EP4362918A1 - Nouvelle nanoémulsion huile-dans-eau - Google Patents

Nouvelle nanoémulsion huile-dans-eau

Info

Publication number
EP4362918A1
EP4362918A1 EP22732977.8A EP22732977A EP4362918A1 EP 4362918 A1 EP4362918 A1 EP 4362918A1 EP 22732977 A EP22732977 A EP 22732977A EP 4362918 A1 EP4362918 A1 EP 4362918A1
Authority
EP
European Patent Office
Prior art keywords
nanoemulsion
oil
nanoemulsion according
acid
emulsifier
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22732977.8A
Other languages
German (de)
English (en)
Inventor
Thorge DEBUS
Oliver DROZDALSKI
Tobias MELLER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tiny Technologies GmbH
Original Assignee
Tiny Technologies GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tiny Technologies GmbH filed Critical Tiny Technologies GmbH
Publication of EP4362918A1 publication Critical patent/EP4362918A1/fr
Pending legal-status Critical Current

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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
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/06—Emulsions
    • A61K8/062—Oil-in-water emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/345—Alcohols containing more than one hydroxy group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/37—Esters of carboxylic acids
    • A61K8/375—Esters of carboxylic acids the alcohol moiety containing more than one hydroxy group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55—Phosphorus compounds
    • A61K8/553—Phospholipids, e.g. lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/60—Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/92—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
    • A61K8/922—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof of vegetable origin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/10—General cosmetic use
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/41—Particular ingredients further characterized by their size
    • A61K2800/413—Nanosized, i.e. having sizes below 100 nm

Definitions

  • the invention relates to a novel oil-in-water nanoemulsion based on vegetable oil, which is particularly suitable for preparing fat-soluble substances.
  • the nanoemulsion consists exclusively of natural substances and is therefore particularly suitable for oral application.
  • the nanoemulsion is characterized by high long-term stability and storability.
  • the nano emulsion can be used in the field of pharmacology or cosmetics and also as an additive in food.
  • a method for preparing the novel oil-in-water nano-emulsion is also provided.
  • nanoemulsions kinetically stable colloidal systems
  • nanoemulsions have a droplet size in the order of 100 nm or less.
  • nanoemulsions have improved functional properties, which makes their use in many industrial areas attractive.
  • nanoemulsions are used to administer lipophilic substances in pharmacology, in cosmetics and in the food industry.
  • a frequently observed problem with nanoemulsions is their low stability and their insufficient ability to provide lipophilic substances in sufficient quantities.
  • Emulsions that are able to administer high amounts of lipophilic substances often turn out to be relatively unstable in practice, so that they can only be stored stably for a few weeks.
  • stable emulsions with small droplet sizes regularly have a low capacity when loading the oil phase, so that the amounts of the substances to be administered is low.
  • the production of nanoemulsions which have balanced properties, ie on the one hand exhibit high storage stability and on the other hand have a high loading capacity, is extremely difficult in practice.
  • nanoemulsion with balanced properties which can be stored for a period of several months or even years and at the same time is characterized by a high loading capacity of the oil phase.
  • the nanoemulsion should be well tolerated and not very toxic so that it can be used in pharmaceuticals as well as in food.
  • this object is achieved by a selection of ingredients that lead to nanoemulsions ren, which are extremely stable even during storage, and also loaded with large amounts of lipophilic substances who can who, after administration to a subject with egg ner high bioavailability are provided to these.
  • the present invention thus relates to an oil-in-water nanoemulsion, the oil-in-water nanoemulsion comprising the following components:
  • an emulsifier selected from the group consisting of lecithin, mono and diglycerides of fatty acids, lactic acid and/or citric acid and mixtures thereof;
  • ethanol wherein the nanoemulsion has a mean particle diameter (Dm) of 70 nm or less.
  • the mean particle diameter (Dm) is understood here to mean the mean diameter of the oil droplets dispersed in the continuous phase.
  • the mean particle diameter of the nanoemulsion is less than 70 nm, preferably less than 65 nm, less than 60 nm, less than 55 nm, less than 50 nm, less than 45 nm, or even less than 40 nm
  • the average particle diameter of the nanoemulsion according to the invention can be in the range of 40-70 nm, such as in the range of 45-65 nm or in the range of 50-60 nm.
  • the nanoemulsion of the present invention comprises an oil phase dispersed in a continuous aqueous phase.
