Classifications

• • 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
• • 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
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
  • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • 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
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • 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
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
• • 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
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • 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
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof
• • 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
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P23/00—Anaesthetics
  • A61P23/02—Local anaesthetics

Definitions

• the invention relates to novel formulations for topical local anesthesia, analgesia or as a sexual retarder.
• Anesthetic creams are applied to the skin before a blood test, an injection or in dermatology before an act of surgery or laser.
• Two drugs currently available in France are EMLA ® and its generic, anesderm ® .
• the oily phase of the EMLA ® cream currently used for topical local anesthesia is a liquid eutectic mixture of anesthetics (EMLA: Eutectic Mixture of Liquid Anesthetic).
• EMLA ® also has an analgesic effect (ie pain relief) (Pediatric Archives, 2004, 11, 921-925).
• EMLA is a mixture containing equal masses of two local anesthetics, prilocaine (CAS 721-50-6) and lidocaine (CAS 137-58-6).
• EMLA is liquid at room temperature, whereas both pure compounds are solid. The mutual lowering of the melting temperature of the two compounds in the mixture results from a physical effect which does not modify the chemical nature of the constituents of the mixture: the eutectic effect.
• This liquid phase is both active ingredient and oil phase of an oil in water emulsion in which the pharmaceutical formulation is a cream: EMLA ® cream.
• the oily phase of the EMLA ® cream diffuses through the Stratum Corneum which is the main physiological barrier of human skin.
• EMLA ® has an adverse effect caused by prilocaine, it can cause methemoglobinemias, especially in newborns and young children. This is the transformation of hemoglobin into methemoglobin at toxic thresholds, induced by metabolites of prilocaine (Best Pratice & Clinical Research Clinical Anesthesiology, 2003, 17, 111-136, Cox et al). Several accidents caused by prilocaine have been reported (Eur J Pediatr, 1999, 158, 785-788, Frey et al, The Journal of Emergency Medicine, 2004, 26, 85-88, Hahn et al).
• One of the aims of the invention is the use of an oil phase with eutectic invariant (PHE) for the preparation of oil-in-water emulsions.
• PHE eutectic invariant
• a second object of the invention is to provide an oil phase with eutectic invariant (PHE), liquid, homogeneous, rich in anesthetic and which does not necessarily contain prilocaine.
• This oil phase with eutectic invariant (PHE) has physicochemical properties that are advantageous compared to EMLA in terms of thermodynamic stability and interesting in diffusion behavior through the human Stratum Corneum.
• a third object of the invention is to provide an oil-in-water emulsion, lipophilic in hydrophilic (L / H), comprising said eutectic invariant oil phase (PHE).
• Another object is to use said emulsion as a local anesthetic, analgesic or sexual retardant.
• the present invention relates to the use of an oil phase with eutectic invariant (PHE) comprising at least one local anesthetic in a proportion of 10% to 60% by weight relative to the total mass of the oily phase (PHE) and at least a fatty acid in a proportion of 40% to 90% by weight relative to the total mass of the oily phase (PHE), for the constitution of an oil-in-water emulsion (W / H) in which the pH of the hydrophilic phase is especially comprised from 6 to 8, more particularly from 6.5 to 7.5, said oily phase (PHE) being of weakly ionic nature and in homogeneous liquid form and stable at a temperature of between 0 ° C.
• PHE eutectic invariant
• W / H oil-in-water emulsion
• said oily phase (PHE) being of weakly ionic nature and in homogeneous liquid form and stable at a temperature of between 0 ° C.
• lipophilic in hydrophilic (L / H)
• L / H lipophilic in hydrophilic
• a discontinuous lipophilic phase in particular an oil, dispersed in the form of droplets in a hydrophilic continuous phase.
• a “local anesthetic” is an active ingredient that reversibly inhibits the propagation of signals along the nerves by blocking sodium channels and produces anesthetic effects on a patient's body part without the need for endoimir.
• a "fatty acid” is a hydrophobic compound with a carboxylic acid function C 5 to C 24 , preferably C 1 to C 24 aliphatic chain, linear or branched, saturated or unsaturated.
• the fatty acid is poorly soluble in the aqueous phase and does not form co-crystals with the local anesthetic.
• fatty acid can also refer to a similar hydrophobic-hydrophilic balance fatty acid analog, consisting of the fatty acid of a hydrophobic hydrocarbon portion and a carboxylic acid group, but additionally including another chemical as an ester function or an alcohol function for example.
• eutectic invariant oily phase means that at a constant temperature, called eutectic, the total melting of at least one of the two solids constituting the mixture is observed, regardless of the proportion of the compounds present in the mixture.
• solid is meant either one of the two pure bodies if there is complete immiscibility between them in the solid state, or a solid solution formed by a homogeneous mixture of the pure constituents.
• An essential property of the eutectic invariant mixtures, for immiscible solids in the solid state, is to lower the melting point of the pure compounds constituting the mixture, in other words the liquidus curve, over the entire range of compositions. . Indeed, on both sides of the eutectic point, and above the eutectic temperature, only one of the two pure constituents is in equilibrium with a homogeneous liquid. This lowering of temperature is maximum to the eutectic composition.
• the liquidus curve corresponds, at that moment, to a balance between a homogeneous liquid and a solid solution whose composition varies with temperature. It is none the less true that the temperature of this liquidus, at which the whole solid solution disappears, is always lower than the melting point of the pure body from which the corresponding liquidus curve originates.
• oily phases of the invention are therefore in liquid form regardless of the anesthetics and fatty acid used.
