus increase the dose loaded in the formulation.
• the dispersion of type IV formulations in water forms micellar solutions with a clear appearance.
• a solid is characterized by a regular stacking of molecules, atoms or ions on a periodic lattice in the three directions of space. Position correlations are said to be long-range.
• Liquid crystals have long-range orientation or position order while maintaining liquid-like disorder in at least one of the spatial directions. They are therefore systems having a number of symmetries intermediate between those of the solid and liquid phases. There are many mesophases which differ in the type and degree of self-organization of molecules. This collective directional behavior depends on the nature and structure of the mesogens but also on a certain number of external parameters such as mechanical, electrical or magnetic forces.
• a liquid crystal is a state of matter which combines properties of a conventional liquid and those of a crystallized solid. Its state is expressed by the term mesophase or mesomorphic state (from the Greek "of intermediate form").
• mesophase or mesomorphic state (from the Greek "of intermediate form").
• the nature of the mesophase differs according to the nature and structure of the mesogen, the molecule at the origin of the mesophase, as well as the conditions of temperature, pressure and concentration.
• thermotropic liquid crystals There are two main classes of liquid crystals: thermotropic liquid crystals and lyotropic liquid crystals. Thermotropes change phase as a function of temperature while lyotropes are substances in which mesophases are induced by the presence of a solvent and depend on the concentration of the solvent as well as on the temperature.
• the molecules making it possible to generate thermotropic phases as well as lyotropic phases in the presence of solvent are called amphotropic.
• the different mesophases can also be distinguished by their different optical properties, such as birefringence.
• liquid crystals when interacting with light show remarkable optical properties that are different from those of a simple liquid phase.
• thermotropic liquid crystals CLT
• CLL lyotropic liquid crystals
• thermotropic liquid crystals the shape of molecules dictates the order of orientation, and thermal motion gives mobility.
• Lyotropic liquid crystals are governed by the relative concentration of the solute.
• a lyotropic liquid crystal is made up of two or more components that exhibit liquid crystal properties in certain concentration ranges.
• lyotropes Unlike thermotropic liquid crystals, lyotropes have an additional degree of freedom of concentration which allows them to induce a variety of different phases.
• thermotropic and lyotropic would not be complete without mentioning amphotropic liquid crystals which exhibit both thermotropic and lyotropic properties.
• the liquid crystal classification scheme divides them into three different types of mesogens, based on the order level of molecules in the material mass. This structural classification is based on criteria of order and symmetry in molecular arrangements and includes three liquid crystal phases: • The nematic phase
• This collective directional behavior depends on the nature and structure of the mesogens but also on a certain number of external parameters such as mechanical and / or thermodynamic and / or chemical and / or electrical forces, and / or optical and / or magnetic.
• the different mesophases of liquid crystals can be distinguished by optical properties such as birefringence.
• optical properties such as birefringence.
• a liquid crystal material When viewed through a microscope under polarized light, a liquid crystal material will appear to be made up of areas of distinct texture. Each "zone" corresponds to a domain where the molecules are oriented in a different direction.
• the BCS system
• the biopharmaceutical classification system is a system for differentiating active ingredients according to their solubility and permeability. This system restricts the prediction using the parameters of solubility and intestinal permeability.
• the classification of solubility is based on the American Pharmacopoeia, while that of intestinal permeability is based on a comparison with intravenous injection. All of these factors are very important because 85% of the top-selling drugs in the United States and Europe are administered orally.
• bioavailability of these products is limited by their solvation rate.
• a correlation between bioavailability in vivo and solvation in vitro can be found.
• Class IV - low permeability, low solubility These compounds have poor bioavailability. Usually they are not well absorbed from the intestinal mucosa and a high variability is expected, this is due to the fact that a small variation in bioavailability results in a large relative variation thereof.
• the active ingredients are classified on the basis of solubility, dissolution (the rate of dissolution) and permeability.
• solubility class is based on the highest dose of an immediate release product.
• a drug is considered highly soluble when the highest dose is soluble in 250 ml or less of aqueous medium in a pH range of 1 to 7.5.
• the volume estimate of 250 ml is derived from typical bioequivalence study protocols which prescribe the administration of a drug product to fasting human volunteers with a glass of water.
• an immediate release product is considered to dissolve rapidly when at least 85% of the labeled amount of the drug substance dissolves in 15 minutes using the USP 1 dissolver at 100 rpm or the device 2 at 50 rpm in a volume of 900 ml or less in the following media:
• HLB is a method, proposed in 1949 by Griffin, which makes it possible to quantify the balance existing between the hydrophilic part and the lipophilic part of the surfactant molecule, an equilibrium linked to the solubility in water.
• the scale varies from 0 to 20: the higher the value, the greater the solubility in water.
• the invention describes novel structures of betaine in the form of lyotropic and / or anisotropic and / or amphotropic liquid crystals.
• these new liquid crystals behave like nanoemulsions with the remarkable and unique feature of being completely free of oils or lipid compounds with the exception of the lipid entities which they would transport and / or which they would dissolve.
• the invention claims a unique hybrid character of the present forms and / or the present vectors. Indeed, in addition to their character of new liquid crystals, the present forms also constitute a new and fifth category in the LFCS classification which has only four.
• Types IV are subjected to precipitation phenomena when they are resolubilized in water (ionic forces), phenomena to which the products of the invention resist remarkably over long periods (test in H20). .
• the present invention describes these new liquid crystals with remarkable properties and which constitute new chemical and / or physical and / or biological entities.
• the present invention also describes the new processes for obtaining these new chemical and / or biochemical and / or physical entities in the form of liquid crystals and / or nano-emulsions and / or nano-crystals.
• the present invention also describes the combinations and / or new associations of these liquid crystals and / or new vectors with various soluble, sparingly soluble or insoluble entities, for obtaining new pharmaceutical and / or chemical and / or biochemical and / or biochemical entities. physical in the form of liquid crystals.
• hydrophobic actives / entities having a LogP greater than 1, preferably a LogP greater than 1.5 "more preferably a LogP greater than 2" preferably a LogP greater than 3 "more preferably a LogP greater than 4" more preferably a LogP greater than 5 ", advantageously a LogP greater than 6", preferentially a LogP greater than 7 ", even more preferably a LogP greater than 8, very preferably a LogP greater than 9.
• anhydrous betaine is preferred.
• the monohydrate form can also be used.
• each surfactant is assigned a number between 1 and 20, the whole constituting the Griffin scale. This number is called the HLB index (Hydrophilic / Lipophilic Balance) the index 1 is given to oleic acid and the index 20 to potassium oleate.
• HLB index Hydrophilic / Lipophilic Balance
• This scale makes it possible to assess the lipophilic or, on the contrary, the hydrophilic character of an amphiphilic.
• HLB index less than 9 will make the amphiphile say that it is lipophilic (it will then be used as an anti-foaming agent (if HLB ⁇ 3), as a water-in-oil emulsifier (if 3 ⁇ HLB ⁇ 6) and as a wetting agent beyond) and an index greater than 10 that it is hydrophilic (it will be used as an emulsifier of oil in water (if 9 ⁇ HLB ⁇ 13), as a detergent (if 13 ⁇ HLB ⁇ 15) and as a solubilizer above 15.
• the surfactant and / or the surfactant and / or the surfactant is water-soluble and has an HLB greater than or equal to 10, HLB being the “hydrophilic / hydrophobic balance”.
• the water-soluble surfactant having an HLB greater than or equal to 10 can also be chosen from the groups consisting of esters of PEG-6 of almond oil, esters of PEG almond oil.
• apricot kernel oil PEG-6 esters capric triglycerides PEG-4 esters, caprylic / capric triglyceride complexes PEG-4, caprylic / capric glycerides PEG-6 esters, caprylic / capric glycerides PEG-8 esters , castor oil PEG-50 esters, hydrogenated PEG-5 esters, hydrogens Castor oil PEG-7 esters, 9 hydrogenated castor esters PEG-9, corn oil PEG-6 esters, corn oil PEG-8 esters, glycerides corn PEG-60 esters, olive oil PEG-6 esters, hydrogenated palm oil / palm kernel PEG-6 esters, palm kernel oil / hydrogenated palm kernel PEG-6 esters with palm kernel oil and PEG-6 and palm oil, palm kernel oil PEG-40 esters, peanut oil esters PEG-6, glycerol esters of saturated C8-C18 fatty acids, glyceryl esters of C12-C18 saturated fatty acids,
• water-soluble surfactants having an HLB greater than or equal to 12 of the above list being according to the invention preferred.
• polysorbates or Tween 20 (E432- HLB 15), Tween 80 (E433- HLB 15), Tween 40 (E434- HLB 15,6), Tween 60 (E435- HLB 14) , 9), Tween 65 (E436- HLB 10.5), as well as their mixtures, will be preferred due in particular to their low toxicities, their low costs, their ease of use, their effectiveness, as well as their uses at room temperature ( 15 to 25 ° C - or even 30 ° C and more) for the production of liquid crystals and / or for the production of compositions comprising the liquid crystals of the invention and / or the liquid crystals of the invention comprising cargo entities and / or host entities and / or active hydrophobic entities.