  • the oil phase comprises a vegetable oil.
  • the vegetable oil can be an LCT vegetable oil or an MCT vegetable oil.
  • the vegetable oil is an LCT vegetable oil.
  • LCT vegetable oils are considered to be vegetable oils which consist of 70% (w/w) or more long-chain triglycerides (LCT), based on the total weight of the vegetable oil.
  • long-chain triglycerides are understood to mean triglycerides which are esterified with fatty acids which have a chain length of C14-C24.
  • fatty acids include the saturated fatty acids myristic acid (C14), palmitic acid (C16), stearic acid (C18), arachidic acid (C20), behenic acid (C22) and lignoceric acid (C24) as well as the unsaturated fatty acids palmitoleic acid (C16), oleic acid (C18 ), gadoleic acid (C20) and cetoleic acid (C22).
  • Vegetable oils that are 70% or more long-chain triglycerides include sunflower oil, rapeseed oil, olive oil, linseed oil, corn oil, wheat germ oil, palm oil, hemp oil and soybean oil.
  • the vegetable oil is an MCT vegetable oil.
  • MCT vegetable oils are considered to be those vegetable oils which consist of less than 70% (w/w) of long-chain triglycerides, based on the total weight of the vegetable oil.
  • these vegetable oils contain a high proportion of medium-chain triglycerides.
  • medium-chain triglycerides are understood to mean triglycerides which are esterified with fatty acids which have a chain length of C6-C12. These fatty acids include the saturated fatty acids caproic acid (C6), caprylic acid (C8), capric acid (CIO) and lauric acid (C12).
  • MCT vegetable oils which can be used in the practice of the invention typically have a medium chain triglycerides content of 20% (w/w) or more, preferably 30% (w/w) or more, based on the total weight of the vegetable oil.
  • Preferred MCT vegetable oils within the scope of the invention are coconut oil and palm kernel oil.
  • the oil phase of the nanoemulsion according to the invention comprises palm oil. In one embodiment, the oil phase of the nanoemulsion according to the invention comprises sunflower oil. In a further embodiment, the oil phase of the nanoemulsion according to the invention comprises rapeseed oil. In yet another embodiment, the oil phase of the nanoemulsion of the invention comprises olive oil. In yet another embodiment, the oil phase of the nanoemulsion of the invention comprises linseed oil. In yet another embodiment, the oil phase of the nanoemulsion of the invention comprises corn oil. In an even further embodiment, the oil phase of the inventive ssen nanoemulsion wheat germ oil. In yet another embodiment, the oil phase of the nanoemulsion according to the invention comprises soybean oil. In yet another embodiment, the oil phase of the nanoemulsion of the invention comprises coconut oil. In yet another embodiment, the oil phase of the nanoemulsion according to the invention comprises palm kernel oil.
  • the proportion of vegetable oil is between 5% and 15% (w/w), based on the total weight of the emulsion.
  • the vegetable oil can be, for example, in an amount of more than 5% (w/w), more than 6% (w/w), more than 7% (w/w), more than 8% (w/w), more than 9% (w/w), more than 10% (w/w), more than 11% (w/w), more than 12% (w/w), more than 13% (w/w) or more than 14% (w/w). It is particularly preferred that the vegetable oil is present in the emulsion in an amount of 5-10% (w/w), for example in an amount of 6-10% (w/w), 7-10% (w/w) w) or 8-10% (w/w).
  • the nanoemulsion according to the invention comprises a continuous phase which, in addition to other possible constituents, comprises water and glycerol.
  • the proportion of glycerine in the continuous phase can vary depending on the application of the emulsion. According to the invention, however, the proportion of glycerol is between 30% and 70% (w/w), based on the total weight of the emulsion.
  • the proportion of glycerol in the nanoemulsion according to the invention is at least 30% (w/w), at least 35% (w/w), at least 40% (w/w), at least 45% (w/w ), at least 50% (w/w), at least 55% (w/w), at least 60% (w/w) or at least 65% (w/w) based on the total weight of the emulsion.
  • the proportion of glycerin in the nanoemulsion can be 35-70% (w/w), 40-70% (w/w), 45-70% (w/w), 50-70% (w/w), 55 -70% (w/w) or between 60-70% (w/w) based on the total weight of the emulsion.
  • the nanoemulsion according to the invention also comprises one or more emulsifiers which facilitate the production of the nanoemulsion and stabilize the emulsion after its production.