• the expression "being of weakly ionic nature" means that the amino function of lidocaine is not in its acid form RTSTSH + and that the carboxylic acid function of lidocaine is not in its basic form R "COO " .
• the salt content is negligible, less than a value of 10% by weight, in particular less than a value of 5% by weight, more particularly less than a value of 1% by weight.
• homogeneous means according to the invention that all of the anesthetic (s) present (s) and fatty acid (s) present (s) in the liquid mixture are miscible.
• stable means that the oily phase remains liquid and homogeneous, without altering its chemical nature, ideally indefinitely.
• the eutectic lidocaine-lauric acid mixture in a closed bottle disposed in the dark remains in its transparent liquid form for at least 10 months, in particular at least 18 months.
• PHE homogeneous eutectic liquid phases
• L / H emulsions
• One advantage is the choice of the local anesthetic, which allows in the case of the exclusion of prilocaine to avoid methemoglobinemias in premature infants, newborns and young children.
• the idea of associating a fatty acid with lidocaine for the formulation of an oil phase with eutectic invariant (PHE) is original and judicious.
• the fatty acids include a carboxylic acid (COOH) function that is known to associate with hydrogen double bonds specific for primary or secondary amide functions (NHCO).
• COOH carboxylic acid
• NHCO primary or secondary amide functions
• Local anesthetics of the amide ester class, such as lidocaine have been found to include such a function. But it also happens that these specific hydrogen associations lead in many cases to the formation of solid co-crystals between the two compounds. In the case of the formulation of the oily phase of an emulsion, the spontaneous formation of solid co-crystals would be unfortunate.
• the fatty acids have another virtue, they include a hydrocarbon chain, whose linear or branched molecular symmetry is far removed from that of local anesthetics, like that of lidocaine, which includes a system conjugate and which is more compact. Such a difference in molecular symmetry greatly reduces the chances of formation of co-crystals. However, these specific hydrogen interactions remain ultimately in the liquid state, which has the effect of significantly lowering the eutectic melting temperature.
• the advantage of these mixtures is therefore to have a low eutectic melting temperature, lower than that of all the binary eutectic mixtures of lidocaine reported to date, which widens the temperature range of storage and use of these formulations: for the invention, the melting temperatures of lidocaine-lauric acid and lidocaine-tridecanoic acid eutectic mixtures are 5 ° C and 6 ° C, respectively.
• the eutectic melting temperatures are 29 ° C and 38 ° C for the lidocaine-menthol mixture (Journal of Physical Chemistry B, 2010, 1 14, 5420-5426, Corvis et al.
• lidocaine-salol mixtures (Thermochimica Acta, 2010, 497, 124-128, Lazerges et al.) and lidocaine-prilocaine (Journal of Pharmaceutical Sciences, 1984, 73, 481-484, Brodin. et al).
• the present invention relates to the use of an oily phase as defined above, in which the local anesthetic is in a proportion of 10% to 50% by weight of the total mass of the phase.
• oily and fatty acid is in a proportion of 50% to 90% by mass relative to the total mass of the oily phase (PHE).
• the present invention relates to the use of an oily phase as defined above, in which the local anesthetic is in a proportion of 20% to 60% by weight of the total mass of the phase.
• Oily and fatty acid is in a proportion of 40% to 80% by weight relative to the total mass of the oily phase (PHE).
• the present invention relates to the use of an oily phase as defined above, in which the local anesthetic is in a proportion of 30% to 60% by weight of the total mass of the oily phase and the fatty acid is in a proportion of 40% to 70% by weight relative to the total mass of the oily phase (PHE).
• the present invention relates to the use of an oily phase as defined above, in which the local anesthetic is in a proportion of 30% to 50% by weight of the total mass of the phase.
• Oily and fatty acid is in a proportion of 50% to 70% by mass relative to the total mass of the oily phase (PHE).
• the present invention relates to the use of an oily phase as defined above as defined above, wherein said local anesthetic is in a proportion of 40% to 50% by weight and said fatty acid in a proportion of 50% to 60% by weight relative to the total mass of the oily phase (PHE), said oily phase with eutectic invariant being in the form of a homogeneous liquid and stable at a temperature of 0 ° C at 37 ° C.
• PHE oily phase
• the oily aqueous phase as defined above comprises at least one local anesthetic in a proportion of 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49% , or 50%) by mass and at least one fatty acid in proportion of 50%, 51%, 52%, 53%, 54% o, 55%, 56%, 57%, 58%, 59% or 60% in mass relative to the total mass of the oily phase (PHE).
• PHE total mass of the oily phase
• the present invention relates to the use of an oily eutectic invariant phase (PHE) as defined above, in which the local anesthetic is chosen from lidocaine, levobupicaine, prilocaine, articaine, ropivacaine and dibucaine and mixtures thereof.
• PHE oily eutectic invariant phase
• lidocaine 137-58-6
• mepivacaine 96-88-8
• bupivacaine 38396-39-3
• the present invention relates to the use of an oil phase with eutectic invariant (PHE) as defined above, in which the local anesthetic is lidocaine.
• PHE eutectic invariant
• the present invention relates to the use of an oil phase with eutectic invariant (PHE) as defined above, in which the local anesthetic is lidocaine in a proportion of 50% by weight relative to the total mass of the oily phase (PHE).
• PHE eutectic invariant
• the present invention relates to the use of an oil phase with a eutectic invariant (PHE) as defined above, in which the local anesthetic is lidocaine in a proportion of 50% by weight and The fatty acid is in a proportion of 50% by weight relative to the total mass of the oily phase (PHE).