• the plant saponins in general and particularly the extracts of the plant Quillaja Saponaria Molina (E999) can be used as surfactants in replacement of polysorbates and / or other surfactants, and / or in combinations with polysorbates and / or other surfactants.
• the Quillaja Saponaria Molina extract typically contains molecules of nonionic surfactant types which can reorganize into micelles with high emulsifying power. In the context of the invention, they can replace and / or advantageously supplement the polysorbate (s) in formulations and / or products claiming compositions 100% of plant origin and / or claiming better acceptability and / or tolerability by the user.
• the present liquid crystals require, due to the use of betaine, minimum or much smaller amounts of surfactants such as polysorbates.
• surfactants such as polysorbates.
• the preferred solvent is water for obtaining the present liquid crystals.
• liquid crystals when used to solubilize certain molecules and / or hydrophobic entities, it may prove to be useful and / or necessary and / or desirable during the production procedure, to solubilize said molecules and / or hydrophobic entities in a water-miscible organic solvent, such as ethanol and / or methanol and / or propanol and / or butanol and / or DMSO and / or chloroform and / or similar water-soluble solvents.
• a water-miscible organic solvent such as ethanol and / or methanol and / or propanol and / or butanol and / or DMSO and / or chloroform and / or similar water-soluble solvents.
• any water-miscible solvent also making it possible to dissolve the cargo / host entity can be used; provided that this solvent can be removed, preferably completely removed, in a subsequent stage of production of the final product, to obtain a dry and / or substantially dry product free and / or substantially free of this solvent; and / or liquid and / or capable of being in liquid form, substantially free of this solvent.
• the solvent can also be used for liquid and / or semi-liquid formulations and / or in the form of gels.
• the final dry forms ie. forms free and / or substantially free from liquids and / or liquid solvents (other than or the surfactants of the invention) will be preferred.
• These final dry forms are preferably in pulverulent forms, powders, micro-powders (micronized), chips, granules, micro-granules; as well as their combinations.
• the dry forms exhibit properties of increased stability.
• betaine liquid crystals can be formed and / or organized beyond the critical micellar concentration (CMC) of betaine and in the presence of a precise amount of one or more surfactants and / or nonionic surfactants having an HLB greater than or equal to 10, preferably greater than 12, preferably greater than 14.
• CMC critical micellar concentration
• the mixtures are preferably made in the strict proportions of the invention, the preferred solvent being water. It is important to note that too low concentrations of surfactants, as well as too high concentrations of surfactants give bad results or no results at all with, in particular in the case of high concentrations of surfactants, whitish solutions whose particle size exceeds 500 nanometers. .
• Types I, II, Ilia & 111b which all contain oils impossible to dry, and we only retain Type IV which is free of oils but contains by against water-soluble surfactants (HLB> 12) in a proportion of S0 to 80% which are impossible to dry, not to mention other ingredients such as water-insoluble surfactants (0 to 20%) and co-solvents hydrophilic such as PEG, propylene glycol or Transcutol ® (0 to 50%) which are also impossible to dry.
• water-soluble surfactants HLB> 12
• water & cargoes not included water & cargoes not included
• betaine betaine
• the products in dry form are obtained in a crystallization step after evaporation of the water and of the possible other solvent in addition. Since the cargo entities are enveloped, their lipophilic characteristics cannot be expressed and do not come into account in the drying processes.
• Usual proportions of the ingredients, for the formation of the present liquid crystals and / or nano-emulsions and / or vectors and / or carriers, are in percentage by weight between 25 and 75% betaine, 25 and 75% water and / or solvent and between 0.1% and 10% surfactant (s), to which can be added, if desired, the host / cargo entity to be solubilized / encapsulated / transported.
• a usual mixture according to the invention consists of 2 grams of betaine, 2 milliliters of water (2 g) and 50 to 100 milligrams of surfactant having an HLB greater than 12, to which one or more entities and / or can be added. or insoluble cargoes.
• Usual proportions of cargo and / or host entities which according to the invention may be situated in percentage by weight in their mixtures with liquid crystals between 0.1% and 20%.
• the total percentage betaine (s) / solvent (s) / surfactant (s) / cargo unit (s) being 100%.
• one of the many mixtures of the invention, to form the present liquid crystals, with possibly their cargoes could be composed as follows: 2 grams of anhydrous betaine, 2 grams of 'water, 50 to 100 mg of surfactant and 100 mg to 200 mg of cargo / host entity, the mixture being carried out at room temperature (between 15 ° C and 30 ° C) and at a normal atmospheric pressure of 1 (1013 , 25 hPa).
• the solubilization processes are advantageously carried out at room temperature and under normal atmospheric pressure.
• the profile of the host / cargo entity requires it, these conditions can be varied by a factor of
• the weight of the cargo entity may preferably be greater than that of the surfactant.
• the order and the sequences of mixtures and / or solubilizations of the ingredients, as well as the respective proportions of said ingredients are important because they condition the quality and the properties of liquid crystals obtained. Varying these parameters can lead to results ranging from no effect at all (no formation of the LCs of the invention) to 100% of solubilization and / or encapsulation effects.
• the mixing conditions are important, especially by way of example but not limited to mixtures by centrifugation and / or mixtures by ultrasound and / or mixtures by cavitation and / or by shear forces and / or or mixtures by pressure and / or mixtures under specific thermal conditions.
• These conditions can influence and / or generate and / or organize and / or induce and / or condition the director of the present liquid crystals.
• the director being the vector indicating the average direction of alignment and / or organization and / or orientation of the molecules of the present liquid crystals.
• the director of the present liquid crystals can be induced and / or influenced and / or generated and / or directed by mechanical and / or thermodynamic and / or shear and / or chemical and / or electrical and / or forces. optical and / or magnetic, as well as their combinations and / or their alternations.
• the methods of centrifugations 500 to 10,000 revolutions / minute) and / or ultracentrifugations (10,000 to 100,000 revolutions / minute) being preferred, alone or in combination with other induction means ( cited above), both for their efficiency in obtaining the present liquid crystals and for the ease of their use.
• these methods of centrifugations and / or ultracentrifugations and / or cavitations and / or shears, in addition to generating / conditioning the directors of present liquid crystals prove to be particularly useful when it comes to 'integrate and / or imprison and / or load and / or house and / or associate and / or encapsulate and / or solubilize the cargo entities described in the invention.
• the production procedures for making the present crystals can also be carried out at ambient temperatures (15 to 25 ° C, or even 30 ° C and above).
• the present invention can be carried out at room temperature, it is particularly indicated for the development of vaccines and / or products and / or molecules and / or proteins and / or fragments of living organisms, having a sensitivity and / or a lack stability and / or denaturation when exposed to heat and / or excess calories.
• the liquid crystals associated with their cargoes and / or the resulting products are suitable for being subjected and / or being subjected to one or more solubilization processes and / or to one or more drying processes and / or to one or more heating processes and / or one or more dehydration processes and / or one or more lyophilization processes and / or one or more atomization processes and / or one or more precipitation processes and / or or to one or more sedimentation processes and / or to one or more gravitation processes and / or to one or more cryonics processes and / or to one or more irradiation processes and / or to one or more separation processes and / or to one or more skimming processes and / or one or more sonication processes and / or one or one or more ultrasonic processes and / or one or more trituration processes and / or one or more mixing processes and / or one or one or more magnetic mixing processes and / or one or more acoustic mixing processes and / or one or
• the present betaine liquid crystals possess birefringence properties.
• the present betaine liquid crystals possess amphotropic properties, i.e. can exhibit thermotropic properties (be temperature dependent) and / or lyotropic properties (be concentration and / or concentration dependent). temperature).
• the mesophases of betaine liquid crystals organize themselves and / or have an internal interfacial zone consisting of hydrophilic domains and hydrophobic. These domains are distinct, separate and capable of trapping hydrophilic and / or hydrophobic and / or amphiphilic entities.
• the porosity at the nanometric scale of the present betaine liquid crystals provides a large internal and external surface in which, according to the present invention, the hydrophobic entities and / or active agents are housed and / or inserted and / or associated. and / or hydrophilic and / or amphiphilic of interest. We can speak of "molecular sponges".
• the present liquid crystals can be ordered in a hexagonal columnar phase, where the betaine molecules and the surfactant (s) (HLB> 12) form long cylinders which are arranged in a hexagonal network. It can be said that the present liquid crystals form molecular cannelloni, said cannelloni being able to encapsulate and / or to transport and / or to associate with other entities, in particular entities having a LogP greater than 2. In this respect. case the cargo entities and / or companions would constitute the stuffing of said cannelloni.
• the present liquid crystals can be ordered in a lamellar phase, where the betaine molecules and the surfactant (s) (HLB> 12) form long sheets separated by thin layers of water. It can be said that the present liquid crystals form molecular pasticcios, said pasticcios being able to encapsulate and / or to transport and / or to associate with other entities, in particular entities having a LogP greater than 2. In this case the cargo and / or companion entities would constitute the stuffing of said pasticcios.