  • the emulsifier or emulsifiers act as surface-active substances which reduce the interfacial tension at the oil-water phase interface.
  • the emulator or emulators used are selected from the group consisting of lecithin and mono- and diglycerides of fatty acids, lactic acid and/or citric acid and mixtures thereof.
  • the nanoemulsion comprises lecithin as an emulsifier.
  • the nanoemulsion comprises monoglycerides and/or diglycerides of fatty acids, lactic acid and/or citric acid or mixtures thereof as an emulsifier.
  • the nanoemulsion can comprise glycerol mono- or di-esterified with an acid.
  • the acid can be a saturated or unsaturated fatty acid, lactic acid and/or citric acid.
  • the fatty acids linoleic acid, oleic acid, stearic acid are particularly preferred.
  • the nanoemulsion can thus comprise one or more of the following compounds as an emulsifier: glyceryl citrate, glyceryl lactate, glyceryl linoleate, glyceryl oleate (Imwitor 948), glyceryl stearate (Imwitor 491), glyceryl lactate citrate, glyceryl linoleate citrate, glyceryl stearate citrate (Imwitor 372P), glyceryl oleate citrate, glyceryl linoleate lactate, glyceryl stearate lactate, glyceryl oleate lactate, glyceryl oleate linoleate, glyceryl stearate linoleate, glyceryl oleate stearate and mixtures of said compounds.
  • an emulsifier glyceryl citrate, glyceryl lactate
  • the nanoemulsion comprises lecithin as the sole emulsifier.
  • the nanoemulsion comprises glyceryl citrate as the sole emulsifier.
  • the nanoemulsion comprises glyceryl lactate as the sole gene emulsifier.
  • the nanoemulsion comprises glyceryl linoleate as the sole emulsifier.
  • the nanoemulsion comprises glyceryl oleate as the sole emulsifier.
  • the emulsifier used in the production of the nanoemulsion according to the invention is a mixture of mono- and diglycerides of lactic acid, citric acid, linoleic acid and oleic acid (glyceryl citrate/lactate/linoleate/oleate ).
  • Such a mixture of ver different emulsifiers is marketed by several suppliers under the name Imwitor 375.
  • the emulsifier present in the nanoemulsion is Imwitor 375.
  • the emulsifier present in the nanoemulsion is glyceryl stearate, which is sold by several suppliers under the name Imwitor 491.
  • the emulsifier present in the nanoemulsion is glyceryl stearate citrate, which is marketed by several suppliers under the name Imwitor 372 P.
  • the emulsifier present in the nanoemulsion is glyceryl oleate, which is marketed by several suppliers under the name Imwitor 948.
  • the total amount of emulsifier in the nanoemulsion is between 2-10% (w/w), more preferably between 3-10% (w/w), 4-10% (w/w), 5-10 % (w/w), 6-10% (w/w), 7-10% (w/w) or 8-10% (w/w) based on the total weight of the emulsion.
  • the total amount is Emulsifier in the nanoemulsion according to the invention preferably more than 3% (w/w), more than 4% (w/w), more than 5% (w/w), more than 6% (w/w), more than 7% (w/w) or more than 8% (w/w).
  • a total amount of emulsifier of 5-6% (w/w) is particularly preferred herein.
  • the emulsifier in the nanoemulsion is lecithin, present in a total amount between 3-10% (w/w), 4-10% (w/w), 5-10% (w/w) , 6-10% (w/w), 7-10% (w/w) or 8-10% (w/w) based on the total weight of the emulsion.
  • the total amount of lecithin in the nano emulsion is preferably more than 3% (w/w), more than 4% (w/w), more than 5% (w/w), more than 6% (w/w), more than 7% (w/w) or more than 8% (w/w).
  • a total amount of lecithin of 5-6% (w/w) is particularly preferred herein.
  • the emulsifier in the nanoemulsion is a mixture of two or more of the compounds glyceryl citrate, glyceryl lactate, glyceryl linoleate, glyceryl oleate (Imwitor 948), glyceryl stearate (Imwitor 491), glyceryl lactate citrate , glyceryl linoleate citrate, glyceryl stearate citrate (Imwitor 372P), glyceryl oleate citrate, glyceryl linoleate lactate, glyceryl stearate lactate, glyceryl oleate lactate, glyceryl oleate linoleate, glyceryl stearate linoleate and glyceryl oleate stearate, the mixture being present in a total amount between 3- 10% (w/w), 4-10% (w/w),
  • the mixture can be used in a total amount of more than 3% (w/w), more than 4% (w/w), more than 5% (w/w), more than 6% (w/w), more than 7% (w/w) or more than 8% (w/w).