• PHE eutectic invariant
• the present invention relates to the use of a eutectic invariant oil phase (PHE) as defined above, wherein said fatty acid is a saturated or unsaturated fatty acid, linear or branched, comprising from 12 to 24 carbon atoms.
• PHE eutectic invariant oil phase
• Saturated linear fatty acids having 12 to 24 carbon atoms are the following general formulas acids H 3 C- (CH 2) "- COOH, where n varies from 10 to 22.
• linear saturated fatty acids comprising from 12 to 24 carbon atoms without being limited to these are the following: lauric acid or dodecanoic acid (C12: 0), tridecyl acid or tridecanoic acid (C13: 0), myristic acid or acid tetradecanoic acid (C14: 0), palmitic acid or hexadecanoic acid (C16: 0), stearic acid or octodecanoic acid (Cl 8: 0), arachidic acid or eicosanoic acid (C20: 0), acid Behenic or docosanoic acid (C22: 0) and lignoceric acid or tetracosanoic acid (C24: 0).
• unsaturated fatty acid comprising from 12 to 24 carbon atoms refers to a monounsaturated or polyunsaturated fatty acid.
• the monounsaturated linear fatty acids comprising from 12 to 24 carbon atoms are the acids of the following general formulas:
• H 2 C CH- (CH 2 ) p -COOH, where p varies from 9 to 21
• the stereoisomerism of each unsaturation can be cis or go.
• linear monounsaturated fatty acids comprising from 12 to 24 carbon atoms without being limited to them are the following:
• Lauroleic acid or ⁇ -9-dodecanoic acid (C12: 1 -3), oleic acid or ⁇ -9-octadecenoic acid (C18: lw-9) and selacholeic acid or ⁇ -15-tetracosonic acid ( C24: lw-9).
• linear polyunsaturated fatty acids comprising from 12 to 24 carbon atoms without being limited thereto are the following: Linoleic acid or cis-cis-9,12-octadecadienoic acid (C18: 2-w-6), g- linoleic acid or acid cis-cis-cis-6,9,12-octadécatriéno 'ic (C18 W-6) and arachidonic acid or cis-cis-cis-cis-5,8,11,14-icosatetraenoic acid (C20: 4-w-6).
• the present invention relates to the use of an oil phase with eutectic invariant (PHE) as defined above, wherein said fatty acid is chosen from the following: lauric acid or dodecanoic acid , tridecylic acid or tridecanoic acid, myristic acid or tetradecanoic acid, palmitic acid or hexadecanoic acid, stearic acid or octodecanoic acid, arachidic acid or eicosanoic acid, behenic acid or docosanoic acid, lignoceric acid or tetracosanoic acid, lauroleic acid or ⁇ -9-dodecanoic acid, selacholeic acid or ⁇ -15-tetracosonic acid, ⁇ -linoleic acid or cis-cis-cis-6,9 acid, 12 octadecatrienoic and arachidonic acid or cis-cis-cis-5
• PHE eute
• the present invention relates to the use of an oil phase with eutectic invariant (PHE) in which said fatty acid is chosen from the following: lauric acid or dodecanoic acid, tridecylic acid or acid tridecanoic acid, myristic acid or tetradecanoic acid, palmitic acid or hexadecanoic acid, stearic acid or octodecanoic acid, arachidic acid or eicosanoic acid, behenic acid or docosanoic acid, lignoceric acid or tetracosanoic acid, lauroleic acid or cis-9-dodecanoic acid, selacholeic acid or cis-15-tetracosonic acid, g-linoleic acid or cis-cis-cis-6,9,12-octadecatrienoic acid and arachidonic acid or cis-cis-cis-5, 8,
• the present invention relates to the use of an oil phase with eutectic invariant (PHE) as defined above, wherein said local anesthetic is lidocaine and said fatty acid is lauric acid or tridecanoic acid (Example 1).
• PHE eutectic invariant
• lidocaine only a local anesthetic, lidocaine, is used.
• lidocaine-lauric acid and lidocaine-tridecanoic acid mixtures have a broad mass composition range for which the mixture is a homogeneous liquid at 25 ° C.
• the diffusion properties of the local anesthetic are slightly slower than for EMLA ® , but a better regularity, in the case where the oily phase (PHE) is a mixture of lidocaine 46% by weight and lauric acid (Example 2).
• the present invention relates to the use of an oil phase with eutectic invariant (PHE) as defined above, wherein said oily phase is in homogeneous liquid form and stable at a temperature of from ° C at 25 ° C, in particular 0 ° C to 10 ° C.
• PHE eutectic invariant
• Another advantage of the invention is to be able to keep the oil-in-water emulsions of the invention cold while the oily phase present in said emulsions, at temperatures of between 0 ° C. and 10 ° C., remains homogeneous and liquid during the entire shelf life allowed for the use of said emulsion, which makes it possible to prevent the possible oxidation of the oily phases at temperatures of between 25 ° C. and 37 ° C.
• the present invention relates to the use of an oil phase with eutectic invariant (PHE) as defined above, in which local anesthetic is lidocaine in a proportion of 50% by weight and the acid fat is in proportion to 50% by weight relative to the total mass of the oily phase (PHE) and said oily phase is in homogeneous liquid form and stable at a temperature of 0 ° C to 10 ° C.
• PHE eutectic invariant
• the present invention relates to the use of a eutectic invariant oil phase (PHE) as defined above, in which the local anesthetic is lidocaine in a proportion of 50% by weight and the fatty acid is lauric acid or tridecanoic acid in a proportion of 50% by weight relative to the total mass of the oily phase (PHE) and said oily phase is in homogeneous liquid form and stable at a temperature of 0 ° C at 10 ° C.