• the present liquid crystals can be ordered in cubic phase (also called viscous isotropic), where the betaine molecules and the surfactant (s) (HLB> 10) form spheres creating a dense cubic network. . These spheres can also be connected to each other, forming a bicontinuous cubic phase.
• cubic phase also called viscous isotropic
• the present liquid crystals are of hexagonal phase (hexagonal cylindrical phase) and / or of lamellar phase and / or of bicontinuous cubic phase depending on the concentration of betaine and / or depending on the betaine / surfactant ratio and / or of the betaine / solvent ratio.
• the present liquid crystals can also be ordered in Inverted hexagonal columnar phase and / or Inverted cubic phase in micellar phase depending on the concentration of betaine and / or depending on the betaine / surfactant ratio and / or the betaine / ratio. solvent.
• Ton can generate reverse phases such as reverse hexagonal columnar phases (water columns encapsulated by betaines + surfactants) and / or reverse micellar phases (liquid crystals with cavities. spherical water).
• reverse phases such as reverse hexagonal columnar phases (water columns encapsulated by betaines + surfactants) and / or reverse micellar phases (liquid crystals with cavities. spherical water).
• each crystal obtained can be characterized by one or more measurements chosen from the group of: solubility of (mg / ml), a size of, density, diffraction, refraction, reflectivity, photo-reactivity, polarization , wavelength, viscosity, conductivity, solubility, microscopy, resistivity, structure, spectroscopy, mass spectroscopy, Raman spectroscopy, DLS, NMR, HPLC, melting point, cloud point, cargo,% cargo, hygroscopy, volumetric weight , Isoelectric point, Kraft point, Stockes displacement, calorimetry, microcalorimetry as well as all other state-of-the-art measurements used to characterize a crystal and / or a nanocrystal.
• solubility of mg / ml
• each liquid crystal and / or each hydrophobic substance / liquid crystal combination will have a unique profile according to the invention and may be considered as a new chemical entity. and / or physical and / or therapeutic.
• the modular and versatile side of the present liquid crystals constitutes a real advantage, due to the simplicity of their embodiments as well as their various industrial destinies.
• the manufacturing procedures for making the present crystals can be carried out at ambient temperatures (15 to 30 ° C). Likewise, the procedures of drying and / or removal procedures of the solvent (s) can be carried out below 70 ° C, preferably at temperatures which do not denature the cargoes (proteins, peptides, RNA, DNA, aptamers, envelopes of viruses and / or bacteria, biological entities, fragments of living things, etc.), which is a real advantage.
• the cargoes proteins, peptides, RNA, DNA, aptamers, envelopes of viruses and / or bacteria, biological entities, fragments of living things, etc.
• the liquid crystals of the invention in addition to their solubilizing powers, can also offer the host / cargo entities protection against attacks tending to denature them.
• These protective activities extend in particular to the actions that could have, on the cargo entities mentioned above, physical and / or chemical and / or biological and / or enzymatic and / or light denaturants (photo-oxidation) other than temperature. .
• the present liquid crystals can advantageously replace most formulations of the prior art.
• the present products form nanostructures in solution and that these stable nanostructures made it possible, in addition to dissolving the host entities, to improve their dissolution profiles in water, and / or in physiological fluids.
• the present liquid crystals provide encapsulation properties. and / or combinations making it possible to optimize the stability and / or acceptability and / or safety and / or efficiency profiles of these entities.
• Stabilities in the present context means the protection provided by these crystals against degradations such as oxidation and / or light and / or UV and / or acids and / or enzymes and / or any biological and / or chemical phenomenon and / or physical which would deteriorate and / or denature the cargo entities before they are delivered to the target sites (cells and / or tissues and / or organs).
• the present crystals are suitable and / or suitable for being subjected to the reduction and / or elimination of their solvents in order to initiate a nucleation (or germination) preferably spontaneous which corresponds to the appearance of a stable crystalline phase obtained from supercooled liquids and / or supersaturated solutions.
• This nucleation being of the heterogeneous primary type with germs forming on the walls of the container, in opposition to the homogeneous primary nucleation of betaine solutions alone where the germs remain confined in the volume of the solution (Fig. 1).
• heterogeneous nucleation requires much less energy than homogeneous nucleation.
• the betaine / surfactant combinations (HLB> 10) in the proportions of the invention induce new heterogeneous nucleations.
• nucleations prove to be particularly useful for the syntheses and / or crystallizations and / or the methods of concentration of forms containing proteins and / or fragments and / or whole parts derived from living organisms (insulins, viruses, DNA, RNA, etc. aptamers, enzymes, etc.). They also allow and / or similar ways of concentrating and / or transporting the other cargo entities of the invention.
• the present crystals have crystallization governed by the topology of the container. Under particular conditions, the present crystals can also self-assemble and / or self-crystallize at ambient temperatures.
• the present cargo entities promote and / or optimize the formation of these heterogeneous nucleations.
• the present liquid crystals transform the cargo entities into their most stable AND simultaneously the most soluble polymorphs. This is quite unexpected in view of the prior art. (Nucleation and phase transitions in pharmaceutical chemistry - Laurent Lafferere - Thesis September 2002).
• the growth of the present crystals appears to be of the coral type with columns and / or concretions which grow stacking on top of each other; these kind of structures can be fractal representations of the molecular structures of the present liquid crystals.
• the crystals of the invention show rates, growth amplitudes, crystal volumes, original densities, as well as new macroscopic and / or microscopic and / or molecular shapes. Unexpectedly, the liquid crystals of the invention are transformed on drying into crystals possessing a particular capacity for growth.
• liquid crystals of the invention possess, in certain betaine / solvent / surfactant proportions, a cloud point which is temperature dependent.
• the invention also describes a process for forming liquid crystals by nucleation (or germination) corresponding to the appearance of a stable crystalline phase from a supercooled liquid and / or a solution supersaturated with betaine.
• the process continues with crystal growth, that is, the increase in the size of the seeds to lead to crystals. It is characterized by the stacking on the surface of the crystal of new particles which are lodged in preferential sites.
• the 2 models of germination of crystals resulting from supersaturated solutions can be applied:
• critical size crystalline clusters smaller than the critical size tend to redissolve under the effect of thermal fluctuations; conversely, crystal clusters larger than the critical size tend to grow on average, until they form macroscopic crystals.
• the second model applies for the crystallization of proteins and is based on the formation of a crystalline cluster (cluster) containing a solution of the species to be crystallized, followed by the orderly reorganization of these species. to give a germ which, like the classic model, grows to give a crystal.
• the solutions on drying turn into crystals having a particular growth capacity, that is to say a growth which is appreciably different from that, if any, of its ingredients, in particular betaine alone in solution.
• the surfactants of the invention do not crystallize or only slightly or very hardly on drying, which induces a viscous and / or sticky final product and little or no pulverulent.
• the solutions from which these crystals are derived make it possible to solubilize and / or increase the bioavailability and / or increase the half-life and / or increase the efficiency and / or increase the safety and / or be physiological vectors and / or constitute stealth vectors and / or protective envelopes for different molecules and / or compounds and / or entities that are poorly or not soluble.
• the germination / nucleation processes make it possible to optimize the quality and / or the proportion and / or the quantity and / or the content of the cargo ingredients in the final composition and / or in particular to reduce, preferably significantly, the amounts of surfactants (HLB sup 10) used.
• the reduction in the amount of surfactants is advantageous and desirable with regard to the safety and acceptability of the final products by living organisms.
• the present liquid crystals are suitable for being subjected to one or more crystallizations to obtain a powder and / or a dry product and / or a salt and / or crystals, free and / or or substantially free of water and / or free of solvents.
• the invention also describes the nucleation or germination of the present liquid crystals to obtain a water-soluble crystal and / or crystalline form. According to the invention, this growing crystallization surprisingly makes it possible to optimize the solubility properties and / or the stability of the cargo entities and / or combinations of the invention.
• drying makes it possible to set the structures and / or nanostructures obtained until administration.
• the stabilities of compositions of the invention are therefore increased compared to those of the existing formulations.
• the drying processes used according to the invention can be all those known from the state of the art and can for example be processes using heat and / or cold and / or air and / or pressure and / or any process known to those skilled in the art making it possible to eliminate or substantially eliminate one or more liquid solvents.
• the drying processes should preferably respect the formation of crystals and / or the quality of the cargo entities by being so-called "soft" processes, that is to say now and / or optimizing the properties of the ingredients and / or of the cargoes and / or associations.
• the drying operations can take place at temperatures below 100 ° C, preferably below 90 ° C, more preferably below 80 ° C, preferably below 70 ° C, so preferably less than 60 ° C, more preferably less than 50 ° C%, advantageously less than 40 ° C, preferably less than 30 ° C, even more preferably less than 20 ° C, very preferably less than 10 ° C.