  • a total of 5-6% (w/w) of the mixture in the emulsion is particularly preferred herein, based on the total weight of the emulsion.
  • the mix acts it is preferably Imwitor 375 (glyceryl citrate/lactate/linoleate/oleate).
  • the emulsifier in the nanoemulsion is a mixture of lecithin with one or more of the compounds glyceryl citrate, glyceryl lactate, glyceryl linoleate, glyceryl oleate (Imwitor 948), glyceryl stearate (Imwitor 491), glyceryl lactate Citrate, glyceryl linoleate citrate, glyceryl stearate citrate (Imwitor 372P), glyceryl oleate citrate, glyceryl linoleate lactate, glyceryl stearate lactate, glyceryl oleate lactate, glyceryl oleate linoleate, glyceryl stearate linoleate and glyceryl oleate stearate, the mixture being present in a total amount between 3 - 10% (w/w), 4-10
  • the mixture of lecithin with one or more of the above glycerol esters can be present in a total amount of more than 3% (w/w), more than 4% (w/w), more than 5% (w/w), more than 6% (w/w), more than 7% (w/w) or more than 8% (w/w).
  • a total of 5-6% (w/w) of the mixture in the emulsion is particularly preferred herein, based on the total weight of the emulsion.
  • the mixture is preferably a mixture of lecithin and Imwitor 375 (glyceryl citrate/lactate/linoleate/oleate).
  • the nanoemulsion according to the invention comprises ethanol as a further component.
  • the ethanol is preferably present in the nano-emulsion in an amount of 2-20% (w/w).
  • the ethanol can be, for example, in an amount greater than 2% (w/w), greater than 3% (w/w), greater than 4% (w/w), greater than 5% (w/w), greater than 6% (w/w), more than 7% (w/w), more than 8% (w/w), more than 9% (w/w), more than 10% (w/w), more than 11% (w/w), more than 12% (w/w), more than 13% (w/w), more than 14% (w/w), more than 15% (w/w), more than 16% (w/w), more than 17% (w/w), more than 18% (w/w) or more than 19% (w/w).
  • the ethanol is present in the emulsion in an amount of 5-10% (w/w), e.g. in an amount of 6-10% (w/w), in an amount of 7-10% ( w/w) or in an amount of 8-10% (w/w).
  • the oil phase of the nanoemulsion according to the invention comprises a poorly water-soluble or water-insoluble lipophilic compound which is to be released after the nanoemulsion has been taken up.
  • the poorly water-soluble or water-insoluble lipophilic compound is preferably selected from the group consisting of cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), tetrahydrocannabinol (THC), melatonin, resveratrol, astaxanthin, coenzyme Q10, vitamin A, vitamin C, vitamin E, vitamin D3, vitamin K2, flavonoids, glutathione, ß-caryophyllene, 2-arachidonylglycerol (2-AG), palmitoylethanolamide (PEA), anandamide, oleoylethanolamide (OEA) and oligomeric proanthocyanin - idines (OPC).
  • CBD cannabidiol
  • the nanoemulsion according to the invention can include other optional components, depending on the field of application of the respective emulsion.
  • the oil phase comprises an essential oil.
  • This component can on the one hand serve as a preservative or antioxidant.
  • the essential oil can influence the taste of a nanoemulsion intended for oral administration as well as the dissolving behavior of the other components.
  • Suitable essential oils include, for example, orange peel oil, lemon oil and peppermint oil. According to the invention, the essential oil is used in an amount of 0.5-5% (w/w),
  • the nanoemulsion according to the invention can comprise substances which increase the bioavailability of the lipophilic compound to be administered.
  • suitable substances for increasing the bioavailability are selected from the group consisting of piperine, curcumin, resveratrol, quercetin, menthol, naringin, bergamottin, kaempferol and rutin.
  • the oil phase of the nanoemulsion according to the invention can also comprise oleic acid and/or ethyl oleate.
  • Oleic acid and ethyl oleate can act as co-emulsifiers or solvents in the nanoemulsion. You can also prevent and/or delay the ripening (ripening) of the nanoemulsion.