• PHE eutectic invariant oil phase
• the present invention relates to an oil-in-water (L / H) emulsion comprising an eutectic invariant oil phase (PHE) comprising at least one local anesthetic in a proportion of 10% to 60% by weight relative to the total mass of the oily phase (PHE) and at least one fatty acid in a proportion of 40% to 90% by weight relative to the total mass of the oily phase (PHE), said oily phase (PHE) being of weak ionic nature and in homogeneous and stable liquid form at a temperature of from 0 ° C to 37 ° C, provided that when said local anesthetic is mepivaçain or bupivacaine, or said local anesthetic is associated with at least a second local anesthetic different from those at least two different fatty acids are used, so that obtain a eutectic invariant, as defined above, and in which the pH of the hydrophilic phase is from 6.5 to 7.5.
• PHE eutectic invariant oil phase
• One of the advantages of the emulsions of the invention is that they have a slower diffusion, which makes it possible to have properties of effect delay or effect longer in time, compared to the EMLA which has a rapidly decreasing diffusion kinetics, the emulsions of the invention have a slower diffusion kinetics which therefore decreases more slowly.
• the present invention relates to an oil-in-water (L / H) emulsion as defined above, wherein said oily phase (PHE) comprises at least one local anesthetic in a proportion of 10% to 50% in mass relative to the total mass of the oily phase (PHE) and at least one fatty acid in a proportion of 50% to 90% by weight relative to the total mass of the oily phase (PHE).
• said oily phase comprises at least one local anesthetic in a proportion of 10% to 50% in mass relative to the total mass of the oily phase (PHE) and at least one fatty acid in a proportion of 50% to 90% by weight relative to the total mass of the oily phase (PHE).
• the present invention relates to an oil-in-water (L / H) emulsion as defined above, wherein said oily phase (PHE) comprises at least one local anesthetic in a proportion of 20% to 60% in mass relative to the total mass of the oily phase (PHE) and at least one fatty acid in a proportion of 40% to 80%) by mass relative to the total mass of the oily phase (PHE).
• said oily phase comprises at least one local anesthetic in a proportion of 20% to 60% in mass relative to the total mass of the oily phase (PHE) and at least one fatty acid in a proportion of 40% to 80%) by mass relative to the total mass of the oily phase (PHE).
• the present invention relates to an oil-in-water (L / H) emulsion as defined above, wherein said oily phase (PHE) comprises at least one local anesthetic in a proportion of 30% to 60% in mass relative to the total mass of the oily phase (PHE) and at least one fatty acid in a proportion of 40% to 70% by weight relative to the total mass of the oily phase (PHE).
• said oily phase comprises at least one local anesthetic in a proportion of 30% to 60% in mass relative to the total mass of the oily phase (PHE) and at least one fatty acid in a proportion of 40% to 70% by weight relative to the total mass of the oily phase (PHE).
• the present invention relates to an oil-in-water (L / H) emulsion as defined above, wherein said oily phase (PHE) comprises at least one local anesthetic in a proportion of 30% to 50% in mass relative to the total mass of the oily phase (PHE) and at least one fatty acid in a proportion of 60% to 70%) by mass relative to the total mass of the oily phase (PHE).
• said oily phase comprises at least one local anesthetic in a proportion of 30% to 50% in mass relative to the total mass of the oily phase (PHE) and at least one fatty acid in a proportion of 60% to 70%) by mass relative to the total mass of the oily phase (PHE).
• the present invention relates to an oil-in-water (L / H) emulsion as defined above, wherein said oily phase (PHE) comprises at least one local anesthetic in a proportion of 40% to 50% in mass relative to the total mass of the oily phase (PHE) and at least one fatty acid in a proportion of 50% to 60% by weight relative to the total mass of the oily phase (PHE).
• said oily phase comprises at least one local anesthetic in a proportion of 40% to 50% in mass relative to the total mass of the oily phase (PHE) and at least one fatty acid in a proportion of 50% to 60% by weight relative to the total mass of the oily phase (PHE).
• the present invention relates to an oil-in-water (L / H) emulsion as defined above, wherein said oily phase (PHE) comprises at least one local anesthetic in a proportion of 40%, 41% , 42%, 43%, 44% o, 45%, 46%, 47%), 48%), 49% or 50%> by weight relative to the total mass of the oily phase (PHE) and at least one 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57% fatty acids, 58%>, 59%) or 60% by weight relative to the total mass of the oily phase (PHE).
• said oily phase (PHE) comprises at least one local anesthetic in a proportion of 40%, 41% , 42%, 43%, 44% o, 45%, 46%, 47%), 48%), 49% or 50%> by weight relative to the total mass of the oily phase (PHE) and at least one 50%, 51%, 52%, 53%, 54%, 55%, 56%, 5
• the present invention relates to an oil-in-water (L / H) emulsion as defined above, wherein said local anesthetic is chosen from lidocaine, mepivacaine, bupivacaine, levobupicaine and prilocaine. , articaine, ropivacaine and dibucaine and their mixtures.
• the present invention relates to an oil-in-water (L / H) emulsion as defined above, wherein said local anesthetic is chosen from lidocaine, levobupica ⁇ ne, prilocaine, articaine, ropivacaine and dibucaine and their mixtures.
• said local anesthetic is chosen from lidocaine, levobupica ⁇ ne, prilocaine, articaine, ropivacaine and dibucaine and their mixtures.
• the present invention relates to an oil-in-water (L / H) emulsion as defined above, wherein said local anesthetic is lidocaine.
• the present invention relates to an oil-in-water (L / H) emulsion as defined above, wherein said local anesthetic is lidocaine in a proportion of 50% by weight relative to the total mass of the oily phase (PHE).