• the drying methods according to the invention can be all those known from the state of the art and can for example be methods using heat and / or cold and / or air and / or pressure.
• the present dry and / or substantially dry products obtained having a moisture content and / or a liquid content of less than 10%, preferably less than 9%, more preferably less than 8%, preferably less than 7%. %, preferably less than 6%, more preferably less than 4%, advantageously less than 2%, preferably less than 1%, even more preferably less than 0.5%, very preferably less 0.1%.
• the present pulverulent products and / or dry and / or substantially dry products being stable and capable of being resolubilized in one or more solvents, preferably water, and / or one or more physiological liquids.
• the present products and / or processes having fixed and / or substantially fixed and / or stabilized dissolution and / or solubilization properties over time.
• the present powdery products and / or dry and / or substantially dry products having a stability such that when resolubilized in water over a period of 1 to 36 months, the solubility and / or the content of API (entity host) and / or the particle size and / or the Zeta potential and / or the polydispersity of the particles in the solutions obtained are substantially similar to those of the initial solution with a variation of less than 20%, preferably less than 15% , more preferably less than 10%, preferably less than 8%, more preferably less than 6%, more preferably less than 4%, advantageously less than 3%, preferably less than 2%, even more preferably less than 1%, very preferably less than 0.5%.
• solutions from which these crystals are derived make it possible to solubilize and / or increase the bioavailability and / or increase the half-life and / or increase the stability and / or increase the efficiency and / or increase the safety and / or be physiological vectors and / or stealth vectors and / or protective envelopes for different molecules and / or compounds and / or entities which are soluble and / or sparingly soluble and / or not soluble in water.
• the advantage of the invention lies in obtaining stable pulverulent products, optionally including cargo entities, the solubility properties of which, acquired thanks to the present liquid crystals, are fixed thanks to one or more drying and / or dehydration, said stable products being able to be reconstituted and / or resolubilized on demand in a liquid, preferably in a physiological liquid, and able to retain their solubility properties giving them better bioavailability after administration.
• the present liquid crystals are stable in acidic environments (such as the stomach) and are also stable in basic environments such as the intestinal environment where absorption takes place towards blood flow.
• acidic environments such as the stomach
• basic environments such as the intestinal environment where absorption takes place towards blood flow.
• the present crystals are optimal transporters for insulins and / or other proteins in oral formulations and / or in formulations known in the art.
• the invention also describes the use of cold surfactants, which proves to be a simpler method with much less surfactants and capable of providing final products in dry forms.
• the excess of surfactants unlike other formulations of the art, gives poor results.
• the low concentrations give good results with respect to the formations and / or the properties of the present liquid crystals.
• the present liquid crystals require an amount of surfactants substantially less than the amount required in the prior art to solubilize the cargo entities of the invention, of less than 10%, preferably of less than 20%. %, more preferably less than 30%, preferably less than 40%, more preferably less than 50%, more preferably less than 60%, more preferably less than 65%, more preferably less than 70% , even more preferably less than 80%, very preferably less than 90%.
• these drying processes also make it possible to freeze and / or stabilize one or more of the properties of the present liquid crystals.
• the advantage of the invention lies in obtaining stable products, that is to say whose solubility properties are fixed, capable of being reconstituted in one or more liquids, preferably physiological, and capable of retaining their best performance. (solubilities, dissolutions, stability, bioavailability, acceptability, etc.).
• an amorphous precipitation can also be obtained, where the cargo entity precipitates in amorphous form in the liquid crystals.
• the state of high energy the cargo entity in this system produces dissolution rates much greater than the inert forms of the cargo entities.
• the conversion of a cargo entity to an amorphous form following co-precipitation in the crystals of the invention resulting in increased dissolution.
• the cargo entity acquires an amorphous structure and / or is able to remain amorphous in an appropriate galenic envelope.
• One of the concepts of the present invention is to obtain forms and / or crystallogeneses and / or crystals of betaine with remarkable properties and the examples as well as the emulsifiers (surfactants) and co-solutes described here can be extended. to all those known to those skilled in the art, without being outside the scope or outside the concepts described by the present invention.
• the present liquid crystals and / or their crystallized dry forms are used to increase the water solubility of a hydrophobic substance by a factor of 5, preferably by a factor of more than 10, more preferably more than 50, preferably more than 100, more preferably more than 500, more preferably more than 1000, advantageously more than 2000, preferably more than 3000, even more preferably more than 4000, very preferably by a factor of more than 5000, said solubility being able to be calculated for example by the USP Paddle method and / or by the dissolved weight of the hydrophobic substance in a given volume of water (examples of descriptive and non-limiting techniques).
• the present co-precipitates and / or liquid crystals can be dried one or more times, optionally under vacuum, to remove and / or substantially remove any solvent and / or surfactant freely adhering to the surface of the particles.
• the present co-precipitates can optionally be added before and / or during and / or after a buffer / buffer for injectable use, said buffer / buffer suitable for rendering the solutions physiological or at physiological pH.
• liquid crystals and / or their crystallized dry forms being suitable for being contained in one and / or dietetic and / or pharmaceutical forms for oral, parenteral, topical, dermal, transdermal, inhaled, applied to mucous membranes and their combinations.
• the present liquid crystals and / or their crystallized dry forms being able to be integrated and / or transformed and / or contained in / into galenical and / or pharmaceutical and / or dietetic and / or cosmetic forms for oral and / or enteral use and / or parenteral and / or injectable and / or cutaneous and / or subcutaneous and / or ocular and / or applicable to mucous membranes (buccal, sublingual, lingual, ocular, pulmonary, nasal, vaginal or rectal).
• the present liquid crystals and / or their crystallized dry forms (with their included / associated cargoes) being suitable for incorporation into gastro-resistant capsules and / or envelopes resistant to gastric acid pH and releasing their contents in the intestine at pH neutral or basic.
• the present liquid crystals and / or their crystallized dry forms being suitable for incorporation into foods and / or drinks.
• the invention consists of a process making it possible to trap an insoluble compound in a supersaturated solution of betaine and / or in a betaine structure preferably less than 300 nanometers (nm), then to freeze and / or stabilize this combination by a crystallization and / or by crystal growth.
• the present liquid crystals and / or their crystallized dry forms characterized in that they contain / or include and / or include and / or are associated with one or more hydrophobic substances having a partition coefficient LogP greater than or equal to 1.5
• the present methods of obtaining based on nucleations and / or germinations and / or co-crystallizations can be extended to all the therapeutic cargo entities.
• the present liquid crystals and / or their dry crystallized forms can be used in the processes of amorphous precipitation: Amorphous precipitation occurs. produced when the drug precipitates in amorphous form in the inert carrier. The high energy state of the drug in this system generally produces dissolution rates much greater than the corresponding crystal forms of the drug. The conversion of a drug to an amorphous form of co-precipitation resulting in increased dissolution.
• the present liquid crystals suitable for being subjected to one or more crystallizations to obtain a dry product and / or a salt and / or crystals, free and / or substantially free of water and / or solvents.
• the present liquid crystals and / or their crystallized dry forms being stable and able to be resolubilized in one or more solvents, preferably water, and / or one or more physiological liquids.
• liquid crystals and / or their crystallized dry forms being suitable for being contained in one and / or dietetic and / or pharmaceutical forms for oral, parenteral, topical, dermal, transdermal, inhaled, pulmonary, applied to mucous membranes, and to their combinations.
• the present liquid crystals and / or their crystallized dry forms being able to be integrated and / or transformed into / into galenical and / or pharmaceutical and / or dietetic forms for oral and / or enteral and / or parenteral and / or injectable use and / or / or cutaneous and / or ocular and / or applicable to mucous membranes (buccal, sublingual, lingual, pulmonary, nasal, vaginal and / or rectal).
• the invention consists of a method making it possible to trap and / or encapsulate and / or transport a soluble and / or insoluble compound in a supersaturated solution of betaine and / or in a structure having a size preferably less than 350 nanometers. (nm), then optionally to freeze and / or stabilize this combination by drying and / or dehydration and / or crystallization and / or by crystal growth.
• the size of the structures and / or nanoparticles (including cargoes) of the previous paragraph being less than 300 nanometers (nm), preferably less than 250 nm, more preferably less than 200 nm, preferably less than 100 nm, more preferably less than 80 nm, more preferably less than 60 nm, advantageously less than 50 nm, preferably less than 40 nm, even more preferably less than 20 nm, very preferably less than 10 nm.
• the present liquid crystals and / or their crystallized dry forms characterized in that they contain / or comprise and / or encompass 1 or more hydrophobic substances having a partition coefficient LogP greater than or equal to 1.5.
• the present liquid crystals and / or their crystallized dry forms and / or their resolubilized dry forms can be characterized by one or more measures chosen from the group of: solubility of (mg / ml), a size of nanoparticles ( DLS), polydispersity of nanoparticles, Zeta potential, microcalorimetry, electron microscopy, density, viscosity, surface tension, diffraction, refraction, reflectivity, photo-reactivity, polarization, wavelength, conductivity, resistivity, structure, spectroscopy, spectroscopy of mass, NMR, HPLC, melting point, cargo, cloud point,% cargo, hygroscopy, volumetric weight, as well as all other measurements known to the state of the art and used to characterize a crystal and / or a liquid crystal and / or a nano-emulsion.