  • Oleic acid and ethyl oleate can be present in the nanoemulsion in an amount of 0.5-10% (w/w) in total.
  • the nanoemulsion according to the invention can comprise one or more sugar esters.
  • the sugar ester can be a sucrose ester.
  • Suitable sucrose esters which are suitable as an additive for the nanoemulsions according to the invention include, inter alia, sucrose stearate, sucrose palmitates, sucrose myristates and/or sucrose laurates.
  • the sugar ester(s) can be present in the nanoemulsion in a total amount of 0.5-3% (w/w).
  • the sucrose ester is sucrose stearate of the following structure:
  • the nanoemulsion according to the invention has the particular advantage that only purely natural compounds can be used in its production. According to the invention, it is also possible to produce nanoemulsions with the special, advantageous properties without having to resort to ethoxylated compounds.
  • the nanoemulsion according to the invention contains only a minimal amount of ethoxylated compounds, such as ethoxylated glyceryl fatty acid esters or sorbitan fatty acid esters, such as polysorbate 80.
  • the total amount of ethoxylated compounds in the nanoemulsion according to the invention is less than 0, 5% (w/w), more preferably less than 0.4% (w/w), less than 0.3% (w/w), less than 0.2% (w/w), less than 0, 1% (w/w), less than 0.09% (w/w), less than 0.08% (w/w), less than 0.07% (w/w), less than 0.06% (w/w), less than 0.05% (w/w), less than 0.04% (w/w), less than 0.03% (w/w), less than 0.02% (w /w), less than 0.01% (w/w), less than 0.005% (w/w) or less than 0.001% (w/w).
  • the nanoemulsion described here does not contain any ethoxylated compounds, such as ethoxylated glyceryl fatty acid esters or sorbitan fatty acid esters.
  • the nanoemulsion of the present invention is characterized by a particularly long shelf life. This means that the mean particle size of the nanoemulsion does not change significantly even after prolonged storage. According to the invention, it is preferred that the average particle size of the nanoemulsion changes more after storage for 2 months. preferably 4 months, even more preferably 6 months, does not exceed a size of 100 nm. Storage preferably takes place in a temperature range of 20-24°C.
  • the nanoemulsion according to the invention has an average particle size of 100 nm or less, and preferably 80 nm or less, after 2 months storage at a temperature of 20-24°C. In a further embodiment, the nanoemulsion according to the invention has an average particle size of 100 nm or less, and preferably 80 nm or less, after storage for 4 months at a temperature of 20-24°C. In yet another embodiment, the nanoemulsion according to the invention has a mean particle size of 100 nm or less, and preferably 80 nm or less, after 6 months storage at a temperature of 20-24°C.
  • the present invention relates to an oil-in-water nanoemulsion which comprises the following components:
  • an oil phase comprising a vegetable oil comprising medium chain and/or long chain triglycerides, the vegetable oil being present in an amount of 5-15% (w/w) based on the total weight of the emulsion;
  • a continuous phase comprising water and glycerin, the glycerin being present in an amount of 30-70% (w/w) based on the total weight of the emulsion;
  • an emulsifier selected from the group consisting of lecithin, mono- and diglycerides of fatty acids, lactic acid and/or citric acid and mixtures thereof, the emulsifier being present in an amount of 2-10% (w/w). ten is based on the total weight of the emulsion; (d) ethanol present in an amount of 2-20% (w/w) based on the total weight of the emulsion; wherein the nanoemulsion has a mean particle diameter (Dm) of 70 nm or less.
  • Dm mean particle diameter
  • the present invention relates to an oil-in-water nanoemulsion that includes the following components:
  • an oil phase comprising a vegetable oil comprising medium-chain and/or long-chain triglycerides, the vegetable oil being present in an amount of 5-8% (w/w) based on the total weight of the emulsion;
  • a continuous phase comprising water and glycerin, the glycerin being present in an amount of 50-70% (w/w) based on the total weight of the emulsion;
  • an emulsifier selected from the group consisting of lecithin, mono- and diglycerides of fatty acids, lactic acid and/or citric acid and mixtures thereof, the emulsifier being present in an amount of 5-8% (w/w). ten is based on the total weight of the emulsion;
  • the present invention relates to an oil-in-water nanoemulsion that includes the following components: (a) an oil phase comprising one or more vegetable oils selected from the group consisting of palm oil, sunflower oil, olive oil and soybean oil;
  • a continuous phase comprising water and glycerin, the glycerin being present in an amount of 50-70% (w/w) based on the total weight of the emulsion;
  • an emulsifier an emulsifier, the emulsifier being lecithin, present in an amount of 5-8% (w/w) based on the total weight of the emulsion;
  • the present invention relates to a method for preparing a nanoemulsion as described above, the method comprising steps in which one
  • step (c) subjecting the mixture to high pressure homogenization at a pressure of 800-1500 bar.