• said local anesthetic is lidocaine in a proportion of 50% by weight relative to the total mass of the oily phase (PHE).
• the present invention relates to an oil-in-water (L / H) emulsion as defined above, in which said local anesthetic is lidocaine in a proportion of 50% and the fatty acid is in proportion 50% by weight relative to the total mass of the oily phase (PHE).
• said local anesthetic is lidocaine in a proportion of 50% and the fatty acid is in proportion 50% by weight relative to the total mass of the oily phase (PHE).
• the present invention relates to an oil-in-water (L / H) emulsion as defined above, wherein said local anesthetic is lidocaine in a proportion of 50% and the fatty acid is in proportion to 50%> by weight relative to the total mass of the oily phase (PHE), said oily phase being in homogeneous liquid form and stable at a temperature of 0 ° C to 10 ° C.
• said local anesthetic is lidocaine in a proportion of 50% and the fatty acid is in proportion to 50%> by weight relative to the total mass of the oily phase (PHE), said oily phase being in homogeneous liquid form and stable at a temperature of 0 ° C to 10 ° C.
• the present invention relates to an oil-in-water (L / H) emulsion as defined above, wherein said fatty acid is a linear or branched, saturated or unsaturated fatty acid comprising from 12 to 24 carbon atoms.
• the present invention relates to an oil-in-water (L / H) emulsion as defined above, wherein said fatty acid is chosen from the following: lauric acid or dodecanoic acid, the acid tridecylic acid or tridecanoic acid, myristic acid or tetradecanoic acid, palmitic acid or hexadecanoic acid, stearic acid or octodecanoic acid, arachidic acid or eicosanoic acid, behenic acid or docosanoic acid, lignoceric acid or tetracosanoic acid, lauroleic acid or cw-9-dodecanoic acid, selacholeic acid or cw-15-tetracosonic acid, g-linoleic acid or cis-cis-cis-6,9, 2-octadecatrienoic acid and arachidonic acid or cis-cis-cis-5,
• the present invention relates to an oil-in-water (L / H) emulsion as defined above, wherein said fatty acid is chosen from the following: lauric acid or dodecanoic acid, the acid tridecylic acid or tridecanoic acid, myristic acid or tetradecanoic acid, palmitic acid or hexadecanoic acid, stearic acid or octodecanoic acid, arachidic acid or eicosanoic acid, behenic acid or docosanoic acid, lignoceric acid or tetracosanoic acid, lauroleic acid or cis-9-dodecanoic acid, selacholeic acid or cis-15-tetracosonic acid, g-linoleic acid or cis-cis-cis-6,9,12-octadecatrienoic acid and arachidonic acid or cis-cis-cis-5
• the present invention relates to an oil-in-water (L / H) emulsion as defined above, wherein said oily phase (PHE) is chosen from the following oily phases (PHE): lidocaine-acid lauric or lidocaine - tridecanoic acid.
• PHE oil-in-water
• the present invention relates to an oil-in-water (L / H) emulsion as defined above, said eutectic invariant oil phase (PHE) being in proportion to the total mass of the emulsion. from 5% to 25% by weight, preferably from 10% to 25% by weight.
• PHE eutectic invariant oil phase
• the present invention relates to an oil-in-water (L / H) emulsion comprising a eutectic invariant oil phase (PHE) as defined above, in which the oily phase is dispersed in a hydrophilic phase including one or more thickeners and one or more emulsifiers.
• PHE eutectic invariant oil phase
• thickeners refers to all the thickeners that can be used in the preparation of an emulsion and are well known to those skilled in the art.
• Preferred thickeners are: cellulose and derivatives (methyl and carboxymethyl celluloses), alginates, gelatin, anionic polymers, gums (arabic, tragacanth), colloidal silica, wool fat, beeswax.
• emulsifiers refers to all the emulsifiers and self-emulsifiers that can be used in the preparation of an emulsion and are well known to those skilled in the art.
• Preferred emulsifiers are: ester-bonded nonionic emulsifiers (sorbitan esters, polysorbates), ether bonded (PEG fatty alcohol ethers), lecithins, glycerol, glycerol esters and fatty acid esters (triglycerides) .
• the present invention relates to an oil-in-water (L / H) emulsion as defined above, comprising:
• polysorbate 85 from 5% to 15% by weight of polysorbate, in particular of polysorbate 85, and
• a hydrophilic phase optionally thickened with 0% to 3% by weight of a cellulose derivative.
• Glycerol is used here as an autoemulsifier and the emulsion therefore corresponds to an autoemulsion.
• autoemulsifier refers to an emulsification which occurs spontaneously, in other words, it refers to any agent or composition capable of forming a stable emulsion with an aqueous phase, with virtually no energy input (i.e. without the need for a supply of thermal energy and / or mechanical) for example by dispersion in the aqueous phase by slow mechanical stirring, and otherwise called autoemulsion.
• the emulsions described in this embodiment are therefore emulsions having autoemulsion properties, that is to say that, if after a certain storage time, for example 15 days in a container, the emulsion demixed it is sufficient to manually agitate again said container to reform said emulsion in said container without having to provide a strong agitation or activation energy. They also have the advantage of having a vesicle size smaller than that of conventional emulsions, that is to say less than ⁇ ⁇ whereas that of conventional emulsions is greater than 1 ⁇ .
• the emulsion of this embodiment is preferably intended for analgesic application.
• the present invention relates to an oil-in-water (L / H) emulsion as defined above, comprising:
• lecithins from 1% to 3% by weight of lecithins, in particular of eggs or soya
• a hydrophilic phase in particular thickened with 1% to 3% by weight of a cellulose derivative.