• solubility of mg / ml
• DLS size of nanoparticles
• polydispersity of nanoparticles Zeta potential
• each crystal will have a unique profile according to the invention.
• the liquid and / or solid crystals of the invention can serve as vectors and / or transport and / or capsules for proteins, metals (radiotherapy), contrast products, radioelements, fluorophores, DNA and / or RNA sequences, vaccines, viruses and / or bacteria and / or spores and / or fungi, as well as their envelopes and / or fragments; to different entities for therapeutic uses, to different entities for dietetic uses, to different entities for chemical uses, to different entities for electronic uses, to different entities for physical uses, to different entities for cosmetic uses, to insecticides, to flavorings, to perfumes, vitamins, mineral extracts, plant extracts, metal extracts, animal extracts, human extracts, as well as combinations of two or more of the preceding cargo entities.
• the dry and / or substantially dry products of the invention having a particle size of at least 35 mesh, preferably at least 50 mesh, more preferably at least 60 mesh, preferably at least 70 mesh, preferably at least 80 mesh, more preferably at least 90 mesh, advantageously at least 100 mesh, preferably at least 125 mesh, even more preferably at least 150 mesh, very preferably at least 200 mesh.
• the finest particle sizes are possible by virtue of the reductions in the amounts of surfactants which the synergies of the latter with betaine allow.
• Formulations containing more surfactants prove difficult if not impossible to dry completely, the end products being tacky or viscous due to the surfactants.
• the particle sizes of the finest dry powders make it possible to optimize the pharmaceutical manufacturing processes and also to have homogeneous powders having defined flows (for example in the filling hoppers) and / or physicochemical characteristics. necessary or mandatory to meet industry prerequisites, in particular those of the pharmaceutical industry.
• the dry forms of the present liquid crystals are suitable for being integrated and / or transformed into / into dosage and / or pharmaceutical and / or dietetic forms for oral and / or enteral and / or parenteral and / or injectable and / or cutaneous use and / or ocular and / or applicable to the mucous membranes (buccal, sublingual, lingual, pulmonary, nasal, vaginal or rectal).
• liquid crystals and / or their crystallized dry forms of the invention being suitable for being formulated in delayed and / or controlled release and / or prolonged release formulations.
• the releases of one or more cargo entities that can be checked / extended over time and / or checked / extended over time. at the sites of administration and / or absorption with, for example, gastro-resistant and / or enteric-soluble formulations and / or other similar formulations.
• the latter may have similar and / or different release profiles, depending on the targets and / or the uses and / or the therapeutic objectives required.
• the present liquid crystals and / or their crystallized dry forms being suitable for incorporation in foods and / or in food supplements and / or in drinks.
• the general concept of the present invention is to obtain a liquid crystal and / or a form and / or a nanoemulsion and / or a crystallogenesis and / or a betaine crystal with remarkable properties and the examples as well as the emulsifiers and co-solutes described here can be extended to all those known to those skilled in the art without being outside the scope or outside the concepts described by the present invention.
• the methods make it possible to fix the characteristics of the microemulsions until their use in vivo, thus avoiding the phenomena of coalescence and degradation over time of the liquid forms of the microemulsions.
• the methods allow greater stability of the dosage and / or therapeutic forms.
• crystallization makes it possible to filter and / or attract and / or concentrate and / or imprison the entity to be solubilized.
• the present dry and / or substantially dry products having a stability such that when resolubilized in water over a period of 1 to 36 months, the particle size and / or the Zeta potential and / or the polydispersity of the solutions obtained are substantially similar to those of the initial solution with a variation of less than
• the present methods of obtaining based on nucleations and / or germinations and / or co-crystallizations can be extended to all the host therapeutic entities and / or cargoes.
• a drug is considered to be poorly soluble in water if its maximum therapeutic dose is not soluble in 250 ml or less of aqueous medium in a pH range of 1 to 7, 5.
• the present liquid crystals have surprisingly been found to be particularly effective in solubilizing hydrophobic substances. They also show great stability at different pHs ranging from 2 to 8, which corresponds to the range of acidity / alkalinity encountered in the living body.
• compositions for pharmaceutical and / or biochemical and / or biological and / or dietetic and / or cosmetic uses comprising a mixture of anhydrous betaine and / or its salts AND of a hydrophobic and / or substantially hydrophobic substance having a LogP partition coefficient greater than or equal to 1.5, both ingredients being in a proportion by weight betaine / hydrophobic substance of 200 to 1, preferably 100 to 1, advantageously 50 to 1, preferably 25 to 1, said composition characterized in that betaine increases the solubility of the hydrophobic substance in water by a factor of at least 100 compared to the solubility of the hydrophobic substance alone in water.
• drug is conventional, denoting a compound having beneficial prophylactic and / or therapeutic properties when administered to an animal, particularly to humans.
• the drug is a "low water solubility drug", meaning that the drug has minimal aqueous solubility at a physiologically relevant pH (i.e., pH 1-8) of. about 0.1 mg / ml or less.
• compositions of the present invention are preferred for low solubility drugs having an aqueous solubility of less than 0.1 mg / ml, advantageously less than 0.05 mg / ml and more preferably less than 0.01 mg. / ml.
• the liquid crystals of the invention are particularly useful for serving as carriers and / or vehicles and / or companions and / or vectors and / or containers and / or containers and / or encapsulants and / or protectors.
• the preferred classes of physiologically active molecules and / or entities and / or drugs having a partition coefficient (LogP) greater than or equal to 1.5 include, without being limited thereto, anticancer agents, antihypertensives, antihypertensives for pulmonary hypertension and / or portal hypertension, anxiolytic agents, anticoagulants, cardiovascular agents, antiaggregants, antidiabetics, glucagon, anticonvulsants, steroid agents, diuretic agents , the agents antidiuretics, hypoglycemic agents, decongestants, vasodilators, antihistamines, antineoplastics, beta blockers, pain relievers, anti-migraine agents, anti-inflammatory drugs, nonsteroidal anti-inflammatory drugs, corticosteroids, corticosteroids, antipyretics , antipsychotics, antidepressants, sleeping pills, sedatives, appetite suppressants, opioid analgesics, psychotropic agents, cognition enhancers, antispas
• the invention is advantageously useful for dissolving and / or increasing the bioavailability of the treatments and / or molecules and / or entities and / or agents, as well as their salts and / or their isomers and / or their esters, and / or their esters. ethers and / or their derivatives, from the previous paragraph belonging to Classes II and IV of the BCS (Biopharmaceutical Classification System).
• entities belonging to Class III of BCS can also benefit from the advantages of the invention with particular regard to the protection of these entities against - with respect to the enzymatic degradation and / or the metabolic degradation and / or their better intestinal absorption for the purposes of a better bioavailability and / or a prolonged and / or modulated half-life in the body.
• the present liquid crystals make it possible to increase and / or optimize the membrane permeability and / or the membrane passage of the cargo entities.
• the invention is aimed at molecules and / or entities having an oral bioavailability of less than 70%, 60%, 50%, 40%, 30%, 20%, 15%, 10%, 5%, etc.
• the present liquid crystals can transport and / or be associated with one or more cargo entities selected from the groups consisting of (i) acetylcholinesterase inhibitors selected from the group comprising donepezil, tacrine and pyridostigmine; (ii) analgesics and nonsteroidal anti-inflammatory drugs (NSAIAs) chosen from the groups: aloxiprine, auranofin, azapropazone, ibuprofen, fenoprofen, benorylate, capsaicin, diclofenac, naproxen, naproxone flunomide, leclofenamic acid mefenamic acid, nabumet, ivermectin, mebendazole, oxamniquine, oxfendazole, oxantel
• Q10 (ubiquinone), polyphenols, flavonoids, catechins, epicatechins, epicatechins gallate, quercetin, resveratrol, lycopene, lutein, polyunsaturated fatty acids, b-carotene or vitamin A, a-tocopherol or Vitamin E,
• Vitamin D isoflavones, leuprolide acetate, Buprenorphine, Peptides, proteins, DNA and / or RNA sequences, plant extracts, minerals, therapeutic agents used in Immunology, Neurology-psychiatry, Ophthalmology, inhibitors of HIV protease, Menopause, Rheumatism, Sleep disorders, Erectile dysfunction, osteoporosis, fibromyalgia thyroid disorders, Vaccination, Venous insufficiency (Veinotonics), Stress, Osteoarthritis, Errata and / or Androgenic alopecia, Rheumatism, Smoking; (Xxxxi) nutraceutical agents such as calcitriol, carotenes, chrysin, dihydrotachysterol, flavonoids, hesperetin, jasmonates, lipoic acid, lutein, lycopene, essential fatty acids, non-essential fatty acids, naringenin, phytonadiol,
• any similar therapeutic entity can be integrated into it provided that said entity encounters, after administration to the host, problems of solubility and / or bioavailability and / or efficacy and / or toxicity and / or half-life and / or degradation which would be related to its structure.