  • step (a) of the process according to the invention glycerine, water, ethanol and one or more emulsifiers selected from the group consisting of lecithin, mono- and diglycerides of fatty acids, lactic acid and/or citric acid and mixtures thereof are mixed together.
  • the individual components can be added in the respective amounts to a suitable vessel, such as a glass container or glass flask, with stirring.
  • a vegetable oil comprising medium-chain or long-chain triglycerides is added.
  • Vegetable oils which are suitable for the preparation of the nanoemulsions according to the invention have been described above.
  • the vegetable oil added to the previously prepared mixture is a vegetable oil that is greater than 50% medium chain triglycerides, such as coconut oil or palm kernel oil.
  • the vegetable oil that is added to the previously prepared mixture is a vegetable oil that is over 50% long-chain triglycerides, such as sunflower oil, rapeseed oil, olive oil, linseed oil, corn oil, wheat germ oil or soybean oil .
  • the oil phase of the nanoemulsion according to the invention comprises palm oil. In another embodiment, the oil phase of the nanoemulsion according to the invention comprises sunflower oil. In a further embodiment, the oil phase of the nanoemulsion according to the invention comprises hemp oil. In a further embodiment, the oil phase of the nanoemulsion according to the invention comprises rapeseed oil. In yet another embodiment, the oil phase of the nanoemulsion of the invention comprises olive oil. In yet another embodiment, the oil phase of the nanoemulsion of the invention comprises linseed oil. In yet another embodiment, the oil phase of the invention comprises application-specific nanoemulsion corn oil. In yet another embodiment, the oil phase of the nanoemulsion of the invention comprises wheat germ oil.
  • the oil phase of the nanoemulsion of the invention comprises soybean oil. In yet another embodiment, the oil phase of the nanoemulsion of the invention comprises coconut oil. In yet another embodiment, the oil phase of the nanoemulsion of the invention comprises palm kernel oil.
  • step (c) of the method according to the invention the mixture obtained from the previous step (b) is subjected to high pressure homogenization at a pressure of 800-1500 bar in order to reduce the size of the oil droplets in the continuous phase.
  • This step is preferably carried out in a device suitable for high-pressure homogenization.
  • Devices for high-pressure homogenization are well known in the prior art and can be obtained from several commercial suppliers. Suitable devices include, for example, the LM10 Microfluidizer or the M-110L Microfluidizer (Microfluidics, Westwood, USA). Microfluidization devices reduce the average size of oil droplets in the continuous phase by passing the starting emulsion through a chamber with geometrically defined channels at high pressure and high velocity.
  • the microfluidization device chamber may comprise a plurality of geometrically defined channels, such as 2, 3, 4, 5, 6, 7, 8, 9, 10 or more channels.
  • the chamber of the microfluidization device is preferably made of ceramic or stainless steel.
  • the high-pressure homogenization for example the microfluidization, is carried out at a pressure between 800-1500 bar. It is particularly preferred according to the invention that the high-pressure homogenization, e.g. microfluidization, at a pressure of at least 800 bar, more preferably at least 850 bar, at least 900 bar, at least 950 bar, at least 1000 bar, at least 1050 bar, at least 1100 bar, at least 1150 bar, at least 1200 bar, at least 1250 bar, at least 1300 bar, at least 1350 bar, at least 1400 bar, or at least 1450 bar is carried out.
  • the high-pressure homogenization e.g. microfluidization, at a pressure of at least 800 bar, more preferably at least 850 bar, at least 900 bar, at least 950 bar, at least 1000 bar, at least 1050 bar, at least 1100 bar, at least 1150 bar, at least 1200 bar, at least 1250 bar, at least 1300 bar, at least 1350 bar, at least 1400 bar
  • step (b) it can be advantageous to pass the mixture obtained from step (b) through the device for high-pressure homogenization several times, since the particle size in the continuous phase decreases further with each pass.