• Glycerol is used here as an autoemulsifier and the emulsion thus corresponds to an autoemulsion.
• the emulsion of this embodiment is preferably intended for an analgesic or sexual delaying application.
• the present invention relates to an oil-in-water (L / H) emulsion as defined above, comprising:
• polysorbate 85 from 5% to 15% by weight of polysorbate, in particular of polysorbate 85, and
• a hydrophilic phase optionally thickened with 0.5% to 3% by weight of an alginate.
• Glycerol is used here as an autoemulsifier and the emulsion thus corresponds to an autoemulsion.
• the emulsion of this embodiment is preferably intended for ⁇ ⁇ antalgic or sexual delaying application.
• the present invention relates to an oil-in-water (L / H) emulsion as defined above, comprising:
• hydrophilic phase optionally thickened with 0.5% to 3% by weight of gelatin.
• the emulsion of this embodiment is preferably intended for an analgesic or sexual delaying application.
• the present invention relates to an oil-in-water (L / H) emulsion as defined above, comprising:
• polysorbate 85 from 5% to 15% by weight of polysorbate, in particular of polysorbate 85, and
• a hydrophilic phase optionally thickened with 0.5% to 3% by weight of an anionic polymer.
• the emulsion of this embodiment is preferably intended for an analgesic or sexual delaying application.
• the present invention relates to an oil-in-water (L / H) emulsion as defined above, further comprising a vegetable or synthetic short, medium or long chain triglyceride oil.
• vegetable or synthetic short chain triglyceride oil are meant short chain ( ⁇ 8 carbon atom) fatty acids such as propionic acid, butyric acid.
• medium chain triglyceride oil is meant medium chain fatty acids (8 to 12 carbon atoms) such as caprylic, capric, lauric and coconut oils.
• vegetable or synthetic long chain triglyceride oil should be understood to include long chain (> C12) fatty acids such as palmitic, oleic, linoleic, linolenic and olive, soy, corn, peanut, sunflower.
• the present invention relates to an oil-in-water (L / H) emulsion further comprising a vegetable or synthetic vegetable of short, medium or long chain triglycerides as defined above, in which said oil of water triglycerides is a medium chain triglyceride oil, said medium chain triglyceride oil being present in particular up to 15% by weight.
• the oily phase (PHE) of the oil-in-water (L / H) emulsion as defined above consists of 50% by weight of lidocaine and 50% by weight of lauric acid.
• the oily phase (PHE) to the water in oil emulsion (W / H) as defined above is constituted by 50% by weight of lidocaine and 50%> by weight of tridecanoic acid.
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising an oil-in-water (L / H) emulsion comprising an eutectic invariant oil phase (PHE) as defined above, in combination with a pharmaceutically acceptable vehicle.
• L / H oil-in-water
• PHE eutectic invariant oil phase
• pharmaceutically acceptable carrier a support for transporting the oily phase and which is not an excipient.
• examples of support without being limited to these are cream, gel and patch.
• the present invention relates to a pharmaceutical composition in association with a pharmaceutically acceptable vehicle as defined above, in a form that can be administered topically at a dose of 0.5 g / 10 cm 2 to 4 g / 10 cm 2. .
• the present invention relates to an oil-in-water emulsion comprising an oily phase as defined above, for its use as a medicament, in particular as an analgesic, antalgic or sexual retardant.
• the oil phase with eutectic invariant comprises a fatty acid devoid of toxicity, which acts as a transdermal diffusion promoter of the anesthetic.
• analgesic refers to a drug intended to reduce pain.
• sexual retarder refers to a drug that slows the onset of ejaculation.
• the present invention relates to an oil-in-water emulsion comprising an oily phase as defined above, for its use as a medicament, as defined above, in particular as an analgesic.
• the present invention relates to an oil-in-water emulsion comprising an oily phase as defined above, for its use as a medicament, as defined above, in particular as an analgesic.
• the present invention relates to an oil-in-water emulsion comprising an oily phase as defined above, for its use as a medicament, as defined above, in particular as a sexual retarder.