• the cargo nutraceutical agents can for example be chosen from the groups comprising calcitriol, carotenes, chrysin, dihydrotachysterol, flavonoids, hesperetin, jasmonates, lipoic acid, lutein, lycopene, essential fatty acids, non-essential fatty acids, naringenin, phytonadiol, quercetin, vitamins, including vitamin A, vitamin B2, vitamin D and its derivatives, vitamin E, and vitamin K, coenzyme Q10 (ubiquinone), as well as the combinations of two or more treatments and / or molecules and / or entities and / or agents of the preceding list of vitamins, as well as in combinations with the other entities and / or agents of different classes ( anticancer, anti-inflammatory, etc.) described and listed in this document.
• Metals and / or minerals such as iron, gold, silver, zinc, platinum, copper, hafnium oxide, barite, can be encapsulated by the liquid crystals of the invention.
• the anticancer and / or immunosuppressive agents can for example be selected from the groups comprising abarelix, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminoglutethimide, amsacrine, anastrozole, arsenic oxide, asparagimeturant and amalgutogluturant, amalgamuturin, amalgidetinase health bicalutamide, bisantrene, bleomycin, bortezomib, busulfan, calusterone, camptothecin, capecitabine, carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cisplatin, cladribine, cladarine, clofarabine, cyclofosphamine, cyclophosphamine, cyclosporine, cytarabine, dacarbazine, dactinomycin, darbep
• the advantage of the invention is to be able to freeze and / or fix the properties of the solutions obtained by crystallizing them, preventing them from degrading over time as a result of the known phenomena of decomposition, oxidation, deliquescence, coalescence, aggregation, flocculation and "Otswald Ripening" that liquid forms are bound to undergo over prolonged periods.
• this process by freezing the solutions obtained in dry and / or crystalline forms, makes it possible to retain and / or fix and / or stabilize and / or prolong their pharmacological and / or chemical and / or dynamic properties and / or biological over time.
• these pharmacological and / or chemical and / or thermodynamic properties are directly restored when the dry and / or crystalline forms are resolubilized.
• the polymers and / or additives and / or excipients generally known in the art of formulation and / or in the art of galenics can optionally be added.
• excipients such as bulking agents, disintegrating agents, pigments, binders, lubricants, slip agents, flavorings, etc. can be used for customary purposes and in amounts typical of the art, without adversely affecting the properties of the compositions.
• excipients can be used before and / or during and / or after the formation of the composition in order to formulate it in tablets, capsules, suppositories, suspensions, powders for suspension, creams, transdermal patches, patches, sprays, injectables, sublingual products. , drops, tinctures, gels, ointments, deposits, etc.
• compositions of the present invention can be formulated in various forms as delivered as a suspension of particles in a liquid vehicle.
• These suspensions can be formulated as a liquid or paste at the time of manufacture, or as a dry powder with a liquid, usually water, added at a later time, but before oral administration.
• These powders formed in suspension are sachets or oral powder formulations for constitution (OPC).
• OPC oral powder formulations for constitution
• Such dosage forms can be formulated and reconstituted. The simplest approach is to formulate the dosage form as a reconstituted dry powder by simply adding water and stirring. Alternatively, the dosage form can be formulated as a liquid and a dry powder which are combined and stirred to form the oral suspension. In yet another embodiment, the dosage form can be formulated as two powders which are reconstituted by first adding water to a powder to form a solution to which the second powder is combined with agitation to form suspension.
• Dosage forms can be protected by a film and / or barrier and / or wrap having an adequate MVTR. A high MVTR to protect these shapes against humidity.
• the drug dispersion is formulated for long term dry storage as this promotes the chemical and physical stability of the drug.
• the liquid crystals of the invention are particularly useful for serving as carriers and / or companions and / or carriers and / or containers and / or containers and / or encapsulants and / or protectors and / or carriers. envelopes with different cargo entities having a pharmacological action and / or a therapeutic action and / or a biological action and / or a pharmaceutical action.
• the liquid crystals of the invention can optimize the action of these cargo entities, both in terms of their solubilities and / or their bioavailability and / or their stabilities, and / or their half-lives and / or their safety and / or the reduction of their undesirable effects and / or the increase in their efficacy and / or their acceptability in living organisms.
• these entities and / or cargo entities can be chosen alone and / or in combinations from the groups comprising: (i) acetylcholinesterase inhibitors such as donepezil, tacrine and pyridostigmine; (ii) Analgesics (iii) nonsteroidal anti-inflammatory drugs (NSAIDs) such as aloxiprine, auranofin, azapropazone, benorylate, capsaicin, diclofenac, Aceclofenac, Indomethacin, Ketoprofen, flunomide, meclofenamic acid, mefenamic, nabumet, ivermectin, mebendazole, oxamniquine, oxfendazole, oxantel embonate, praziquantel, pyrantel embonate and thiabendazole; (iv) anti-acne agents such as isotretinoin and tretinoin; (v) antianginal
• liquid crystals of the invention can improve their actions and / or optimize their stabilities and / or their solubilities and / or their solutions and / or their solutions. bioavailability and / or provide them with better half-lives and / or optimize their duration of actions and / or optimize their effectiveness and / or reduce their undesirable effects and / or increase their safety and / or their effectiveness and / or their acceptability in living things.
• Antineoplastics are drugs used to block the proliferation of cancer cells - neoplasm refers to a tumor or cancer.
• antineoplastics are not drugs with a specific effect on neoplastic cells since they also affect healthy cells.
• the present liquid crystals are particularly indicated for optimizing the effects and / or the acceptability and / or the efficacy of the entities of this therapeutic class.
• the liquid crystals of the invention serving for better solubilizations and / or better stabilities and / or better safety and / or better half-lives and / or better efficiencies and / or better acceptabilities and / or better targeting in living organisms.
• Antineoplastics include several dozen drugs, including alkylating agents, anti-metabolites, intercalating agents and antimitotics.
• Antimetabolites Antifolics: Methotrexate, Raltitrexed, Pemetrexed.
• Antipyrimidics Mercaptopurine, Thioguanine, Pentostatin, Cladribine, Fludarabine Other antimetabolites: Hydroxycarbamide, Gemcitabine.
• Alkylating agents such as nitrogen mustard: Chlorambucil, Melphalan, Chlormethine, Ifosfamide, Cyclophosphamide;
• Nitrosourea Fotemustine, Lomustine, Carmustine, Streptozocin; Organoplatin: Carboplatin, Cisplatin, Oxaliplatin; Ethylene imine: Thiotepa, Altretamine; Amide Imidazole: Procarbazine, Temozolomide, dacarbazine; Other alkylating agents: Busulfan, Mitomycin C, Pipobroman.
• Intercalating Agents Camptothecin, Irinotecan, Topotecan Anthracycline: Epirubicin, Daunorubicin, Doxorubicin, Pirarubicin, Idarubicin, Mitoxantrone, Amsacrine, Elliptinium, Actinomycin D, Etoposide, Bleomycin Molecules having an action on the mitotic spindle: Vinca-alkaloid, spindle poison, Vinorelbine, Vindesine, Vincristine, Vinblastine;
• Taxoids Paclitaxel, Docetaxel;
• Tyrosine kinase inhibitors VEGFR inhibitors: Sunitinib, Axitinib, Pazopanib; EGFR inhibitors: Afatinib, Erlotinib, Gefitinib, Lapatinib,; BCR-Abl fusion protein inhibitors: Imatinib, Dasatinib, Nilotinib, Bosutinib, Ponatinib, Sorafenib, Regorafenib; RAF serine-threonine kinase inhibitors: Dabrafenib, Vemurafenib, Sorafenib, Regorafenib; MEK serine threonine kinase inhibitors: Cobimetinib, Trametinib; MTor serine-threonine kinase inhibitors: Temsirolimus, Everolimus; Other tyrosine kinase inhibitors: Crizotinib,
• Anti-VEGF Bevacizumab
• Anti-EGFR Cetuximab, Panitumumab
• Anti-HER2 Trastuzumab, Pertuzumab
• Anti-CD20 Rituximab, Ibritumomab, Ofatumumab
• Other monoclonal antibodies Alemtuzumab, Blinatumomab, Daratumumab, Ipilimumab, Panitumumab.
• Viruses and modified viruses oncolytic adenoviruses.
• Anti-cancer monoclonal antibodies fall into the category of targeted therapies. They can have a cytolytic effect by fixing a membrane target which allows the activation of complement or the recruitment of cytotoxic immune cells. Some have a neutralizing effect, thus preventing the binding of the ligand to its receptor.
• the use of the present crystals in associations and / or in combinations is particularly useful in the pharmaceutical field, because in addition to their optimizing and / or transport activities, they protect sensitive active agents against degradation (enzymatic and / or metabolic) and oxidation.