  • the mixture obtained from step (b) can preferably be passed through the device at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times or at least 10 times for high-pressure homogenization.
  • the nanoemulsions according to the invention can be used in many areas. For example, they can be used in the field of medicine or pharmacology to deliver lipophilic pharmaceutical agents.
  • the present invention thus relates to a nanoemulsion as described above for use in medicine or pharmacology.
  • the nanoemulsion can be formulated for various forms of administration for these purposes. However, it is preferred that the nanoemulsion is formulated for oral administration.
  • the present invention thus relates to the use of a nanoemulsion as described above for the production of a pharmaceutical or cosmetic composition.
  • the pharmaceutical or cosmetic composition comprises a lipophilic compound that is pharmaceutically or cosmetically active, such as cannabidiol (CBD).
  • CBD cannabidiol
  • the invention also relates to a nanoemulsion as described above for the production of a foodstuff or animal feed, such as a drink.
  • the invention therefore also relates to the use of a nanoemulsion as described above as an additive in foods or in cosmetics. Since the nanoemulsion can penetrate the upper layers of the skin and reach deeper layers of the skin when applied topically, it is particularly suitable for delivering lipophilic cosmetic or pharmaceutical active ingredients to the deeper layers of the skin.
  • the present invention relates to a nanoemulsion as described above for use in a therapeutic method in which a lipophilic pharmaceutically active agent is administered.
  • the present invention relates to a nanoemulsion as described above for delivering a lipophilic compound to a subject in need of that compound.
  • the lipophilic compound is preferably cannabidiol (CBD).
  • Figure 1 shows the results of the particle size determination of nanoemulsion 1 prepared in Example 1.
  • FIG. 2 shows the results of the particle size determination of nanoemulsion 2 produced in Example 1.
  • FIG. 3 shows the results of the particle size determination of nanoemulsion 3 produced in Example 1.
  • FIG. 4 shows the results of the particle size determination of nanoemulsion 4 prepared in Example 1.
  • FIG. 5 shows the results of determining the long-term stability of nanoemulsion 1 prepared in example 1.
  • Figure 6 shows the values for the polydispersity index (PDI) of nanoemulsion 1 prepared in Example 1.
  • Nanoemulsion 1 To produce a first nanoemulsion, a pre-emulsion of lecithin P75 (Lipoid GmbH), glycerin (99%, Gustav Heess GmbH), ethanol (96%, Sigma-Aldrich) and unrefined red palm oil (Gustav Heess GmbH ) manufactured. For this purpose, 6% (w/w) lecithin was added to a mixture of 60% (w/w) glycerol, 16%
  • the pre-emulsion was obtained by stirring with a VISCO-JET at 800 rpm and 40°C for two hours. ten. The pre-emulsion was then passed 12 times at 1400 bar through a microfluidizer (LM10 Microfluidizer, Microfluidics International Corporation, Canada). After each run, the mixture was cooled to below 20°C.
  • a microfluidizer LM10 Microfluidizer, Microfluidics International Corporation, Canada
  • Nanoemulsion 2 To produce a second nanoemulsion, a pre-emulsion of Imwitor 375 (IOI Oleo GmbH), glycerin (99%, Gustav Heess GmbH), ethanol (96%, Sigma-Aldrich) and unrefined red palm oil (Gustav Heess GmbH ) manufactured.
  • Imwitor 375 IOI Oleo GmbH
  • glycerin 99%, Gustav Heess GmbH
  • ethanol 96%, Sigma-Aldrich
  • unrefined red palm oil Gustav Heess GmbH
  • 6% (w/w) Imwitor 375 was added to a mixture of 60% (w/w) glycerol, 16% (w/w) demineralised water and 10% (w/w) ethanol at 40°C with constant stirring solves. After 3 hours, 8% (w/w) unrefined red palm oil was added as the oil phase.
  • the pre-emulsion was obtained by stirring with a VISCO-JET at 800 rpm and 40°C for two hours. The pre-emulsion was then passed 12 times at 1400 bar through a microfluidizer (LM10 Microfluidizer, Microfluidics International Corporation, Canada). After each run, the mixture was cooled to below 20°C.