• the present invention relates to an oily eutectic invariant phase (PHE) comprising at least one local anesthetic in a proportion of 10% to 60% by weight relative to the total mass of the oily phase (PHE) and at least a fatty acid in a proportion of 40% to 90% by weight relative to the total mass of the oily phase (PHE), for the constitution of an oil-in-water emulsion (L / H) in which the pH of the phase hydrophilic range is from 6.5 to 7.5, said oily phase (PHE) being of weakly ionic nature and in homogeneous liquid form and stable at a temperature of 0 ° C to 37 ° C, provided that when said local anesthetic is mepivacaine or bupivacaine, it is associated with a local anesthetic different from these or at least two different fatty acids, so as to obtain a eutectic invariant,
• PHE oily eutectic invariant phase
• said local anesthetic is selected from lidocaine, mepivacaine, bupivacaine, levobupicain, prilocaine, articaine, ropivacaine and dibucaine and mixtures thereof and said fatty acid is selected from the following: lauric acid or dodecanoic acid, tridecyl acid or tridecanoic acid, myristic acid or tetradecanoic acid, palmitic acid or hexadecanoic acid, stearic acid or octodecanoic acid, arachidic acid or eicosanoic acid, behenic acid or acid docosanoic acid, lignoceric acid or tetracosanoic acid, lauroleic acid or cis-9-dodecanoic acid, selacholeic acid or cis-15-tetracosonic acid, g-linoleic acid or cis-cis-cis-6 acid, 9,12-octa
• the present invention relates to an oily eutectic invariant phase (PHE) comprising at least one local anesthetic in a proportion of 10% to 60% by weight relative to the total mass of the oily phase (PHE) and at least a fatty acid in a proportion of 40% to 90% by weight relative to the total mass of the oily phase (PHE), for the constitution of an oil-in-water emulsion (L / H) in which the pH of the hydrophilic phase is between 6.5 and 7.5, the said oily phase (PHE) being of weak ionic nature and in homogeneous liquid form and stable at a temperature of 0 ° C to 37 ° C, provided that when said local anesthetic is mepivacaine or bupivacaine, it is associated with a local anesthetic different from these or at least two different fatty acids, in order to obtain a eutectic invariant,
• PHE oily eutectic invariant phase
• said local anesthetic is selected from lidocaine, levobupicaine, prilocaine, articaine, ropivacaine and dibucaine and mixtures thereof and said fatty acid is selected from the following: lauric acid or dodecanoic acid, acid tridecylic acid or tridecanoic acid, myristic acid or tetradecanoic acid, palmitic acid or hexadecanoic acid, stearic acid or octodecanoic acid, arachidic acid or eicosanoic acid, behenic acid or docosanoic acid, lignoceric acid or tetracosanoic acid, lauroleic acid or cis-9-dodecanoic acid, selacholeic acid or cis-15-tetracosonic acid, g-linoleic acid or cis-cis-cis-6,9,12-octadecatrienoic acid and arachidonic acid or g
• the present invention relates to an oily eutectic invariant phase (PHE) as defined above, wherein said local anesthetic is in a proportion of 10% to 50% by weight relative to the total mass of the oily phase (PHE) and said fatty acid is in a proportion of 60%> to 90% by weight relative to the total mass of the oily phase (PHE).
• PHE oily eutectic invariant phase
• the present invention relates to an oily eutectic invariant phase (PHE) as defined above, in which said local anesthetic is in a proportion of 20% to 60% by weight relative to the total mass.
• the oily phase (PHE) and said fatty acid is in a proportion of 40% to 80% by weight relative to the total mass of the oily phase (PHE).
• the present invention relates to an oily eutectic invariant phase (PHE) as defined above, wherein said local anesthetic is in a proportion of 30% to 60% by weight relative to the total mass of the oily phase (PHE) and said fatty acid is in a proportion of 40% to 70% by weight relative to the total mass of the oily phase (PHE).
• PHE oily eutectic invariant phase
• the present invention relates to an oily eutectic invariant phase (PHE) as defined above, wherein said local anesthetic is in a proportion of 30% to 50% by weight relative to the total mass of the oily phase (PHE) and said fatty acid is in a proportion of 50% to 70% by mass relative to the total mass of the phase oily (PHE).
• PHE oily eutectic invariant phase
• the present invention relates to an oily eutectic invariant phase (PHE) as defined above, wherein said local anesthetic is in a proportion of 40% to 50% by mass and said fatty acid in proportion from 50% to 60% by weight, said eutectic invariant oil phase being in the form of a homogeneous and stable liquid at a temperature of 0 ° C. to 37 ° C., in particular of 0 ° C. to 10 ° C. vs.
• PHE oily eutectic invariant phase
• the present invention relates to an oily eutectic invariant phase (PHE) as defined above, wherein said local anesthetic is in a proportion of 41%, 42%, 43%, 44%, 45% , 46%, 47%, 48%, 49%, or 50%) by weight and said fatty acid in a proportion of 50%>, 51%, 52%, 53%, 54%, 55%, 56%>, 57 %, 58%, 59% or 60% by weight.
• PHE oily eutectic invariant phase
• the present invention relates to an oily eutectic invariant phase (PHE) as defined above, wherein said local anesthetic is lidocaine and said fatty acid is chosen from lauric acid or acid. tridecanoic.
• PHE oily eutectic invariant phase
• the present invention relates to an oily eutectic invariant phase (PHE) as defined above, wherein said local anesthetic is lidocaine in a proportion of 50% and said fatty acid is chosen from lauric acid or tridecanoic acid in a proportion of 50%.
• PHE oily eutectic invariant phase
• the present invention relates to an oily eutectic invariant phase (PHE) as defined above, wherein said local anesthetic is lidocaine in a proportion of 50% and said fatty acid is lauric acid. in a proportion of 50%, said oil phase with eutectic invariant being in the form of a homogeneous liquid and stable at a temperature of 0 ° C to 10 ° C.
• PHE oily eutectic invariant phase
• Figure 1 liquid-solid phase diagram of a binary system with eutectic invariant consisting of lidocaine and lauric acid established by differential scanning calorimetry.
• X axis mass percentage of lidocaine in the lidocaine-lauric acid mixture.
• T (° C) is the temperature expressed in degrees Celsius.
• Figure 2 liquid-solid phase diagram of a binary system with eutectic invariant consisting of lidocaine and tridecanoic acid established by differential scanning calorimetry.
• X axis percentage of lidocaine in the lidocaine-tridecanoic acid mixture.
• T (° C) is the temperature expressed in degrees Celsius.
• Figure 3 Diffusion of anesthetics in eutectic invariant mixtures (oily phases) over a period of 6 hours.
• X axis: t (h) is the time in hours.
• FIGS. 4A and B Autoemulsion of Example 5 Including a Lidocaine-Lauryl Acid Mixture
• Figure 4A demixed autoemulsion. Figure 4A clearly shows two phases.
• Figure 4B After manually stirring the demixed autoemulsion.
• the composition is in emulsion form and has only one phase.
• Figure 5 Diffusion of anesthetics in the emulsion according to Example 5 and in EMLA over a period of 6 hours.