• liquid crystals of the invention can improve their actions and / or optimize their stabilities and / or their solubilities and / or their bioavailability and / or their provide better half-lives and / or reduce their undesirable effects and / or increase their safety and / or their efficacy and / or their acceptability in living organisms.
• the present liquid crystals are physiological or substantially physiological due to the fact that betaine is not a xenobiotic; this will not cause immune reactions and / or allergic reactions and / or metabolic reactions and will thus allow the transport of cargo entities without being detected, metabolized or destroyed by the immune system and / or by enzymatic systems. This will make it possible to increase the therapeutic action of the cargo entities by allowing them to reach their specific action sites in optimal and / or targeted ways.
• the cargo units are encapsulated and / or wrapped and / or housed in a shell made of betaine.
• the cargo entities are, thanks to the present liquid crystals, in the form of molecular dispersions in the solvent.
• the products obtained are stealthy.
• the present liquid crystals can be considered as nano-transporters and / or nano vectors and / or nano-sponges and / or nano-crystals and / or quantum dots and / or fractal structures which, due to their physiological characteristics, will have the advantage and the quality of being stealthy, that is to say not or hardly detectable by the immune defense systems.
• the present liquid crystals are particularly useful and indicated for transporting entities such as proteins, in particular insulin, in oral formulations.
• entities such as proteins, in particular insulin, in oral formulations.
• the envelope and / or the capsule constituted by betaine will allow insulin and / or other entities of interest to escape the enzymatic actions of the gastrointestinal tract while allowing them to d. 'be usefully absorbed and effectively directed into the blood stream.
• these protective and / or optimizing activities of the present liquid crystals can be applied not only to the cargo entities listed in this document, but also be extended to RNA and / or DNA sequences and / or peptides and / or aptamers and / or dendrimers and / or oligonucleotides for the production of optimal formulations, whether oral and / or parenteral and / or injectable and / or cutaneous and / or pulmonary and / or ophthalmic and / or nasal and / or sublingual and / or administered via the mucous membranes.
• the cargo entity does not necessarily have to have a LogP greater than 1 but can be water soluble (LogP ⁇ 1).
• the liquid crystals of the invention serving for purposes other than solubilization, such as better stability and / or better safety and / or better half-lives and / or better efficiencies and / or better acceptabilities in the field. living.
• the methods of the invention advantageously apply to the molecule and / or to the principles crude and / or pure active ingredients of these drugs; as well as their analogs, esters, precursors and metabolites.
• the methods of the invention can also be applied to their final and / or semi-finished formulations.
• the advantage of using a water-soluble surfactant also resides in the fact that it is possible to produce dry or substantially dry forms after eliminations and / or evaporations and / or dehydration and / or drying of the or solvents (preferably water) for the present liquid crystals.
• These dry or substantially dry forms will have the advantages of better stability profiles and / or better release profiles, both in their galenical and / or pharmaceutical forms, and in their absorption and / or action profiles in living organisms.
• the advantage of the invention is that it can replace PEGs in all the known formulations using this molecule, with a notable improvement in the higher acceptability by living organisms of the present physiological liquid crystals compared to PEGs.
• the uses of the present crystals are particularly useful in the field of vaccination and vaccines because they provide the antigenic agents and / or biological materials (DNA, RNA, aptamers) of the vaccines an envelope and / or a shell which is at the same time protective and which optimizes their deliveries and / or their effectiveness at the sites of biological actions.
• the present invention which can be carried out at room temperature, is particularly indicated for the development of vaccines and of products and / or molecules having a sensitivity and / or a lack of stability to heat and / or to caloric excesses.
• the present liquid crystals are particularly indicated for optimizing the effects and / or the acceptability and / or the efficacy of the entities of this therapeutic class.
• the liquid crystals of the invention serving for better solubilizations and / or better stabilities and / or better protections and / or better safety and / or better half-lives and / or better efficiencies and / or better acceptabilities in living organisms.
• the present crystals can exert lipid polymorphism and / or exhibit a character. biomimetic. and can mix easily with biological membranes and / or cell membranes, without high energy requirements during this process.
• endocytosis by osmosis and / or passive and / or by active transport can be promoted by the crystals and / or cargoes of the invention.
• Betaine having established osmotic activity.
• the present crystals exert a beneficial activity via the caveolae, for optimal delivery of their cargoes.
• Lyotropic liquid crystal phases are abundant in living systems; this is called lipid polymorphism. Accordingly, the present lyotropic liquid crystals possess biomimetic properties mimicking the structure of biological membranes and / or cell membranes, both of which are forms of liquid crystals. Their constituent molecules (eg phospholipids) are perpendicular to the surface of the membrane, but the membrane is flexible. The constituent molecules can mix easily, but tend not to leave the membrane due to the high energy requirements of this process.
• the present liquid crystals due to their mimicry with membranes and / or cells, are suitable for better delivery of cargo entities through and / or to biological and / or cellular membranes. This is further facilitated by the little energy that this process mobilizes thanks to the present liquid crystals.
• the use of the present crystals is particularly useful in the field of cosmetics, because in addition to their optimizing activities similar to those provided to drugs, they allow better skin absorption and the transport and protection of sensitive assets. that they protect against degradation (enzymatic and / or metabolic) and oxidation.
• the present liquid crystals can also be used for therapeutic and / or cosmetic applications such as in Acne, Cellulite, Hair loss. hair, Sensitive skin, Creams, Serums, Face and / or body masks, Make-up, Aesthetic medicine, Slimming, Perfumes, Wrinkles, Hair health, Anti-aging care, Hair care, Body care, Facial care, Q10 enzyme , Vitamins, Slimming treatments, Diet to lose weight.
• liquid crystals of the invention allow drastic reductions in the doses of these toxic compounds, thus allowing better preservation of the environment.
• the present liquid crystals due to their versatility, can also have other industrial applications such as in solar panels, semiconductor and / or superconducting crystals, ferrofluids.
• Electronic uses such as in solar panels, quantum computers, LCDs, blackout windows, optical fibers, cells and energy accumulators (batteries).
• the present liquid crystals are particularly useful and effective in solubilizing / protecting natural lipophilic compounds commonly used in drugs and / or in nutraceuticals which include phytocannabinoids such as cannabidiol, terpenes, terpenoids, essential oils such as beta -karyophyllene, carene phyllene, pinene, linalool, limonene, phytol, nerolidol, myrcene, myrcene, fatty acids such as linoleic, lenolenic, stearidonic, stearic acid, oleic acid, arachidonoylethanolamide (anandamide), compounds such as coenzyme Q-10, pterostilbene, lutein, lycopene, other essential oils such as lemon oil, grapefruit seed extract, green tea extract, l 'EGCG, cocoa extract, epigallocatechin gallate, epigallocatechin, epicatechin, catechin, epicatechin gallate,
• the present liquid crystals are particularly indicated for optimizing the effects and / or the acceptability and / or the efficacy of cannabinoids.
• the liquid crystals of the invention serving for better solubilizations and / or better stabilities and / or better safety and / or better half-lives and / or better efficiencies and / or better acceptabilities and / or better targeting in living organisms.
• the present liquid crystals are particularly indicated for solubilizing natural cannabinoids comprising cannabinoids derived from cannabis comprising cannabinoids obtained from a Cannabis plant comprising cannabidiol (CBD), acid cannabidiol (CBDA), cannabinol (CBN), cannabigerol (CBG); cannabigerol monoethylether (CBGM); Cannabichromene (CBC); Cannabielsoin (CBE); Cannabicyclol (CBL); Cannabicyclol (CBL); Cannabicitran (CBT); Cannabivarin (CBV); Tetrahydrocannabivarin (THCV); Cannabidivarin (CBDV); Cannabichromevarin (CBCV); Cannabigerovarin (CBGV); Cannabigerol monomethyl ether (CBGM); tetrahydrocannabinol (THC), iso-
• the present liquid crystals and / or their crystallized dry forms are used to increase the water solubility of the cannabinoid substances of the previous paragraph by a factor of 5, preferably by a factor of more than 10, more preferably more than 50. , preferably more than 100, more preferably more than 500, more preferably more than 1000, advantageously more than 2000, preferably more than 3000, even more preferably more than 4000, very preferably by a factor of more than 5000, said solubility being able to be calculated for example by the USP Paddle method and / or by the dissolved weight of the hydrophobic substance in a given volume of water.