  • a microfluidizer LM10 Microfluidizer, Microfluidics International Corporation, Canada
  • Nanoemulsion 3 To produce a third nanoemulsion, a pre-emulsion of lecithin P75 (Lipoid GmbH), glycerin (99%, Gustav Heess GmbH), ethanol (96%, Sigma-Aldrich), sugar ester (Sisterna SP70-C, Sisterna ) and unrefined red palm oil (Gustav Heess GmbH). For this purpose, 5.5% (w/w) lecithin and 0.5% (w/w) sugar ester were added to a mixture of 60% (w/w) glycerin, 16% (w/w ) demineralized water and 10% (w/w) ethanol.
  • the pre-emulsion was obtained by stirring with a VISCO-JET at 800 rpm and 40°C for two hours. The pre-emulsion was then passed 12 times at 1400 bar through a microfluidizer (LM10 Microfluidizer, Microfluidics International Corporation, Canada). After each run, the mixture was cooled to below 20°C.
  • a microfluidizer LM10 Microfluidizer, Microfluidics International Corporation, Canada
  • Nanoemulsion 4 To produce a fourth nanoemulsion, a pre-emulsion consisting of Imwitor 375 (IOI Oleo GmbH), glycerin (99%, Gustav Heess GmbH), ethanol (96%, Sigma-Aldrich), sugar ester (Sisterna SP70-C, Sisterna) and unrefined red palm oil (Gustav Heess GmbH). To do this, 5.5% (w/w) Imwitor 375 and 0.5% (w/w) sugar ester were added at 40°C with constant stirring into a mixture of 60% (w/w)
  • the pre-emulsion was obtained by stirring with a VISCO-JET at 800 rpm and 40°C for two hours. The pre-emulsion was then passed 12 times at 1400 bar through a microfluidizer (LM10 Microfluidizer, Microfluidics International Corporation, Canada). After each run, the mixture was cooled to below 20°C.
  • a microfluidizer LM10 Microfluidizer, Microfluidics International Corporation, Canada
  • the particle size of the nanoemulsions produced in Example 1 was determined by dynamic light scattering (DLS, Malvern Nano ZS90, Malvern, UK). The samples (1 ml) were dispersed in 300 ml demineralized water. DLS measurements were performed at 25°C and 173° scattering angle.
  • the mean particle diameter of nanoemulsion 1 was about 47.8 nm.
  • the mean particle diameter of nanoemulsion 2 was about 65.7 nm.
  • the mean particle diameter of nanoemulsion 3 was about 53.2 nm average particle diameter of nanoemulsion 4 was about 61.5 nm.
  • Example 3 Determination of long-term stability
  • Samples of nanoemulsion 1 prepared in Example 1 were stored at room temperature and 4° C. with the exclusion of light. Samples of the nanoemulsions were taken at intervals of one month and characterized by means of DLS measurements.

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Abstract

L'invention concerne une nouvelle nanoémulsion huile-dans-eau à base d'huile végétale, qui convient particulièrement à la fourniture de substances liposolubles. La nanoémulsion est exclusivement constituée de substances naturelles et convient par conséquent spécialement à l'application par voie orale. De plus, la nanoémulsion est caractérisée par une stabilité et une durée de conservation à long terme élevées. La nanoémulsion peut être utilisée dans le domaine de la pharmacologie ou des cosmétiques et également comme additif dans des produits alimentaires. Un procédé de production de la nouvelle nanoémulsion huile-dans-eau est également divulgué.
EP22732977.8A 2021-06-03 2022-06-03 Nouvelle nanoémulsion huile-dans-eau Pending EP4362918A1 (fr)

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DE102021205664.4A DE102021205664A1 (de) 2021-06-03 2021-06-03 Neue Öl-in-Wasser-Nanoemulsion
PCT/EP2022/065202 WO2022254014A1 (fr) 2021-06-03 2022-06-03 Nouvelle nanoémulsion huile-dans-eau

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CH715855B1 (de) * 2003-08-28 2020-08-14 Mibelle Ag Zubereitung bestehend aus mindestens zwei Nanoemulsionen.
EP1598060A1 (fr) 2004-05-18 2005-11-23 Nestec S.A. Émulsion huile dans eau pour livraison
DE102010056192A1 (de) * 2010-12-28 2012-06-28 Gabriele Blume Kolloidales Trägersystem mit penetrierenden Eigenschaften zum Einschließen lipophiler Wirkstoffe und Öle für die topische Anwendung
US20210315817A1 (en) 2018-08-20 2021-10-14 Hexo Operations Inc. Cannabinoid based self-emulsion systems for infused compositions
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