• X axis: t (h) is the time in hours.
• the diffusion of the anesthetic is slower in the case of the emulsion according to the invention, which makes it possible in particular in the context of analgesic and sexual retardant applications to have an attenuated but better distributed effect over time and therefore greater than the EMLA.
• fatty acids that are present in the skin makes it possible to have a formulation adapted to a topical use which is moreover without prilocaine.
• the binary mixtures of lidocaine with lauric acid and tridecanoic acid have such a property.
• the phase diagrams of the mixtures of lidocaine with lauric acid and tridecanoic acid, established by differential scanning calorimetry, are presented respectively in Figures 1 and 2.
• the properties of the lidocaine-fatty acid binary mixtures are reported in FIG. Table I, with regard to the properties of the lidocaine-prilocaine binary mixture (EMLA).
• the lidocaine-fatty acid binary mixtures have better thermodynamic properties than the lidocaine-prilocaine binary mixture (EMLA), ie a lower melting temperature and a broader composition range for which the binary mixture is liquid at temperature. ambient temperature (25 ° C) and low temperature (10 ° C).
• Table I shows the characteristic thermodynamic properties of lidocaine-lauric acid, lidocaine-tridecanoic acid eutectic mixtures according to the invention and lidocaine-prilocaine eutectic mixture (EMLA) for comparison purposes.
• Table I shows the characteristic thermodynamic properties of lidocaine-lauric acid, lidocaine-tridecanoic acid eutectic mixtures according to the invention and lidocaine-prilocaine eutectic mixture (EMLA) for comparison purposes.
• Percentage values are expressed as ⁇ 2% error, ie for L-C12, for example, the range is from 31 ⁇ 2 to 60 ⁇ 2.
• EXAMPLE 2 Kinetics of diffusion through a lipophilic membrane of lidocaine of an oil phase with eutectic invariant (PHE) of composition of 50% by weight of lidocaine and 50% by weight of lauric acid.
• PHE eutectic invariant
• the diffusion kinetics of the anesthetics of these two mixtures are shown in FIG. 3.
• the experimental conditions are as follows: the diffusion membrane is made of a silicone film 125 ⁇ m thick; the surface of the diffusion membrane is 3.1 cm 2 ; the reservoir solution of Franz's cell is an aqueous buffer solution of pH 6.2, this value is close to the physiological pH of the human skin; the tank of Franz's cell is thermostated at 37 ° C, the temperature of the human body.
• Example 3 Emulsion based on triglycerides, egg lecithin and cellulose.
• Oil in water emulsion (L / H) consisting of:
• PHE oily phase
• the lecithins are dispersed in medium chain chain triglyceride oil at a temperature of 60 ° C.
• the methylcellulose is dispersed at 25 ° C in the aqueous phase.
• the emulsification is carried out at 25 ° C. according to the phase inversion method using a disperser, applying a speed of 13000 rpm for 10 minutes.
• the coarse emulsion thus obtained is then homogenized using an ultrasonic homogenizer for 10 minutes.
• the emulsion obtained has a mean diameter of 100 nm, with a polydispersity index of 0.1, and a zeta potential of -50 mV.
• Example 4 Emulsion based on glycerol and polysorbate.
• Oil in water emulsion (L / H) consisting of:
• PHE oily phase
• the manufacturing process is carried out by autoemulsification at 25 ° C., followed by homogenization using a homegenerator for 10 minutes.
• the emulsion obtained has an average diameter of 140 nm, a polydispersity index of 0.3, and a zeta potential of -50mV.
• An autoemulsion including an oily eutectic invariant phase of lidocaine and lauric acid was formulated. This type of emulsion does not require heating stirring vigorous mechanical agitation to be formed.
• the mass composition of this autoemulsion is as follows:
• EXAMPLE 6 Kinetics of diffusion through a lipophilic membrane of lidocaine of an emulsion including an oil phase with eutectic invariant (PHE) of composition of 50% by weight of lidocaine and 50% by weight of lauric acid
• PHE eutectic invariant
• An autoemulsion including an oily eutectic invariant phase of lidocaine and lauric acid was formulated. This type of emulsion does not require vigorous mechanical stirring or agitation to be formed.
• the mass composition of this autoemulsion is as follows: medium chain triglycerides 8%
• lecithin E80 1.2% methylcellulose 0.5%
• Example 8 Nanoemulsions including lidocaine-lauric acid mixture and sodium alginate as thickener
• a nanoemulsion is an emulsion whose size of certain globules is of the order of one nanometer.
• a nanoemulsion including an oily eutectic-invariant phase of lidocaine and lauric acid, as well as sodium alginate as a thickener, was formulated.
• This emulsion is also an autoemulsion, which can be formed by simple manual stirring of its constituents and without heating.
• the bulk compositions of this nanoemulsion is indicated below.
• Dv0.5 which is the maximum diameter of the cells with 50% of the population, was measured, as well as its evolution over 3 days (Table II) after the formulation of the emulsion. This maximum diameter is less than 1 ⁇ .
• the pH of the emulsion is adjusted to 7.0 with sodium hydroxide.
• a nanoemulsion including an oily eutectic-invariant phase of lidocaine and lauric acid, as well as carbopol 981 as a thickener, was formulated.
• This emulsion is also an autoemulsion, which can be formed by simple manual stirring of its constituents and without heating.
• the mass composition of this nanoemulsion is given below.
• Dv0.5 was measured, as well as its evolution over 7 days after emulsion formulation (Table III). This maximum diameter is less than 1 ⁇ .
• the pH of the emulsion is adjusted to 6.7 with sodium hydroxide.

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