• the invention also describes the use of the present crystals in processes for obtaining and / or extracting (from leaves the plant) and / or formulations of one or more water-soluble cannabinoids, cannabinoids obtained from from a Cannabis plant comprising cannabidiol (CBD), cannabidiolic acid (CBDA), cannabinol (CBN), cannabigerol (CBG); cannabigerol monoethylether (CBGM); Cannabichromene (CBC); Cannabielsoin (CBE); Cannabicyclol (CBL); Cannabicyclol (CBL); Cannabicitran (CBT); Cannabivarin (CBV); Tetrahydrocannabivarin (THCV); Cannabidivarin (CBDV); Cannabichromevarin (CBCV); Cannabigerovarin (CBGV); Cannabigerol monomethyl ether (CBGM); tetrahydrocannabinol (
• DELTA.8-tetrahydrocannabinol 11-hydroxy- tetrahydrocannabinol, 11-hydroxy- DELTA.9-tetrahydrocannabinol, levonantradol, .DELTA.11-tetrahydrocannabinol, tetrahydrocannabivarin, dronabinol, amandamide, nabilone; ), the esters thereof, their salts, their, metabolites, their mixtures and / or one or more combinations thereof.
• Tube A1 mix 2 mL of distilled water and 2 g of betaine by vigorous manual stirring, then add 40 ⁇ L of Polysorbate 80 (65 mg), the whole again mixed manually. The mixture of B is then subjected for 15 minutes to a centrifugation of 4000 revolutions / minute.
• Tube B1 mix 2 mL of distilled water and 40 ⁇ L of Polysorbate 80, then add 2 g of betaine, the whole again mixed by vigorous manual stirring. The mixture 3 is then subjected for 15 minutes to a centrifugation of 4000 revolutions / minute.
• Tube C1 pour 2 g of betaine and add 40 ⁇ L of Polysorbate 80 then 2 mL of distilled water, the whole mixed by vigorous manual stirring. The mixture is then subjected for 15 minutes to centrifugation at 4000 revolutions / minute.
• Tube A2 mix 2 mL of distilled water and 2 g of betaine by vigorous manual stirring, then add 40 ⁇ L of Polysorbate 80, the whole again mixed manually. Tube not subjected to centrifugation.
• Tube B2 mix 2 mL of distilled water and 40 ⁇ L of Polysorbate 80, then add 2 g of betaine, the whole again mixed by vigorous manual stirring. Tube not subjected to centrifugation.
• Tube C2 mix 2 g of betaine and add 40 ⁇ L of Polysorbate 80 then 2 mL of distilled water, the whole being mixed by vigorous manual stirring. Tube not subjected to centrifugation.
• the A2 & C2 tubes are opaque / milky in appearance with a slight foamy supernatant while the B2 tube although being transparent also has a foamy supernatant which is larger than for the A2 & C2 tubes.
• the B tubes do not present any optical peculiarities to the naked eye, apart from the B2 tube which is slightly iridescent.
• the A1 B1 & Cl tubes are transparent with iridescent and / or opalescent reflections in the bluish and yellow tints depending on the direction of the light and / or the angle of observation.
• the centrifugation does not only allow the simple mixing of the ingredients. which are water-soluble and which should mix easily, but it also makes it possible to generate and / or modulate and / or organize and / or direct the orientation of these ingredients by imposing on their mixtures in water a direction and / or a manager who arranges them from simple isotropic ingredients (having only one direction) in solution in water, into an anisotropic whole (having several directions).
• centrifugation confers on the Al, B1 & Cl mixtures new characteristics and / or new qualities specific to liquid crystals.
• the director here being generated and / or modulated and / or directed by the centrifugation.
• the contents of the 3 tubes become transparent and acquire the same optical characteristics as those of the tubes A1, B1 & Cl seen previously.
• the contents A2, B2 & C2 are transparent with iridescent and / or opalescent reflections in bluish and yellow hues depending on the direction of the light and / or the viewing angle.
• the contents of the tubes A2, B2 & C2 acquire remarkable optical characteristics demonstrating their birefringences, as well as the liquid crystal character of the mixtures A2, B2 & C2.
• liquid crystals of the invention possess and demonstrate the characters and / or qualities of thermotropic liquid crystals.
• Tube A mix 2 mL of distilled water and 2 g of betaine mixed by vigorous manual stirring. The mixture of the 2 is then subjected for 15 minutes to a centrifugation of 4000 revolutions / minute.
• Tube B mix 2 mL of distilled water and 40 ⁇ L of Polysorbate 80 (65 mg) then mix by vigorous manual stirring, then add 2 g of betaine, the whole again mixed manually. The mixture of B is then subjected for 15 minutes to a centrifugation of 4000 revolutions / minute. Results: Tube B is pearly transparent, confirming a bluish tint of birefringence. Tube A remains transparent without any apparent tint.
• the 2 tubes are poured into glass Petri dishes (diameter 35 mm) and subjected to drying at 60 ° C. in a Stockli hot air dehydrator.
• tube A dry up to crystals which remain confined in the initial volume of the solution.
• the germination / nucleation being of the homogeneous primary type for the betaine solution alone.
• tube B undergo heterogeneous primary type germination / nucleation with germs forming on the walls of the Petri dish and then overflowing the dish. See Figure 1.
• the nucleation rates of the contents of tube B are faster than those of tube A.
• the solution dissolves immediately and gives a transparent solution with a brilliant yellow color.
• the solution stored in the dark did not show any changes over time (24 h).
• 400 ⁇ L of the solution produced are taken and poured into a tube of 5 mL of acetic acid (pH 2.2).
• the solution dissolves immediately and gives a transparent solution with a brilliant yellow color.
• the solution stored in the dark did not show any changes over time (24 h).
• the stock solution obtained after centrifugation is estimated at a concentration of 80 mg / mL of curcumin (weighted at 60 mg / mL - pellet). It remains stable without any deposit for long periods of time.
• a pellet representing 20% of the non-solubilized Fenofibrate remains in the bottom of the tube.
• the remaining fraction is completely solubilized and gives a transparent solution of yellow / green color without any suspended particles.
• the stock solution obtained after centrifugation is estimated at a concentration of 27 mg / mL of fenofibrate (weighted at 20 mg / mL - pellet). It remains stable without any deposit for long periods of time. Poured into a glass of water, it dissolves immediately. The solubility of Fenofibrate in water was increased by a factor of 28,000.
• a pellet representing 35% of the non-solubilized Fenofibrate remains in the bottom of the tube. The remaining fraction is completely solubilized and gives a transparent green / yellow solution without any suspended particles.
• the stock solution obtained after centrifugation is estimated at a concentration of 20 mg / mL of Fenofibrate (weighted at 15 mg / mL - pellet). It remains stable without any deposit for long periods of time.
• Cannabidiol is completely solubilized and gives a transparent solution of golden color with bluish reflections, without any suspended particles. 200 ⁇ L of the solution produced are taken and poured into a tube containing 5 mL of distilled water (pH 7). The solution dissolves immediately and gives a transparent solution with purple / pink reflections. The solution stored in the dark did not show any changes over time (24 h).
• the stock solution obtained after centrifugation is estimated at a concentration of 47 mg / mL of Cannabidiol (unweighted because no pellet). Sheltered from light, it remained stable without any deposit or modification for a year.
• Liquid crystals as in Examples 5, 6 & 7 are made.
• the 3 tubes are poured into glass Petri dishes (diameter 35 mm) and subjected to drying at 50 ° C. in a Stockli hot air dehydrator. Results
• the liquid crystal of Curcumin adopts a bright scarlet yellow color.
• Fenofibrate liquid crystal adopts a whitish / greenish color.
• the liquid crystal of Cannabidiol adopts a pink color tending towards the mauve, whose hues are similar to the flower of cannabis.
• Example 7 The 3 dry products of Example 7 are ground to reach ⁇ 50 mesh and stored away from light and moisture for 6 months.
• Example 9 After 6 months, the 3 dry powders of Example 9 are dissolved in an amount of one gram of dry powder each in 20 centiliters of pure water (pH 7).
• the 3 dry powders resolubilize immediately (a few seconds) giving solutions without particles in suspension, and without deposits or supernatants.
• the pH of the same 3 solutions is then varied from neutral pH at the start (galenic form, tablet, capsule, or others) to acidic pH by adding acetic acid up to pH 2.5 (gastric environment) then these solutions are neutralized by adding baking soda up to pH 8 (intestinal environment).
• the average particle size of the solution is within 10 nanometers, or even less, with very low polydispersity.
• Clofazimine is completely solubilized and gives a transparent solution of yellow-brown color (honey), without any suspended particles.
• 250 ⁇ L of the solution produced are taken and poured into a tube of 5 mL of distilled water (pH 7). The solution dissolves immediately and gives a transparent solution with slight red reflections. The solution stored in the dark did not show any changes over time (24 h).
• 250 ⁇ l of the solution produced are taken and poured into a tube of 5 mL of acetic acid (pH 2.2). The solution dissolves immediately and gives a transparent solution with a carmine red color. The solution stored in the dark did not show any changes over time (24 h).
• the stock solution obtained after centrifugation is estimated at a concentration of 14.7 mg / mL of clofazimine (unweighted because no pellet).
• the color of the crystal formed is red orange.
• the dry product is then ground until it reaches ⁇ 50 mesh and stored away from light and humidity for 10 days.
• the solution remains stable without any precipitation or modification, thereby showing the stability of the products of the invention and their utility for in particular oral uses, as well as all other routes of administration known in the art.

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